
[Federal Register Volume 80, Number 25 (Friday, February 6, 2015)]
[Proposed Rules]
[Pages 6801-6896]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2015-01666]



[[Page 6801]]

Vol. 80

Friday,

No. 25

February 6, 2015

Part II





Department of Health and Human Services





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 Food and Drug Administration





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21 CFR Parts 314 and 320





 Abbreviated New Drug Applications and 505(b)(2) Applications; Proposed 
Rule

  Federal Register / Vol. 80 , No. 25 / Friday, February 6, 2015 / 
Proposed Rules  

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 314 and 320

[Docket No. FDA-2011-N-0830]
RIN 0910-AF97


Abbreviated New Drug Applications and 505(b)(2) Applications

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing 
regulations to implement Title XI of the Medicare Prescription Drug, 
Improvement, and Modernization Act of 2003 (MMA), which amended 
provisions of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) 
that govern the approval of 505(b)(2) applications and abbreviated new 
drug applications (ANDAs). This proposed rule would implement portions 
of Title XI of the MMA that pertain to provision of notice to each 
patent owner and the new drug application (NDA) holder of certain 
patent certifications made by applicants submitting 505(b)(2) 
applications or ANDAs; the availability of 30-month stays of approval 
on 505(b)(2) applications and ANDAs that are otherwise ready to be 
approved; submission of amendments and supplements to 505(b)(2) 
applications and ANDAs; and the types of bioavailability and 
bioequivalence data that can be used to support these applications. 
This proposed rule also would amend certain regulations regarding 
505(b)(2) applications and ANDAs to facilitate compliance with and 
efficient enforcement of the FD&C Act.

DATES: Submit either electronic or written comments on the proposed 
rule by May 7, 2015. Submit comments on information collection issues 
under the Paperwork Reduction Act of 1995 by March 9, 2015 (see the 
``Paperwork Reduction Act of 1995'' section of this document). See 
section VII of this document for the proposed effective date of a final 
rule based on this document.

ADDRESSES: You may submit comments by any of the following methods, 
except that comments on information collection issues under the 
Paperwork Reduction Act of 1995 must be submitted to the Office of 
Regulatory Affairs, Office of Management and Budget (OMB) (see the 
``Paperwork Reduction Act of 1995'' section of this document).

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following way:
     Mail/Hand delivery/Courier (For paper, disk, or CD-ROM 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include Docket No. FDA-
2011-N-0830 for this rulemaking. All comments received may be posted 
without change to http://www.regulations.gov, including any personal 
information provided. For additional information on submitting 
comments, see the ``Comments'' heading of the SUPPLEMENTARY INFORMATION 
section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.regulations.gov and insert the 
docket number, found in brackets in the heading of this document, into 
the ``Search'' box and follow the prompts and/or go to the Division of 
Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Janice L. Weiner, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 6268, Silver Spring, MD 20993-0002, 301-
796-3601.

SUPPLEMENTARY INFORMATION: 

Table of Contents

    Executive Summary
I. Background
    A. Hatch-Waxman Amendments
    B. Requirements for Patent Certification or Statement
    C. Patent Listing Requirements
    D. MMA
II. Description of the Proposed Rule
    A. Definitions
    1. Overview of New, Revised, and Relocated Definitions
    2. Proposed Amendments to Definitions in Sec.  314.3
    3. Proposed Amendments to Definitions in Current Sec.  314.108
    4. Definitions in Current Sec.  320.1
    B. Submission of Patent Information (Proposed Sec.  314.53)
    1. General Requirements for Submission of Patent Information 
(Proposed Sec.  314.53(b) and (c))
    2. When and Where To Submit Patent Information (Proposed Sec.  
314.53(d))
    3. Public Disclosure of Patent Information (Proposed Sec.  
314.53(e))
    4. Correction or Change of Patent Information (Proposed Sec.  
314.53(f))
    C. Patent Certification (Proposed Sec. Sec.  314.50(i) and 
314.94(a)(12))
    1. Method-of-Use Patents (Proposed Sec. Sec.  314.50(i)(1)(iii) 
and 314.94(a)(12)(iii))
    2. Method-of-Manufacturing Patents (Proposed Deletion of 
Sec. Sec.  314.50(i)(2) and 314.94(a)(12)(iv))
    3. Licensing Agreement (Proposed Sec.  314.50(i)(3))
    D. Notice of Paragraph IV Certification (Proposed Sec. Sec.  
314.52 and 314.95)
    1. Timing of Notice
    2. Notice Required for All Paragraph IV Certifications
    3. Contents of Notice
    4. Documentation of Timely Sending and Receipt of Notice
    5. Administrative Consequence for Late Notice
    E. Amended Patent Certifications (Proposed Sec. Sec.  
314.50(i)(6) and 314.94(a)(12)(viii))
    1. Amended Patent Certifications After a Finding of Infringement
    2. Amended Certifications After Request by the NDA Holder to 
Remove a Patent or Patent Information from the List
    3. Amended Certifications Upon Patent Reissuance
    4. Other Amended Certifications
    F. Patent Certification Requirements for Amendments and 
Supplements to 505(b)(2) Applications and ANDAs (Proposed Sec. Sec.  
314.60, 314.70, 314.96, and 314.97)
    1. Types of Amendments or Supplements for Which Patent 
Certification is Required
    2. Requirements for Notice of Paragraph IV Certifications and 
Implications for 180-day Exclusivity
    G. Amendments or Supplements to a 505(b)(2) Application for a 
Different Drug and Amendments or Supplements to an ANDA That 
Reference a Different Listed Drug (Proposed Sec. Sec.  314.60, 
314.70, 314.96, and 314.97)
    1. Amendments to an Unapproved ANDA (Proposed Sec.  314.96(c))
    2. Supplements to an ANDA (Proposed Sec.  314.97(b))
    3. Amendments to an Unapproved 505(b)(2) Application (Proposed 
Sec.  314.60(e))
    4. Supplements to a 505(b)(2) Application (Proposed Sec.  
314.70(h))
    H. Procedure for Submission of an Application Requiring 
Investigations for Approval of a New Indication for, or Other Change 
From, a Listed Drug (Proposed Sec.  314.54)
    I. Petition to Request a Change From a Listed Drug (Proposed 
Sec.  314.93)
    J. Filing an NDA and Receiving an ANDA (Proposed Sec.  314.101)
    1. Notification of Filing of a 505(b)(2) Application or Receipt 
of an ANDA
    2. Other Proposed Revisions
    K. Approval of an NDA and ANDA (Proposed Sec.  314.105)

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    L. Refusal to Approve an NDA or ANDA (Proposed Sec. Sec.  
314.125 and 314.127 and Related Provisions in Proposed Sec. Sec.  
314.90 and 314.99)
    M. Date of Approval of a 505(b)(2) Application or ANDA (Proposed 
Sec.  314.107)
    1. General (Proposed Sec.  314.107(a))
    2. Effect of Patent(s) on the Listed Drug (Proposed Sec.  
314.107(b))
    3. Subsequent ANDA Submission (Proposed Sec.  314.107(c))
    4. Delay of Approval Due to Exclusivity (Proposed Sec.  
314.107(d))
    5. Notification of Court Actions or Documented Agreement 
(Proposed Sec.  314.107(e))
    6. Computation of the 45-Day Time Clock (Proposed Sec.  
314.107(f))
    7. Conversion of Approval to Tentative Approval (Proposed Sec.  
314.107(g))
    N. Assessing Bioavailability and Bioequivalence for Drugs Not 
Intended To Be Absorbed Into the Bloodstream (Proposed Sec.  320.23)
    O. Miscellaneous
    1. Clarifying Revisions and Editorial Changes
    2. Effect of Other Rulemaking
III. Legal Authority
IV. Analysis of Impacts
    A. Summary of the Benefits and Costs of the Proposed Rule
    B. Summary of the Regulatory Flexibility Analysis
V. Paperwork Reduction Act of 1995
VI. Environmental Impact
VII. Effective Date
VIII. Federalism
IX. Request for Comments
X. References

Executive Summary

Purpose of the Regulatory Action

    This proposed rule would implement portions of Title XI of the MMA 
and revise and clarify FDA regulations relating to 505(b)(2) 
applications and ANDAs in a manner intended to reduce unnecessary 
litigation, reduce delays in the approval of 505(b)(2) applications and 
ANDAs that are otherwise ready to be approved, and provide business 
certainty to both brand name and generic drug manufacturers. The MMA 
and sections 505, 505A, and 527 of the FD&C Act (21 U.S.C. 355, 355a, 
and 360cc), in conjunction with our general rulemaking authority in 
section 701(a) of the FD&C Act (21 U.S.C. 371(a)), serve as our 
principal legal authority for this proposal.
    Title XI of the MMA addressed two key concerns identified in a 
Federal Trade Commission (FTC) report on anticompetitive strategies 
that may delay access to generic drugs by: (1) Limiting the 
availability of 30-month stays of approval on 505(b)(2) applications 
and ANDAs that are otherwise ready to be approved and (2) establishing 
conditions under which a first applicant would forfeit the 180-day 
exclusivity period such that approval of subsequent ANDAs would no 
longer be blocked. FDA has been implementing the MMA directly from the 
statute for several years. Based on this experience, FDA is proposing 
to amend its regulations to implement portions of the MMA that pertain 
to 30-month stays and other matters not related to 180-day exclusivity.
    FDA is proposing to amend its regulations regarding 505(b)(2) 
applications and ANDAs to facilitate compliance with and efficient 
enforcement of the FD&C Act, and to clarify and update these 
regulations based on recent court decisions and our practical 
experience implementing provisions related to the approval of 505(b)(2) 
applications and ANDAs. For example, we are proposing to clarify 
requirements for the NDA holder's description of the patented method of 
use (the ``use code'') required for publication in FDA's ``Approved 
Drug Products With Therapeutic Equivalence Evaluations'' (commonly 
known as the Orange Book) to avoid overbroad use codes that may delay 
approval of generic drugs. This is intended to facilitate FDA's 
implementation of the statutory provisions that permit 505(b)(2) and 
ANDA applicants to omit (``carve out'') protected conditions of use 
from labeling and obtain approval for conditions of use that are not 
covered by unexpired patents or exclusivity. As the U.S. Supreme Court 
recently noted in Caraco Pharm. Labs. v. Novo Nordisk A/S: ``An 
overbroad use code . . . throws a wrench into the FDA's ability to 
approve generic drugs as the statute contemplates'' (132 S. Ct. 1670, 
at 1684 (2012)).
    Finally, we are proposing to update the regulations to codify FDA's 
current practice and policy and thereby promote transparency.

Summary of the Major Provisions of the Regulatory Action

    Submission of Patent Information. The proposed rule would revise 
and streamline requirements related to submission of patent information 
on: (1) Patents that claim the drug substance and/or drug product and 
meet the requirements for patent listing on that basis; (2) drug 
substance patents that claim only a polymorph of the active ingredient; 
and (3) certain NDA supplements. The proposed rule would clarify 
requirements for the submission of information related to patents that 
have been reissued by the Patent and Trademark Office (PTO). The 
proposed rule describes our approach to treating the original and 
reissued patents as a ``single bundle'' of patent rights, which first 
became relevant to approval of 505(b)(2) applications and ANDAs with 
the submission of the original patent information.
    We are proposing to codify our long-standing requirement that the 
NDA holder's description of the patented method of use required for 
publication in the Orange Book must contain adequate information to 
assist FDA and 505(b)(2) and ANDA applicants in determining whether a 
listed method-of-use patent claims a use for which the 505(b)(2) or 
ANDA applicant is not seeking approval. To restrain overbroad use 
codes, the proposed rule would expressly require that if the scope of 
the method-of-use claim(s) of the patent does not cover every approved 
use of the drug, the NDA holder's use code must describe only the 
specific portion(s) of the indication or other method of use claimed by 
the patent.
    Timing of Submission of Patent Information. We are proposing to 
expressly describe our current practice with respect to listing patent 
information that has not been submitted to FDA within 30 days after 
patent issuance. Although we list untimely filed patents pursuant to 
section 505(c)(2) of the FD&C Act, we generally do not require an 
applicant with a pending 505(b)(2) application or ANDA to provide a 
patent certification to the untimely filed patent. Thus, the untimely 
filed patent will neither delay approval of a pending 505(b)(2) 
application or ANDA until patent expiration nor necessitate a carve-out 
of information related to a patented method of use.
    We are proposing to expand the category of untimely filed patent 
information to include certain amendments to the NDA holder's 
description of the approved method(s) of use claimed by the patent, if 
such changes do not relate to a corresponding change in approved 
labeling or are submitted more than 30 days after such labeling change. 
This proposed regulatory revision is intended to reduce delays in 
approval related to manipulation of patent use codes in a manner not 
contemplated by the FD&C Act.
    In addition, we are proposing to establish that the submission date 
of patent information provided by an NDA holder after approval would be 
the earlier of the date on which Form FDA 3542 is date-stamped by the 
Office of Generic Drugs (OGD) Document Room or officially received 
electronically by FDA. These proposed revisions are intended to 
facilitate prompt listing in the Orange Book and to remove any

[[Page 6804]]

ambiguity about the date of submission in light of the implications for 
the patent certification obligations of 505(b)(2) and ANDA applicants 
that rely upon the listed drug.
    Correction or Change of Patent Information. We are proposing to 
enhance FDA's response to challenges to the accuracy or relevance of 
submissions of patent use code information to the Agency, in certain 
circumstances. If, in response to such a challenge, the NDA holder 
confirms the accuracy of the information, fails to timely respond, or 
submits a revision to the use code that does not provide adequate 
clarity for FDA to determine whether the scope of a proposed labeling 
carve-out would be appropriate based on the NDA holder's use code and 
approved labeling, we are proposing to review proposed labeling carve-
out(s) for the 505(b)(2) application or ANDA with deference to the 
505(b)(2) or ANDA applicant's interpretation of the scope of the 
patent. In addition, we are proposing to expressly require the 
correction or change of patent information by the NDA holder if: (1) 
The patent or patent claim no longer meets the statutory requirements 
for listing; (2) the NDA holder is required by court order to amend 
patent information or withdraw a patent from the list; or (3) the term 
of a listed patent is extended under patent term restoration 
provisions. These proposed revisions would facilitate implementation of 
the MMA provision related to patent withdrawal and efficient 
enforcement of the FD&C Act.
    Notice of Paragraph IV Certification--Timing. We are proposing to 
revise our regulations to clearly delineate the two limitations on the 
time frame within which notice of a paragraph IV certification can be 
provided to the NDA holder and each patent owner: (1) The date before 
which notice may not be given (reflecting FDA's long-standing practice) 
and (2) the date, established by MMA, by which notice must be given.
    For an original application, a 505(b)(2) or ANDA applicant must 
send notice of a paragraph IV certification on or after the date on 
which it receives an ``acknowledgment letter'' or a ``paragraph IV 
acknowledgment letter'' from FDA stating that the application is 
sufficiently complete to permit a substantive review, but not later 
than 20 days after the date of the ``postmark'' (as defined in the 
proposed rule) on such letter.
    For an amendment or supplement, a 505(b)(2) or ANDA applicant must 
send notice of a paragraph IV certification contained in an amendment 
to an application (that has been received for substantive review) or in 
a supplement to an approved application at the same time that the 
amendment or supplement is submitted to FDA. We are proposing to 
establish a date (the first working day after the day the patent is 
published in the Orange Book) before which an ANDA applicant cannot 
send valid notice of a paragraph IV certification to a newly listed 
patent. This approach is intended to promote equity among ANDA 
applicants seeking eligibility for 180-day exclusivity and to reduce 
the burden on industry and FDA associated with serial submissions and 
multiple notices of paragraph IV certifications related to a newly 
issued patent.
    Notice of a paragraph IV certification that has been sent 
prematurely is invalid, and will not be considered to comply with the 
FD&C Act's notice requirement. We are proposing administrative 
consequences for ANDA applicants who fail to send notice of paragraph 
IV certification within the statutory time frame established by the 
MMA. The date the ANDA was submitted would be deemed to be delayed by 
the number of days by which the time frame was exceeded, which may 
result in the applicant losing eligibility for 180-day exclusivity.
    Notice of Paragraph IV Certification--Content and Methods. We are 
proposing revisions to the content of notice of a paragraph IV 
certification to incorporate requirements added by the MMA and to 
support the efficient enforcement of our regulations. We also are 
proposing to expand the acceptable methods of sending notice of a 
paragraph IV certification beyond registered or certified mail to 
include ``designated delivery services.'' This would reduce the burden 
on 505(b)(2) and ANDA applicants who currently must submit requests to 
send notice by common alternate delivery methods.
    Amended Patent Certifications. We are proposing to clarify the 
requirements for a 505(b)(2) or ANDA applicant to amend a paragraph IV 
certification after a judicial finding of patent infringement to 
reflect statutory changes made by the MMA. We also are proposing to 
clarify the circumstances and time frame in which a 505(b)(2) or ANDA 
applicant must submit an amended patent certification after an NDA 
holder has withdrawn a patent and requested removal of the patent from 
the Orange Book. The proposed rule would codify our current practice of 
not removing a withdrawn patent from the list until FDA has determined 
that no first applicant is eligible for 180-day exclusivity or such 
exclusivity is extinguished, and exempting 505(b)(2) applicants from 
providing or maintaining a certification to withdrawn patents. The 
proposed rule also clarifies an applicant's current patent 
certification obligations with respect to a reissued patent, and 
proposes implications for 180-day exclusivity and a 30-month stay. In 
addition, the proposed rule would expressly codify the current 
requirement for a 505(b)(2) or ANDA applicant to submit a patent 
certification to a newly issued patent that claims the listed drug or 
an approved method of use.
    Amendments or Supplements: Patent Certification Requirements. We 
are proposing to clarify and augment the patent certification 
requirements for amendments and supplements to 505(b)(2) applications 
and ANDAs to ensure that changes to the drug product that could be 
protected by patent are accompanied by a new patent certification. A 
new patent certification currently is required to accompany an 
amendment or supplement to add a new indication or other condition of 
use, or to add a new strength or change an existing strength. The 
regulations also currently require a patent certification to be amended 
if, at any time before approval, the applicant learns that the 
previously submitted patent certification is no longer accurate. We are 
proposing to augment this regulation by requiring a new patent 
certification with an amendment to make other-than-minor changes in 
product formulation or to change the physical form or crystalline 
structure of the active ingredient.
    Limitation on Submission of Certain Amendments and Supplements to a 
505(b)(2) Application or ANDA. We are proposing to codify our current 
interpretation of the MMA's prohibition on submitting an amendment or a 
supplement to seek approval of: (1) ``[A] drug that is a different 
drug'' than the drug identified in the original 505(b)(2) application; 
or (2) ``a drug referring to a different listed drug'' than the drug 
cited as the basis for ANDA submission. We are implementing these 
parallel restrictions on submission of certain types of changes in an 
amendment or a supplement to a 505(b)(2) application or ANDA in a 
manner that is consistent with the statutory text and preserves a 
meaningful opportunity for a single 30-month stay.
    505(b)(2) Applications. We are proposing to require a 505(b)(2) 
applicant to identify a pharmaceutically equivalent product, if already 
approved, as a listed drug relied upon, and comply with applicable 
regulatory requirements. This is intended to help ensure that the 
505(b)(2) pathway is not used to circumvent the statutory patent

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certification obligations that would have applied if the proposed 
product was not ineligible for approval in an ANDA.
    Date of Approval of a 505(b)(2) Application or ANDA. The proposed 
rule would describe, in a more comprehensive manner, the timing of 
approval of a 505(b)(2) application or ANDA based on the patent 
certification(s) or statement(s) submitted by the 505(b)(2) or ANDA 
applicant. We are proposing to revise the regulations to reflect the 
MMA's limitation on multiple 30-month stays of approval of a 505(b)(2) 
application or an ANDA containing a paragraph IV certification to 
certain patents submitted to FDA on or after August 18, 2003.
    We are proposing to clarify that the statutory 30-month stay begins 
on the later of the date of receipt of notice of paragraph IV 
certification by any owner of the listed patent or by the NDA holder 
who is an exclusive licensee (or their representatives). This proposed 
revision codifies our current practice and provides an efficient means 
of ensuring that each patent owner or NDA holder receives the full 
statutory 30-month stay.
    We are proposing to codify the MMA's amendments that clarify the 
type of Federal district and appellate court decisions in patent 
litigation that will terminate a 30-month stay and lead to approval of 
a 505(b)(2) application or ANDA that is otherwise eligible for 
approval. We also are proposing to address other scenarios in which a 
stay may be terminated, including written consent to approval by the 
patent owner or exclusive patent licensee, a court order terminating 
the stay, or a court order of dismissal without a finding of 
infringement. This is intended to avoid unnecessary delays in approval 
of generic drugs while upholding the statutory purpose of the stay 
(i.e., to allow time for patent infringement claims to be litigated 
prior to approval of the potentially infringing product).
    Notification of Commercial Marketing. We are proposing to update 
the regulations to reflect the MMA provisions that modify the types of 
events that can trigger the start of the 180-day exclusivity period. A 
first applicant would be required to submit correspondence to its ANDA 
notifying FDA within 30 days of the date of first commercial marketing 
of the drug product. If the first applicant does not notify FDA within 
this time frame, we are proposing to deem the date of first commercial 
marketing to be the date of the drug product's approval. This may have 
the effect of shortening the 180-day exclusivity period in a similar 
manner to the current regulatory consequence for failure to provide 
``prompt'' notice of first commercial marketing.
    Notification of Court Actions or Documented Agreements. We are 
proposing to expand the scope of documentation that an applicant must 
submit to FDA regarding patent-related court actions and documented 
agreements to ensure that FDA is promptly advised of information that 
may affect the timing of approval of a 505(b)(2) application or ANDA.

Costs and Benefits

    FDA is proposing to amend the regulations for further 
implementation of and consistency with the MMA and to make other 
changes related to 505(b)(2) applications and ANDAs. These changes 
would improve transparency, facilitate compliance and enforcement, and 
preserve the balance struck in the Drug Price Competition and Patent 
Term Restoration Act of 1984 (Pub. L. 98-417).
    Although many provisions of this proposed rule would codify current 
practice, elements of this proposal would lead to changes that generate 
additional benefits and costs. The estimated annual monetized benefits 
of this proposed rule are $194,314, and estimated annual monetized 
costs are $91,371. We have identified, but are unable to quantify, 
impacts from proposed changes to submitted patent information and the 
implementation of an administrative consequence for ANDA applicants who 
fail to provide notice of a paragraph IV certification within the time 
frame required by the MMA.

I. Background

    On December 8, 2003, the MMA (Pub. L. 108-173) was signed into law. 
Title XI of the MMA significantly amended provisions of the FD&C Act 
that govern the approval of NDAs described by section 505(b)(2) of the 
FD&C Act (21 U.S.C. 355(b)(2)) (505(b)(2) applications) and ANDAs 
described by section 505(j) of the FD&C Act.

I.A. Hatch-Waxman Amendments

    The 505(b)(2) application and ANDA approval pathways were enacted 
as part of the Drug Price Competition and Patent Term Restoration Act 
of 1984 (Pub. L. 98-417) (Hatch-Waxman Amendments). The Hatch-Waxman 
Amendments reflect Congress's efforts to balance the need to ``make 
available more low cost generic drugs by establishing a generic drug 
approval procedure for pioneer drugs first approved after 1962'' with 
new incentives for drug development in the form of marketing 
exclusivity and patent term extensions (see H. Rept. 98-857, part 1, at 
14-15 (1984), reprinted in 1984 U.S. Code Congressional and 
Administrative News 2647 at 2647-2648). With passage of the Hatch-
Waxman Amendments, the FD&C Act describes different routes for 
obtaining approval of two broad categories of drug applications: An 
NDA, for which the requirements are set out in section 505(b) and (c) 
of the FD&C Act, and an ANDA, for which the requirements are set out in 
section 505(j). These categories can be further subdivided into a 
``stand-alone'' NDA, a 505(b)(2) application, an ANDA, and a petitioned 
ANDA.
    A ``stand-alone NDA'' is an application submitted under section 
505(b)(1) of the FD&C Act that contains full reports of investigations 
of safety and effectiveness that were conducted by or for the applicant 
or for which the applicant has a right of reference or use.
    A 505(b)(2) application is an NDA that contains full reports of 
investigations of safety and effectiveness, where at least some of the 
information required for approval comes from studies not conducted by 
or for the applicant and for which the applicant has not obtained a 
right of reference or use (e.g., published literature or the Agency's 
finding of safety and/or effectiveness for one or more listed drugs).
    An ANDA is an application for a duplicate of a previously approved 
drug that is submitted under the abbreviated approval pathway described 
in section 505(j) of the FD&C Act. An ANDA must contain information to 
show that the proposed product is the same as a previously approved 
drug (the reference listed drug or RLD) with respect to active 
ingredient, dosage form, route of administration, strength, labeling, 
and conditions of use, among other characteristics. An ANDA applicant 
also must demonstrate that its proposed product is bioequivalent to the 
drug product selected by the Agency as the reference standard for 
assessing bioequivalence with the RLD (see section II.A.2.z). (We note 
that the drug product designated as the RLD may not necessarily be the 
drug product identified in the Orange Book as the reference standard 
for bioequivalence studies, for example, for drug product lines with 
multiple strengths.) An applicant that can meet the requirements for 
approval under section 505(j) of the FD&C Act may rely upon the 
Agency's finding of safety and effectiveness for the RLD and need not 
repeat the extensive nonclinical and clinical investigations required 
for approval of a ``stand-alone'' NDA

[[Page 6806]]

submitted under section 505(b)(1) of the FD&C Act.
    A ``petitioned ANDA'' is a type of ANDA for a drug that differs 
from a previously approved drug product in dosage form, route of 
administration, strength, or active ingredient (in a product with more 
than one active ingredient), for which FDA has determined, in response 
to a suitability petition submitted under section 505(j)(2)(C) of the 
FD&C Act, that clinical studies are not necessary to demonstrate safety 
and effectiveness.
    The timing of approval for a 505(b)(2) application and an ANDA 
(including a petitioned ANDA) is subject to the patent and marketing 
exclusivity protections accorded the listed drug(s) relied upon and the 
RLD, respectively. An NDA applicant (including a 505(b)(2) applicant) 
is required to ``file with the application the patent number and the 
expiration date of any patent which claims the drug for which the 
applicant submitted the application or which claims a method of using 
such drug and with respect to which a claim of patent infringement 
could reasonably be asserted if a person not licensed by the owner 
engaged in the manufacture[,] use, or sale of the drug'' (section 
505(b)(1) of the FD&C Act). Upon approval of an application under 
section 505(c) of the FD&C Act, we publish the patent information 
provided by the applicant in the Orange Book, available electronically 
on FDA's Web site at http://www.fda.gov/cder.

I.B. Requirements for Patent Certification or Statement

    A 505(b)(2) application and ANDA must include a patent 
certification described in section 505(b)(2) or 505(j)(2)(A)(vii) of 
the FD&C Act, respectively, for each timely filed patent that claims 
the listed drug(s) relied upon or RLD, respectively, or a method of 
using the drug for which the applicant is seeking approval and for 
which information is required to be filed under section 505(b) or 
505(c) of the FD&C Act. For each unexpired patent listed in the Orange 
Book, the 505(b)(2) or ANDA applicant must submit either a paragraph 
III certification (section 505(b)(2)(A)(iii) or 505(j)(2)(A)(vii)(III) 
of the FD&C Act) (delaying approval until the date on which such patent 
will expire), a paragraph IV certification (section 505(b)(2)(A)(iv) or 
505(j)(2)(A)(vii)(IV) of the FD&C Act) (certifying that such patent is 
invalid or will not be infringed by the manufacture, use, or sale of 
the drug product for which the 505(b)(2) application or ANDA is 
submitted), or, with respect to a method-of-use patent, a statement 
that the patent does not claim a use for which the applicant is seeking 
approval (section 505(b)(2)(B) or 505(j)(2)(A)(viii) of the FD&C Act). 
If the patent information has not been filed with FDA (i.e., is not 
listed in the Orange Book because the patent information has not been 
submitted or is not eligible for listing) or the patent has expired, a 
505(b)(2) or ANDA applicant may submit a paragraph I certification or 
paragraph II certification, respectively (see section 505(b)(2)(A)(i) 
and (ii) and 505(j)(2)(A)(vii)(I) and (II) of the FD&C Act). If, in the 
opinion of the 505(b)(2) or ANDA applicant and to the best of their 
knowledge, there are no patents that claim the listed drug(s) relied 
upon or the RLD, respectively, or that claim a use of such drug, the 
505(b)(2) or ANDA applicant may submit a ``no relevant patents'' 
certification (see Sec.  314.50(i)(1)(ii) or Sec.  314.94(a)(12)(ii) 
(21 CFR 314.50(i)(1)(ii) or 314.94(a)(12)(ii)).
    An applicant submitting a paragraph IV certification is required to 
give notice of its paragraph IV certification to the holder of the NDA 
for the listed drug(s) relied upon or RLD and each owner of the patent 
that is the subject of the certification. Notice of a paragraph IV 
certification subjects the 505(b)(2) or ANDA applicant to the risk that 
it will be sued for patent infringement. If the NDA holder or patent 
owner initiates a patent infringement action within 45 days after 
receiving notice of the paragraph IV certification, there generally 
will be a statutory 30-month stay of approval of the 505(b)(2) 
application or ANDA while the patent infringement litigation is pending 
(see section 505(c)(3)(C) and (j)(5)(B)(ii) of the FD&C Act). ANDA 
applicants have a statutory incentive to challenge listed patents that 
may be invalid, unenforceable, or not infringed by the drug product 
described in the ANDA. The first applicant to submit a substantially 
complete ANDA that contains, and for which the applicant lawfully 
maintains, a paragraph IV certification may be eligible for a 180-day 
period of marketing exclusivity (180-day exclusivity) during which 
approval of subsequent ANDAs containing a paragraph IV certification to 
a listed patent for the same drug product will not be granted (see 
section 505(j)(5)(B)(iv) of the FD&C Act).

I.C. Patent Listing Requirements

    In July 2002, the FTC published a report on ``Generic Drug Entry 
Prior to Patent Expiration: An FTC Study'' (FTC Report) that, among 
other things, identified circumstances in which ANDA applicants were 
delayed in entering the market (see http://www.ftc.gov/sites/default/files/documents/reports/generic-drug-entry-prior-patent-expiration-ftc-study/genericdrugstudy_0.pdf). These circumstances included multiple 
30-month stays of approval (related to paragraph IV certifications for 
additional patents listed after ANDA submission) and a delay in 
``triggering'' the start of a first applicant's 180-day period of 
marketing exclusivity thereby blocking subsequent ANDA applicants. In 
response to the FTC Report, FDA published a proposed rule in October 
2002 to amend its patent listing requirements and to permit only a 
single 30-month stay of approval for a 505(b)(2) application or ANDA 
(see 67 FR 65448, October 24, 2002) (October 2002 proposed rule). The 
final rule on ``Applications for FDA Approval to Market a New Drug: 
Patent Submission and Listing Requirements and Application of 30-Month 
Stays on Approval of [ANDAs] Certifying That a Patent Claiming a Drug 
Is Invalid or Will Not Be Infringed'' was published in June 2003 (68 FR 
36676, June 18, 2003) (June 2003 final rule).

I.D. MMA

    The MMA was enacted on December 8, 2003, and superseded certain 
sections of the June 2003 final rule regarding the application of 30-
month stays of approval of certain 505(b)(2) applications and ANDAs; 
the superseded regulations were subsequently revoked by technical 
amendment (see ``Application of 30-Month Stays on Approval of [ANDAs] 
and Certain [NDAs] Containing a Certification That a Patent Claiming 
the Drug Is Invalid or Will Not Be Infringed; Technical Amendment'' (69 
FR 11309, March 10, 2004).
    Title XI of the MMA addressed two key concerns identified in the 
FTC Report by limiting the availability of 30-month stays of approval 
on 505(b)(2) applications and ANDAs that are otherwise ready to be 
approved (30-month stays) and by establishing conditions under which a 
first applicant would forfeit the 180-day exclusivity period such that 
approval of subsequent ANDAs would no longer be blocked. Section 1101 
of the MMA provides that a 30-month stay of approval of a 505(b)(2) 
application or ANDA is available only if patent infringement litigation 
was initiated within the 45-day period after receipt of notice of a 
paragraph IV certification for a patent that had been submitted to FDA 
before the date of submission of the 505(b)(2) application or ANDA 
(excluding an amendment or supplement to the

[[Page 6807]]

application). The resulting incentive for an applicant to change the 
listed drug relied upon through an amendment of or a supplement to a 
505(b)(2) application or ANDA is addressed by the MMA's prohibition of 
the submission of certain types of changes (including those requiring 
reference to a different listed drug) in an amendment of or supplement 
to a 505(b)(2) application or ANDA. In addition, section 1101 of the 
MMA amended the FD&C Act to specify the types of court actions that 
will terminate a 30-month stay of approval.
    Section 1101 of the MMA also created new requirements for 505(b)(2) 
and ANDA applicants sending notice of a paragraph IV certification, 
including changes to the timing and contents of such notice. In 
addition, the MMA established conditions under which a 505(b)(2) or 
ANDA applicant may bring a declaratory judgment action to obtain 
``patent certainty'' (i.e., obtain a judicial determination of non-
infringement, invalidity, or unenforceability) with respect to a listed 
patent for which it has given notice of a paragraph IV certification 
but has not been sued by the NDA holder or patent owner(s) within the 
statutory timeframe. If a patent infringement action is initiated 
against the 505(b)(2) or ANDA applicant, the MMA provides that the 
applicant may assert a counterclaim seeking an order requiring a 
correction or deletion of the patent information submitted to FDA for 
listing by the NDA holder or patent owner.
    Section 1102 of the MMA altered the conditions under which a 180-
day period of marketing exclusivity is granted by requiring, among 
other things, that a first applicant lawfully maintain the paragraph IV 
certification contained in its submission of a substantially complete 
ANDA. In addition, section 1102 of the MMA established conditions under 
which a first applicant would forfeit the 180-day exclusivity period.
    Section 1103 of the MMA clarified the types of bioavailability and 
bioequivalence data that can be used to support a 505(b)(2) application 
or ANDA for a drug that is not intended to be absorbed into the 
bloodstream.
    On March 3, 2004, we published a notice in the Federal Register 
entitled ``Generic Drug Issues; Request for Comments'' (69 FR 9982) 
(Request for MMA Comments) which invited public comment to further 
identify issues related to the MMA provisions regarding 30-month stays, 
180-day exclusivity, and bioavailability and bioequivalence, along with 
any suggestions for how to resolve those issues. Comments received in 
response to the Agency's Request for MMA Comments are addressed in this 
document, as appropriate.
    We are currently implementing the 180-day exclusivity provisions of 
the MMA directly from the statute and will determine if additional 
rulemaking is necessary in the future. Where a novel issue of 
interpretation is raised by a particular factual scenario regarding 
forfeiture of 180-day exclusivity, we may open a public docket or 
otherwise seek comment from affected parties in advance of taking 
action (see, e.g., Docket Nos. FDA-2007-N-0445 (acarbose tablets), FDA-
2007-N-0269 (granisetron hydrochloride injection), FDA-2007-N-0035 
(ramipril capsules), and FDA-2008-N-0483 (dorzolamide hydrochloride--
timolol maleate ophthalmic solution), available at http://www.regulations.gov).
    We invite interested parties to comment on any aspect of this 
proposed rule. In addition to requesting general comments on this 
proposal, we have identified issues throughout this document on which 
we are specifically seeking comments.

II. Description of the Proposed Rule

    This proposed rule implements portions of the MMA that pertain to 
30-month stays and other matters not related to 180-day exclusivity, 
and makes our regulations governing 505(b)(2) applications and ANDAs 
consistent with amendments made to the FD&C Act by the MMA. In 
addition, FDA is proposing to amend its regulations regarding 505(b)(2) 
applications and ANDAs to facilitate compliance with and efficient 
enforcement of the FD&C Act, and to clarify and update these 
regulations based on our practical experience implementing the 
provisions related to approval of 505(b)(2) applications and ANDAs.
    Table 1 summarizes the proposed changes related to FDA's patent 
listing, patent certification, and 30-month stay regulations in part 
314 (21 CFR part 314) and bioavailability and bioequivalence 
regulations in part 320 (21 CFR part 320):

 Table 1--Highlights of Proposed Changes to FDA's Patent Listing, Patent
            Certification, and 30-Month Stay Regulations \1\
------------------------------------------------------------------------
                                    Proposed Changes See section of this
  21 CFR Section to which changes   document (identified in parentheses)
               apply                    for more detailed information
                                        regarding the proposed change
------------------------------------------------------------------------
314.3.............................  Overview of New, Revised, and
                                     Relocated Definitions (II.A.1).
                                    Proposed Amendments to Definitions
                                     in Sec.   314.3 (II.A.2).
                                    Definitions in Current Sec.
                                     314.108 (II.A.3).
                                    Definitions in Current Sec.   320.1
                                     (II.A.4).
314.50(i)(1)......................  Patent Certification Requirements
                                     for Method-of-Use Patents (II.C.1).
                                    Procedure for Submission of an
                                     Application Requiring
                                     Investigations for Approval of a
                                     New Indication for, or Other Change
                                     From, a Listed Drug (II.H).
314.50(i)(2)......................  Patent Certification Requirements
                                     for Method-of-Manufacturing
                                     Patents.
                                    (II.C.2).
314.50(i)(3)......................  Licensing Agreements (II.C.3).
314.50(i)(4)......................  Untimely Filing of Patent
                                     Information (II.B.2).
314.50(i)(6)......................  Amended Patent Certifications,
                                     including:
                                    a. Amended patent certifications
                                     after a finding of infringement;
                                    b. Amended certifications after a
                                     request by the NDA holder to remove
                                     a patent from the list;
                                    c. Amended certifications upon
                                     patent reissuance; and
                                    d. Other amended certifications.
                                    (II.E.1 through II.E.4).
314.52(b) and (d).................  Timing of Notice of Paragraph IV
                                     Certification, including:
                                    a. Date before which notice may not
                                     be given;
                                    b. Date by which notice must be
                                     given; and
                                    c. Certification of provision of
                                     notice.
                                    (II.D.1).

[[Page 6808]]

 
314.52(c).........................  Contents of Notice of Paragraph IV
                                     Certification, including:
                                    a. Statement that any required
                                     bioavailability or bioequivalence
                                     studies for a 505(b)(2) application
                                     have been submitted;
                                    b. Statement confirming receipt of
                                     an acknowledgment letter or a
                                     paragraph IV acknowledgment letter;
                                    c. Documentation that paragraph IV
                                     certification was submitted and
                                     notice was sent only for patents
                                     listed in the Orange Book; and
                                    d. Offer of confidential access
                                     accompanying notice.
                                    (II.D.3).
314.52(d).........................  Notice Required for All Paragraph IV
                                     Certifications.
                                    (II.D.2).
314.52(e).........................  Documentation of Timely Sending and
                                     Receipt of Notice of Paragraph IV
                                     Certification, including:
                                    a. Acceptable methods of sending
                                     notice of paragraph IV
                                     certification; and
                                    b. Amendment documenting timely
                                     sending and confirmation of receipt
                                     of notice of paragraph IV
                                     certification.
                                    (II.D.4).
314.53(b) and (c).................  General Requirements for Submission
                                     of Patent Information, including:
                                    Revisions to scope of required
                                     submission of patent information.
                                    (II.B.1).
314.53(d).........................  When and Where To Submit Patent
                                     Information, including:
                                    a. Submission of patent information
                                     for NDA supplements;
                                    b. Untimely filing of patent
                                     information;
                                    c. Where to send submissions of Form
                                     FDA 3542a and 3542; and
                                    d. Submission date of patent
                                     information.
                                    (II.B.2).
314.53(e).........................  Public Disclosure of Patent
                                     Information (II.B.3).
314.53(f).........................  Correction or Change of Patent
                                     Information, including:
                                    a. Patents that claim an approved
                                     method of using the drug product
                                     (method-of-use patents); and
                                    b. Requests by NDA holder to remove
                                     patent information from the list.
                                    (II.B.4).
314.54............................  Procedure for Submission of an
                                     Application Requiring
                                     Investigations for Approval of a
                                     New Indication for, or Other Change
                                     From, a Listed Drug.
                                    (II.H).
314.60(e).........................  Amendments to an Unapproved
                                     505(b)(2) Application for A
                                     Different Drug, including:
                                    a. Applications within the scope of
                                     section 505(b)(4)(A) of the FD&C
                                     Act;
                                    b. Proposed amendments subject to
                                     section 505(b)(4)(A) of the FD&C
                                     Act;
                                    c. Exception for amendments to seek
                                     approval of a different strength;
                                     and
                                    (II.G.3).
314.60(f).........................  Patent Certification Requirements
                                     for Amendments to 505(b)(2)
                                     Applications (II.F).
314.70(h).........................  Supplements to a 505(b)(2)
                                     Application for A Different Drug
                                     (II.G.4).
314.70(i).........................  Patent Certification Requirements
                                     for Supplements to 505(b)(2)
                                     Applications (II.F).
314.90............................  Refusal to Approve an NDA (II.L).
314.93............................  Petition to Request a Change From a
                                     Listed Drug (II.I).
314.94(a)(12)(iii)................  Patent Certification Requirements
                                     for Method-of-Use Patents (II.C.2).
314.94(a)(12)(iv).................  Patent Certification Requirements
                                     for Method-of-Manufacturing Patents
                                     (II.C.3).
314.94(a)(12)(viii)...............  Amended Patent Certifications,
                                     including:
                                    a. Amended patent certifications
                                     after a finding of infringement;
                                    b. Amended certifications after a
                                     request by the NDA holder to remove
                                     a patent from the list;
                                    c. Amended certifications upon
                                     patent reissuance; and
                                    d. Other amended certifications.
                                    (II.E.1 through II.E.4).
314.95(b) and (d).................  Timing of Notice of Paragraph IV
                                     Certification, including:
                                    a. Date before which notice may not
                                     be given;
                                    b. Date by which notice must be
                                     given; and
                                    c. Certification of provision of
                                     notice.
                                    (II.D.1).
314.95(c).........................  Contents of Notice of Paragraph IV
                                     Certification, including:
                                    a. Statement confirming receipt of
                                     an acknowledgment letter or a
                                     paragraph IV acknowledgment letter;
                                    b. Clarification that paragraph IV
                                     certifications may be submitted
                                     only for patents listed in the
                                     Orange Book; and
                                    c. Offer of confidential access
                                     accompanying notice.
                                    (II.D.3).
314.95(d).........................  Notice Required for All Paragraph IV
                                     Certifications (II.D.2).
314.95(e).........................  Documentation of Timely Sending and
                                     Receipt of Notice of Paragraph IV.
                                    Certification, including:
                                    a. Acceptable methods of sending
                                     notice of paragraph IV
                                     certification; and
                                    b. Amendment documenting timely
                                     sending and confirmation of receipt
                                     of notice of paragraph IV
                                     certification.
                                    (II.D.4).

[[Page 6809]]

 
314.96(c).........................  Amendments to an Unapproved ANDA
                                     That Reference a Different Listed
                                     Drug, including:
                                    a. Approval of a pharmaceutically
                                     equivalent RLD in an NDA;
                                    b. Changes to the proposed drug
                                     product would result in
                                     pharmaceutical equivalence to a
                                     different RLD;
                                    c. Exception for amendments to seek
                                     approval of a different strength;
                                     and
                                    d. Procedure for submission of a new
                                     ANDA that identifies a different
                                     RLD.
                                    (II.G.1).
314.96(d).........................  Patent Certification Requirements
                                     for Amendments to ANDAs (II.F).
314.97(b).........................  Supplements to an ANDA That
                                     Reference a Different Listed Drug.
                                    a. Changes to the proposed drug
                                     product would result in
                                     pharmaceutical equivalence to a
                                     different RLD;
                                    b. Exception for supplements to seek
                                     approval of a different strength;
                                     and
                                    c. Procedure for submission of a new
                                     ANDA that identifies a different
                                     RLD.
                                    (II.G.2).
314.97(c).........................  Patent Certification Requirements
                                     for Supplements to ANDAs (II.F).
314.99............................  Refusal to Approve an ANDA (II.L).
314.101...........................  Notification of Filing of a
                                     505(b)(2) Application or Receipt of
                                     an ANDA and
                                    Other Proposed Revisions (II.J.1
                                     through II.J.2).
                                    Administrative Consequence for Late
                                     Notice of Paragraph IV
                                     Certification (II.D.5).
314.105...........................  Approval of an NDA and ANDA (II.K).
314.107(a)........................  Date of Approval of a 505(b)(2)
                                     Application or ANDA (II.M.1).
314.107(b)........................  Effect of Patent(s) on the Listed
                                     Drug, including:
                                    a. Timing of approval based on
                                     patent certification or statement;
                                    b. Patent information filed after
                                     submission of 505(b)(2) application
                                     or ANDA;
                                    c. Disposition of patent litigation;
                                     and
                                    d. Tentative approval.
                                    (II.M.2).
314.107(c)........................  Subsequent ANDA Submission (II.M.3).
314.107(d)........................  Delay of Approval Due to Exclusivity
                                     (II.M.4).
314.107(e)........................  Notification of Court Actions or
                                     Documented Agreement (II.M.5).
314.107(f)........................  Computation of the 45-day time clock
                                     (II.M.6).
314.107(g)........................  Conversion of Approval to Tentative
                                     Approval (II.M.7).
314.108...........................  Definitions in Current Sec.
                                     314.108 (II.A.3).
314.125...........................  Refusal to Approve an NDA (II.L).
314.127...........................  Refusal to Approve an ANDA (II.L).
320.1.............................  Definitions in Current Sec.   320.1
                                     (II.A.4).
320.23............................  Assessing Bioavailability and
                                     Bioequivalence for Drugs Not
                                     Intended To Be Absorbed Into the
                                     Bloodstream (II.N).
------------------------------------------------------------------------
\1\ These highlights reference important proposed revisions to our
  regulations, but should not be relied upon in place of the proposed
  regulation.

II.A. Definitions

II.A.1. Overview of New, Revised, and Relocated Definitions
    We are proposing to amend Sec.  314.3(b) to define terms relevant 
to amendments to the FD&C Act made by the MMA and to add definitions of 
terms that have been used by the Agency for several years in the 
context of implementing section 505(b) and (j) of the FD&C Act. We also 
are proposing amendments to Sec.  314.3(b) and elsewhere to conform 
with other changes that we are proposing in this regulation and to 
incorporate new definitions. Although some of these revisions are not 
required for implementation of the MMA, these proposed changes are 
intended to enhance the clarity of our regulations in part 314 and 
promote consistency throughout our regulations.
    Several definitions that we are proposing to add to Sec.  314.3(b) 
involve terms that are defined specifically by the MMA (see definitions 
of ``180-day exclusivity,'' ``first applicant,'' ``substantially 
complete application,'' and ``tentative approval'' in section II.A.2. 
Our proposed definitions of these terms closely track the statutory 
language with only minor editorial changes (see section 
505(j)(5)(B)(iv)(I) and (j)(5)(B)(iv)(II) of the FD&C Act). We also are 
proposing to add definitions of a ``paragraph IV acknowledgment 
letter'' and an ``acknowledgment letter'' to Sec.  314.3(b), as the 
term ``paragraph IV acknowledgment letter'' is relevant to amendments 
made to section 505(b)(3)(B)(i) and (j)(2)(B)(ii)(I) of the FD&C Act 
regarding timing requirements for notices of paragraph IV 
certifications (see section II.A.2).
    We are proposing to add definitions of terms that have been 
commonly used by the Agency over the years in the context of 
implementing section 505(b) and (j) of the FD&C Act and part 314, but 
that have not been expressly defined in Sec.  314.3(b) (see definitions 
of ``abbreviated new drug application,'' ``ANDA,'' ``dosage form,'' 
``new drug application,'' ``NDA,'' ``ANDA holder,'' ``NDA holder,'' 
``patent owner,'' ``reference standard,'' ``strength,'' and 
``therapeutic equivalents'' in section II.A.2). These proposed 
definitions are intended to codify our longstanding use of these terms, 
rather than substantively change the meaning.
    We are proposing to revise the definitions of certain existing 
terms in Sec.  314.3(b) (see definitions of ``listed drug'' and ``the 
list'' in section II.A.2) to conform with other changes we are 
proposing in this regulation and to clarify the distinction between 
approvals and tentative approvals (see section II.K). We also are 
proposing to revise the definitions of ``abbreviated application'' and 
``applicant'' in Sec.  314.3(b) to reflect statutory changes made by 
the Food and Drug Administration Modernization Act of

[[Page 6810]]

1997 (Public Law 105-115) (FDAMA) that eliminated the previous need to 
distinguish between ANDAs and abbreviated antibiotic applications. We 
are proposing amendments to Sec.  314.3(b) and elsewhere to incorporate 
terms used by the Agency into existing definitions (see proposed 
amendments to definition of ``applicant'' to use terms ``NDA'' and 
``ANDA'' in lieu of ``application'' and ``abbreviated application,'' 
respectively, in section II.A.2).
    For clarity and ease of reference, we are proposing to add 
definitions of ``paragraph IV certification'' and ``commercial 
marketing'' to Sec.  314.3(b) based on the current use of these terms 
in other sections of part 314. As discussed in section II.A.2.v, a 
paragraph IV certification is defined by section 505(b)(2)(A)(iv) and 
(j)(2)(A)(vii)(IV) of the FD&C Act and currently described in 
implementing regulations in part 314. Commercial marketing of certain 
drug products is a statutory trigger for beginning the period of 180-
day exclusivity and is described in current and proposed regulations 
(see sections II.A.2.l and II.M.3). We also are proposing to move the 
definitions of the terms ``active moiety'' and ``date of approval'' in 
current Sec.  314.108(a) to Sec.  314.3(b). These definitions are 
relevant to matters covered in other sections of part 314 and thus 
appropriate for inclusion in the general definition section for this 
part.
    We also are proposing to add definitions of ``active ingredient,'' 
``inactive ingredient,'' and the related term ``component'' to Sec.  
314.3(b) based on the current definitions in Sec.  210.3(b) (21 CFR 
210.3(b)). These definitions reflect the current use of these terms in 
other sections of part 314.
    Finally, we are proposing to move the definitions that currently 
are in Sec.  320.1(a) through (g) to Sec.  314.3(b) for ease of 
reference and organizational convenience. The terms currently defined 
in Sec.  320.1 (``bioavailability,'' ``drug product,'' ``pharmaceutical 
equivalents,'' ``pharmaceutical alternatives,'' ``bioequivalence,'' 
``bioequivalence requirement,'' and ``same drug product formulation'') 
are relevant to matters covered in part 314 in addition to matters in 
part 320, and certain of these terms are already used in part 314. (As 
noted elsewhere in this document, our proposed amendments to part 320 
(discussed in section II.N) would make clear that proposed terms 
defined in Sec.  314.3 will be applicable to part 320 when those terms 
are used in part 320.) With three exceptions (the definitions of 
``bioavailability,'' ``bioequivalence,'' and ``drug product,'' 
discussed in section II.A.2), we are proposing to move the definitions 
in existing Sec.  320.1(a) through (g) to Sec.  314.3(b) without 
changes. We are proposing to modify the definition of bioavailability 
in current Sec.  320.1(a) to reflect a statutory change made by the 
MMA. We are proposing conforming revisions to the definition of 
bioequivalence. It is not necessary to move the definition of drug 
product in Sec.  320.1(b) to Sec.  314.3 because this section already 
includes a definition of drug product that we believe is functionally 
identical.
II.A.2. Proposed Amendments to Definitions in Sec.  314.3
    II.A.2.a. 180-day exclusivity period. The MMA defines the term 
``180-day exclusivity period'' for purposes of section 505(j)(5) of the 
FD&C Act to mean ``the 180-day period ending on the day before the date 
on which an application submitted by an applicant other than a first 
applicant could become effective under this clause'' (see section 
505(j)(5)(B)(iv)(II)(aa) of the FD&C Act). We are proposing to 
supplement this definition for ANDAs subject to the MMA to incorporate 
the statutory trigger for 180-day exclusivity, as described in section 
505(j)(5)(B)(iv)(I) of the FD&C Act, and make minor editorial changes. 
In proposed Sec.  314.3(b), the term ``180-day exclusivity period'' is 
defined as the 180-day period beginning on the date of the first 
commercial marketing of the drug (including the commercial marketing of 
the RLD) by any first applicant of an ANDA (see discussion of 
``commercial marketing'' and ``first applicant'' in sections II.A.2.l 
and II.A.2.q). The 180-day period ends on the day before the date on 
which an ANDA submitted by an applicant other than a first applicant 
could be approved (see section 505(j)(5)(B)(iv)(I) through 
(j)(5)(B)(iv)(II)(aa) of the FD&C Act). As reflected in the 
parenthetical reference to commercial marketing of the RLD, the 180-day 
exclusivity period may be triggered by the commercial marketing of an 
``authorized generic drug,'' as that term is currently defined in Sec.  
314.3(b).
    FDA interprets the 180-day exclusivity provisions added by the MMA 
to apply only to ANDAs referring to an RLD for which the first ANDA was 
submitted after December 8, 2003, whether or not that ANDA contained a 
paragraph IV certification at the time of submission (see section 
1102(b)(1) of the MMA (Effective Date provision)). If one or more ANDAs 
were submitted before December 8, 2003, but the first paragraph IV 
certification was submitted in an ANDA after that date, all ANDAs would 
be governed by the pre-MMA 180-day exclusivity provisions in order to 
impose the same statutory exclusivity scheme on all ANDAs referencing a 
specific RLD and avoid a possible disparate effect on ANDA applicants 
simultaneously undertaking the same patent challenge (see FDA's letter 
to ANDA applicants for topiramate sprinkle capsules dated April 15, 
2009, available on FDA's Web site at http://www.fda.gov).
    II.A.2.b. Abbreviated application, abbreviated new drug 
application, or ANDA. We are proposing to revise the definition of 
``abbreviated application'' to include the alternate terms 
``abbreviated new drug application'' and ``ANDA'' for clarity and 
administrative efficiency. Conforming revisions have been proposed 
throughout the sections of parts 314 and 320 in this rulemaking to 
incorporate the commonly used acronym ``ANDA'' in place of references 
to ``abbreviated application'' and ``abbreviated new drug 
application.''
    In addition, we are proposing to delete the text in Sec.  314.3(b) 
that explains that the term '' `[a]bbreviated application' applies to 
both an abbreviated new drug application and an abbreviated antibiotic 
application'' to reflect statutory changes made by FDAMA. Section 125 
of FDAMA repealed section 507 of the FD&C Act under which marketing 
applications, including ANDAs, for antibiotics had been approved. FDAMA 
provided that ANDAs for antibiotics previously approved under section 
507 of the FD&C Act would be deemed approved under section 505(j) of 
the FD&C Act. We note that there have been subsequent amendments to the 
FD&C Act involving applications for antibiotic drugs (see QI Program 
Supplemental Funding Act of 2008, Public Law 110-379 (2008)); however, 
these amendments are not specifically addressed in this proposed 
rulemaking.
    II.A.2.c. Acknowledgment letter. We are proposing to define the 
term ``acknowledgment letter'' as a counterpart to the term ``paragraph 
IV acknowledgment letter,'' which is proposed for inclusion in Sec.  
314.3(b) to facilitate implementation of the MMA's requirements for the 
timing of notice of a paragraph IV certification (see sections II.A.2.u 
and II.D.1). We propose to define ``acknowledgment letter'' as a 
written, postmarked communication from FDA to an applicant stating that 
the Agency has determined that a 505(b)(2) application or ANDA is 
sufficiently complete to permit a substantive review. The proposed 
definition states that an acknowledgment letter indicates that the 
505(b)(2) application is regarded as

[[Page 6811]]

filed or the ANDA is regarded as received. An acknowledgment letter is 
used for 505(b)(2) applications and ANDAs that contain a patent 
certification or statement other than a paragraph IV certification for 
the listed drug(s) relied upon or RLD, respectively (compare definition 
of ``paragraph IV acknowledgment letter'' discussed in section 
II.A.2.u).
    Although the term ``acknowledgment letter'' applies to both 
505(b)(2) applications and ANDAs that contain a patent certification or 
statement other than a paragraph IV certification, there are important 
practical differences between the letters for each type of application. 
In FDA's Center for Drug Evaluation and Research (CDER), the Office of 
Generic Drugs (OGD) reviews ANDAs after submission to determine whether 
the ANDA may be received for substantive review under Sec.  
314.101(b)(1). OGD will send an acknowledgment letter (or a paragraph 
IV acknowledgment letter, if appropriate) to the applicant after a 
determination has been made that the ANDA is sufficiently complete to 
permit a substantive review.
    For NDAs, including 505(b)(2) applications, a determination 
regarding whether the application may be filed is made within 60 days 
after FDA is in receipt of the application as provided in Sec.  
314.101(a)(1). In the absence of a refusal to file letter sent to the 
NDA applicant on or before day 60, the NDA is deemed filed. In the 
context of a 505(b)(2) application, our proposed definition of 
``acknowledgment letter'' reflects the current practice by CDER's 
Office of New Drugs (OND) with respect to its notification of issues 
identified during the filing review (filing communication) to the 
applicant generally not later than 14 calendar days after the 60-day 
filing date. This filing communication is informally known as a ``74-
day letter'' (see Manual of Policies and Procedures (MAPP) 6010.5, 
``NDAs: Filing Review Issues'' (effective May 8, 2003) (available on 
FDA's Web site at http://www.fda.gov). Under our proposed definition, 
the filing communication sent by the OND review division to the 
505(b)(2) applicant is the ``acknowledgment letter'' from FDA stating 
that the 505(b)(2) application is sufficiently complete to permit a 
substantive review.
    It should be noted that if an original ANDA contains a patent 
certification or statement other than a paragraph IV certification, and 
the applicant submits an amendment containing a paragraph IV 
certification before the ANDA has been received for substantive review, 
the applicant may receive, for administrative reasons, an 
acknowledgment letter, rather than a paragraph IV acknowledgment 
letter. This contingency is addressed in proposed Sec.  314.95 by the 
use of both terms.
    II.A.2.d. Act. We are proposing to modify the definition of ``act'' 
in Sec.  314.3(b) so that the citation to the U.S. Code reflects 
sections added to the FD&C Act by FDAMA, the Food and Drug 
Administration Amendments Act of 2007 (FDAAA), the Food and Drug 
Administration Safety and Innovation Act (FDASIA), and other 
legislation.
    II.A.2.e. Active ingredient. We are proposing to add the definition 
of ``active ingredient'' currently in Sec.  210.3(b)(7) to Sec.  
314.3(b) without changes. The term ``active ingredient'' is relevant to 
matters covered in part 314 in addition to matters in part 210 and thus 
appropriate for inclusion in the general definition section for this 
part.
    II.A.2.f. Active moiety. We are proposing to move the definition of 
the term ``active moiety'' in current Sec.  314.108(a) to Sec.  
314.3(b) without changes. This definition is relevant to matters 
covered in other sections of part 314 and thus appropriate for 
inclusion in the general definition section for this part.
    II.A.2.g. ANDA holder and NDA holder. We are proposing to define 
the terms ``ANDA holder'' and ``NDA holder'' to mean the applicant that 
owns an approved ANDA or NDA, respectively. These terms have been 
commonly used by the Agency over the years in the context of 
implementing section 505(b) and (j) of the FD&C Act and part 314, but 
have not been expressly defined in Sec.  314.3(b).
    II.A.2.h. Applicant. We are proposing to revise the definition of 
``applicant'' to conform with other changes that we are proposing in 
this regulation and incorporate the commonly used acronyms ``NDA'' and 
``ANDA.'' In addition, we are proposing to delete the reference to ``an 
antibiotic drug'' in the current definition of ``applicant'' to reflect 
statutory changes made by FDAMA that eliminated the previous need to 
distinguish between a new drug and an antibiotic drug.
    II.A.2.i. Application, new drug application, or NDA. We are 
proposing to revise the definition of ``application'' to include the 
alternate terms ``new drug application'' and ``NDA'' for clarity and 
administrative efficiency. Conforming revisions have been proposed 
throughout the sections of parts 314 and 320 in this rulemaking to 
incorporate the commonly used acronym ``NDA'' in place of references to 
``application'' and ``new drug application.'' In addition, we are 
proposing to expressly state that the terms ``application, new drug 
application, or NDA'' refer to ``stand-alone'' applications submitted 
under section 505(b)(1) of the FD&C Act and to 505(b)(2) applications. 
Although certain regulations in part 314 refer specifically to 
505(b)(2) applications, 505(b)(2) applications also are subject to any 
applicable regulations governing new drug applications.
    We considered replacing the term ``application'' with ``new drug 
application or NDA,'' rather than including ``new drug application'' or 
``NDA'' as alternate terms, because the term ``application'' is 
sometimes used to generally refer to any application (e.g., a ``stand-
alone'' NDA, 505(b)(2) application, or ANDA) in a concise manner. 
However, such a proposal would have necessitated additional conforming 
revisions throughout part 314 that are beyond the scope of this 
rulemaking. We are proposing to replace the term ``application'' with 
``NDA or ANDA'' in certain sections of part 314 to clarify the text and 
reflect FDA's longstanding interpretation of the provision (see, e.g., 
the definition of ``specification'' in proposed Sec.  314.3(b)).
    II.A.2.j. Bioavailability, bioequivalence. The MMA amended the 
definitions of ``bioavailability'' and ``bioequivalence'' in section 
505(j)(8)(A) and (j)(8)(C) of the FD&C Act to confirm that, for drugs 
not intended to be absorbed into the bloodstream, FDA may ``assess 
bioavailability by scientifically valid measurements intended to 
reflect the rate and extent to which the active ingredient or 
therapeutic ingredient becomes available at the site of drug action'' 
(emphasis added). For such drugs, the MMA provides that FDA may 
establish ``alternative scientifically valid methods to show 
bioequivalence . . .'' (see section 505(j)(8)(C) of the FD&C Act 
(emphasis added)). Section 1103(b) of the MMA expressly states that the 
amendments to section 505(j)(8)(A) and (j)(8)(C) of the FD&C Act ``do[] 
not alter the standards for approval of drugs under section 505(j)'' of 
the FD&C Act.
    The amendments to section 505(j)(8)(A) and (C) of the FD&C Act 
codify FDA's current practice, based on its existing regulations in 
Sec. Sec.  320.1(a) and (e), 320.23(a)(1), and 320.24 and 
implementation of those regulations, regarding assessment of 
bioavailability and demonstration of bioequivalence for drugs not 
intended to be absorbed into the bloodstream (see Schering Corp. v. 
FDA, 51 F.3d 390 (3d Cir. 1995), cert. denied, 516 U.S. 907 (1995) 
(holding that FDA's regulatory standard in Sec.  320.1(e) for 
bioequivalence of non-

[[Page 6812]]

systemically effective drugs is a permissible construction of the 
statute); see also section II.N).
    We are proposing to revise the definitions of bioavailability and 
bioequivalence in Sec.  320.1(a) and (e) to incorporate the textual 
revisions made in section 505(j)(8)(A) of the FD&C Act and move the 
revised definitions to Sec.  314.3(b) in light of their relevance to 
matters covered in part 314 in addition to matters in part 320. The 
proposed definitions include a statement that for drug products that 
are not intended to be absorbed into the bloodstream, bioavailability 
and bioequivalence may be assessed by scientifically valid measurements 
intended to reflect the rate and extent to which the active ingredient 
or active moiety becomes available at the site of action (emphasis 
added). FDA will evaluate the scientific appropriateness of 
methodologies to assess the bioavailability or demonstrate the 
bioequivalence of non-systemically absorbed drugs based on the best 
available scientific evidence. We do not interpret section 505(j)(8)(A) 
and (j)(8)(C) of the FD&C Act to require full analytical method 
validation (which may have the effect of altering the standards for 
approval of ANDAs, contrary to section 1103(b) of the MMA), but rather 
methods that FDA considers to be scientifically valid or appropriate 
(see Docket No. FDA-2004-N-0062-0013 (comment submitted by the 
Biotechnology Industry Organization (BIO)) at 2 to 3, available at 
http://www.regulations.gov (BIO MMA Comment).
    To clarify our interpretation of ``bioavailability'' and conform 
the definition with terminology used to define bioequivalence, we are 
proposing to revise the reference to ``site of action'' in current 
Sec.  320.1(a) to ``site of drug action'' (see Sec.  320.1(e)). For 
locally-acting drug products that are not systemically absorbed or have 
low systemic bioavailability, a pharmacokinetic comparison of drug and/
or metabolite concentrations in plasma would not always reflect the 
rate and extent to which the active ingredient or active moiety becomes 
available at the site of drug action (e.g., gastrointestinal tract or 
lungs). This is consistent with our historical interpretation and 
application of this term and the express language of section 
505(j)(8)(A) of the FD&C Act.
    In addition, we are proposing to substitute the term ``active 
moiety'' for the statutory term ``therapeutic ingredient'' in the 
definitions of ``bioavailability'' and ``bioequivalence.'' This 
approach reflects our longstanding judgment that the term ``active 
moiety'' is more appropriate than the term ``therapeutic ingredient'' 
in the context of section 505(j)(8)(A) of the FD&C Act (see, e.g., 
``Abbreviated New Drug Application Regulations''; final rule, 57 FR 
17950 at 17972, April 28, 1992) (1992 final rule) (``Congress clearly 
intended a meaning different from `active ingredient' by the term 
`therapeutic ingredient' or it would not have used both terms [in what 
is now section 505(j)(8) of the FD&C Act]. The term `active moiety' 
refers to the molecule or ion in an active ingredient, excluding those 
appended portions of the molecule that cause the ingredient to be an 
ester, or a salt or other noncovalent derivative that is responsible 
for the physiological or pharmacological action of the ingredient.'')
    We also are proposing clarifying revisions in Sec.  
314.94(a)(7)(iii) relevant to bioequivalence studies. Proposed Sec.  
314.94(a)(7)(iii) would state that the requirements for submission of a 
description of the analytical and statistical methods used in each 
bioequivalence study applies to in vitro bioequivalence studies as well 
as in vivo bioequivalence studies. An in vitro study used to establish 
or support bioequivalence may include, for example, an in vitro kinetic 
binding study, an in vitro equilibrium binding study, a permeability 
study, and a study of plume geometry, spray pattern, or droplet or 
particle size distribution for nasal spray products.
    II.A.2.k. Bioequivalence requirement. We are proposing to move the 
definition of ``bioequivalence requirement'' currently in Sec.  
320.1(f) to Sec.  314.3(b), with a minor grammatical correction, for 
ease of reference and organizational convenience. The term 
``bioequivalence requirement'' is relevant to matters covered in part 
314 in addition to matters in part 320 and thus appropriate for 
inclusion in the general definition section for this part.
    II.A.2.l. Commercial marketing. We are proposing to define 
``commercial marketing'' to mean the introduction or delivery for 
introduction into interstate commerce of a drug product described in an 
approved ANDA, outside the control of the ANDA holder, except for 
investigational use under part 312 of this chapter, but does not 
include transfer of the drug product for reasons other than sale to 
parties identified in the approved ANDA.
    This proposed definition is based on the use of this term in 
current Sec.  314.107(c)(4); however, we are proposing to alter the 
scope of the exclusion for transfer of the drug product for reasons 
other than sale. Section 314.107(c)(4) currently provides that 
commercial marketing ``does not include transfer of the drug product 
for reasons other than sale within the control of the manufacturer or 
application holder'' (emphasis added). Our proposed definition is 
intended to clarify that the ANDA holder's shipment of a drug product 
described in an approved ANDA to any party named in the ANDA for 
purposes described in the ANDA (e.g., contract packaging) is not 
``commercial marketing'' of the drug product even though such transfer 
arguably places the drug products outside of the control of the 
manufacturer for some period of time. However, shipment of the drug 
product to any other party or for any other purpose would not fall 
within this exception and would be considered ``commercial marketing'' 
(i.e., an introduction or delivery for introduction into interstate 
commerce of a drug product described in an approved ANDA outside the 
ANDA holder's control). For example, if the ANDA holder ships the drug 
product to a wholesaler, a repackager not identified in the ANDA, or 
directly to a pharmacy, hospital, health maintenance organization, or 
other like entity, the ANDA holder will have commercially marketed the 
product as of the date of its shipment (if the ANDA holder complies 
with the notification requirement described in proposed Sec.  
314.107(c)(2)).
    The first commercial marketing of a drug is discussed in section 
II.A.2.a (definition of the 180-day exclusivity period).
    II.A.2.m. Component. We are proposing to add the definition of 
``component'' currently in Sec.  210.3(b)(3) to Sec.  314.3(b) without 
changes. The term ``component'' is used within the defined term 
``active ingredient'' and thus is appropriate for inclusion in the 
general definition section for this part (see section II.A.2.e).
    II.A.2.n. Date of approval. We are proposing to move the definition 
of ``date of approval'' currently in Sec.  314.108(a) to Sec.  314.3(b) 
with several revisions. These proposed revisions to the definition of 
``date of approval'' are not intended to alter our interpretation of 
Sec.  314.108.
    Our proposed revisions to the definition of ``date of approval'' 
incorporate use of the term ``approval letter,'' which also is defined 
in Sec.  314.3(b), and broaden the definition to include the date of 
approval for an ANDA. In addition, we are proposing to remove from the 
definition of ``date of approval'' the caveat that the date of approval 
is the date on the approval

[[Page 6813]]

letter ``whether or not final printed labeling or other materials must 
still be submitted as long as approval of such labeling or materials is 
not expressly required'' (Sec.  314.108(a)). This qualification is 
inapplicable to the date of approval of an ANDA because final printed 
labeling is required as a condition of approval (see Sec. Sec.  
314.94(a)(8) and 314.127(a)(7)). With respect to NDAs (including 
505(b)(2) applications), Sec.  314.105(b) specifically addresses the 
circumstances under which FDA will approve an NDA and issue the 
applicant an approval letter on the basis of draft labeling, and it is 
unnecessary to summarize this approach in the definition of ``date of 
approval.''
    As proposed for revision, the ``date of approval'' is the date on 
the approval letter from FDA stating that the NDA or ANDA is approved. 
The date of approval refers only to a final approval and not to a 
tentative approval. We note that the date on the approval letter 
generally appears on the last page containing the electronic signature 
(endorsement).
    II.A.2.o. Dosage form. We are proposing to define ``dosage form'' 
to mean the physical manifestation containing the active and inactive 
ingredients that delivers a dose of the drug product. This includes 
such factors as (i) the physical appearance of the drug product, (ii) 
the physical form of the drug product prior to dispensing to the 
patient, (iii) the way the product is administered, and (iv) design 
features that affect frequency of dosing. This term has been commonly 
used by the Agency over the years in the context of implementing 
section 505(j) of the FD&C Act and part 314. However, except for the 
examples of dosage forms used in the definition of ``drug product,'' 
the term ``dosage form'' not been expressly defined in Sec.  314.3(b).
    The dosage form is generally determined based on the form of the 
product before dispensing to the patient (see Abbott Laboratories v. 
Young, 691 F. Supp. 462, 464 n. 1 (D.D.C. 1988) (``The final dosage 
form of a drug is the form in which it appears prior to administration 
to the patient''), remanded on other grounds, 920 F.2d 984 (D.C. Cir. 
1990), cert. denied, 502 U.S. 819 (1991)). This is consistent with 
other factors such as physical recognition, dosing, and manner of 
administration that contribute to the determination of dosage form. 
Appendix C to the Orange Book lists the dosage form categories for 
currently marketed products.
    II.A.2.p. Drug product. A ``drug product'' is a finished dosage 
form (for example, a tablet, capsule, or solution) that contains a drug 
substance, generally, but not necessarily, in association with one or 
more other ingredients. We are proposing to delete a similar definition 
of ``drug product'' in current Sec.  320.1(b) when we move the 
definitions in Sec.  320.1 to Sec.  314.3(b), to reflect the fact that 
Sec.  314.3(b) already includes a definition of drug product. Although 
the two definitions of ``drug product'' differ slightly in wording, we 
believe that they are functionally identical, so that this proposed 
revision is intended to eliminate redundancy but not result in any 
substantive change in our interpretation of part 320.
    II.A.2.q. First applicant. The MMA defines the term ``first 
applicant'' for purposes of section 505(j)(5) of the FD&C Act (see 
section 505(j)(5)(B)(iv)(II)(bb) of the FD&C Act). We are proposing to 
add the statutory definition, with minor editorial changes and 
additional clarifying text, to Sec.  314.3(b) to facilitate our 
continuing implementation of the 180-day exclusivity provisions of the 
FD&C Act. We are proposing to define ``first applicant'' in Sec.  
314.3(b) to mean an applicant that, on the first day on which a 
substantially complete ANDA containing a paragraph IV certification is 
submitted for approval of a drug, submits a substantially complete ANDA 
that contains, and for which the applicant lawfully maintains, a 
paragraph IV certification for the drug. We are proposing to delete the 
definition of ``applicant submitting the first application'' in current 
Sec.  314.107(c)(2) because it is superseded by the statutory 
definition (see section II.M.3). We note that an applicant may be a 
``first applicant'' based on the submission of a paragraph IV 
certification in an amendment to an ANDA if other criteria are met.
    We interpret the term ``drug'' in the statutory definition of 
``first applicant'' to mean ``drug product'' as currently defined in 
Sec.  314.3(b) (see section 505(j)(5)(B)(iv)(II)(bb) of the FD&C Act). 
Consistent with our longstanding practice, we note that different 
strengths of a drug product constitute different drug products. For 
example, different ANDA applicants seeking approval for different 
strengths of a drug product approved in a single NDA may each be first 
applicants with respect to a different strength of the drug product, if 
other applicable statutory and regulatory requirements are met (see 
Apotex, Inc. v. Shalala, 53 F. Supp. 2d 454 (D.D.C.), aff'd, 1999 U.S. 
App. LEXIS 29571 (D.C. Cir. 1999)). In addition, there may be multiple 
first applicants for a single drug product if more than one ANDA 
applicant first submitted a substantially complete ANDA that contains, 
and for which the applicant lawfully maintains, a paragraph IV 
certification on the same day.
    We have interpreted the statutory requirement for a first applicant 
to ``lawfully maintain'' a paragraph IV certification to mean that the 
ANDA applicant must, as a condition of retaining first applicant 
status, continue to lawfully assert that a relevant listed patent 
(i.e., at least one of the patents for which a paragraph IV 
certification qualified the ANDA applicant for first applicant status) 
is invalid, unenforceable, or will not be infringed by the manufacture, 
use, or sale of the drug for which the ANDA is submitted (see Letter 
from G. Buehler, Director, Office of Generic Drugs, to ANDA Applicant 
regarding 180-day exclusivity for dorzolamide/timolol ophthalmic 
solution, Docket No. FDA-2008-N-0483-0017 at 5-6, available at http://www.regulations.gov) (Dorzolamide/Timolol Letter). This approach 
comports with comments that we received on the interpretation of the 
phrase ``lawfully maintained'' in response to the Request for MMA 
Comments (see Docket No. FDA-2004-N-0062-0006 (comment submitted by the 
Pharmaceutical Research and Manufacturers of America (PhRMA)) at 3-5, 
available at http://www.regulations.gov (PhRMA MMA Comment); see also 
Docket No. FDA-2004-N-0062-0009 (comment submitted by Eli Lilly and 
Company) at 1-2, available at http://www.regulations.gov (Lilly MMA 
Comment)).
    For example, if an ANDA applicant is sued for infringement of a 
patent that qualified the applicant for first applicant status and a 
court enters a final decision from which no appeal has been or can be 
taken that the patent is infringed (or signs a settlement order or 
consent decree in the action that includes a finding of infringement 
and does not permit market entry before patent expiration), the ANDA 
applicant can no longer lawfully maintain a paragraph IV certification 
with respect to the infringed patent (see Dorzolamide/Timolol Letter at 
6). As discussed in section II.E.1, the ANDA applicant is required to 
submit an amended patent certification under Sec.  
314.94(a)(12)(i)(A)(3) (paragraph III certification) in these 
circumstances. In addition, an ANDA applicant can no longer lawfully 
maintain a paragraph IV certification when the patent expires or if an 
ANDA applicant changes its certification from a paragraph IV 
certification to a 505(j)(2)(A)(viii)

[[Page 6814]]

statement (see proposed Sec.  314.94(a)(12)(viii)(C) and (D); see also 
Dorzolamide/Timolol Letter at 6, note 5).
    It should be noted that an amendment to a substantially complete 
ANDA does not mean that the ANDA is no longer substantially complete or 
that a first applicant has not lawfully maintained its paragraph IV 
certification (unless the amendment requires a new patent certification 
and the amended patent certification is not a paragraph IV 
certification). However, if a first applicant submits several major 
amendments to its ANDA, there is a risk that the applicant may not be 
able to obtain tentative approval within 30 months after the date on 
which the ANDA is filed, thereby forfeiting its eligibility for any 
180-day exclusivity period (see section 505(j)(5)(D)(i)(IV) of the FD&C 
Act).
    We note that certain definitions, such as the definition of ``first 
applicant,'' may be revised or supplemented in the future as we 
continue to implement the 180-day exclusivity provisions of the MMA.
    II.A.2.r. Inactive ingredient. We are proposing to add the 
definition of ``inactive ingredient'' currently in Sec.  210.3(b)(8) to 
Sec.  314.3(b) without changes. The term ``inactive ingredient'' is 
relevant to matters covered in part 314 in addition to matters in part 
210 and thus appropriate for inclusion in the general definition 
section for this part.
    II.A.2.s. Listed drug. We are proposing to revise the definition of 
``listed drug'' to clarify that a listed drug includes a drug product 
that is listed in the discontinued section of the Orange Book and that 
has not been withdrawn or suspended under section 505(e)(1) through 
(e)(5) or 505(j)(6) of the FD&C Act or withdrawn from sale 
(irrespective of whether the NDA has been withdrawn) for what FDA has 
determined are reasons of safety or effectiveness. Accordingly, the 
proposed definition in Sec.  314.3(b) would state that a listed drug is 
a new drug product that ``has been approved'' instead of one that ``has 
an effective approval.'' With respect to the exceptions to listed drug 
status, we are correcting the paragraph number in the reference to the 
statutory provision under which an ANDA may be withdrawn or suspended 
for reasons of safety or effectiveness (see section 505(j)(6) of the 
FD&C Act).
    In addition, we are proposing conforming revisions to incorporate 
other changes we are proposing in this rulemaking regarding the 
distinction between approvals and tentative approvals (see section 
II.K) and reliance upon the electronic version of the Orange Book (see 
section II.A.2.ee).
    Listed drug status is evidenced by the drug product's 
identification in the current FDA's ``Approved Drug Products With 
Therapeutic Equivalence Evaluations'' (the list) as an approved drug. 
However, we note that a drug product is deemed to be a listed drug on 
the date of the approval letter for the NDA or ANDA for that drug 
product, rather than the date on which the product is listed in the 
Orange Book.
    II.A.2.t. Original application, original NDA. We are proposing to 
revise the definition of ``original application'' to include the 
alternate term ``original NDA'' for clarity and administrative 
efficiency. In addition, we are proposing to replace references to 
``application'' with ``NDA'' for consistency with other changes in this 
proposed rulemaking. These minor revisions are not intended to 
substantively change the meaning of the term ``original application.''
    II.A.2.u. Paragraph IV acknowledgment letter. We are proposing to 
define ``paragraph IV acknowledgment letter'' to mean a written, 
postmarked communication from the FDA to an applicant stating that the 
Agency has determined that a 505(b)(2) application or ANDA containing a 
paragraph IV certification is sufficiently complete to permit a 
substantive review (compare definition of ``acknowledgment letter'' 
discussed in section II.A.2.c). An acknowledgment letter or paragraph 
IV acknowledgment letter indicates that the 505(b)(2) application is 
regarded as filed or the ANDA is regarded as received.
    The proposed definition of ``paragraph IV acknowledgment letter'' 
is intended to facilitate implementation of the MMA's timing 
requirements for notice to the NDA holder and each patent owner of a 
paragraph IV certification. A 505(b)(2) or ANDA applicant is required 
to send notice of its paragraph IV certification within 20 days after 
the date of the postmark on the paragraph IV acknowledgment letter (see 
section 505(b)(3)(B)(i) and (j)(2)(B)(ii)(I) of the FD&C Act and 
section II.D.1).
    In response to the Request for MMA Comments, the Generic 
Pharmaceutical Association (GPhA) requested that FDA amend Sec.  
314.101(b)(2) to state that FDA will notify the applicant ``in writing 
via a postmarked notice'' that the ANDA has been received in light of 
the MMA's timing requirements for notice of paragraph IV certification 
(see Docket No. FDA-2004-N-0062-0012 (comment submitted by GPhA) at 4-
5, available at http://www.regulations.gov) (GPhA MMA Comment). 
Incorporation of the term ``paragraph IV acknowledgment letter'' in 
proposed Sec.  314.101(b)(2) would address this concern with respect to 
ANDAs (see section II.J). In addition, although OGD currently sends a 
paragraph IV acknowledgment letter in an envelope bearing a postmark 
made by the U.S. Postal Service, we are proposing to broaden the 
definition the ``postmark'' to accommodate electronic transmissions in 
the future (see section II.A.2.y).
    For ANDAs, OGD currently sends a ``paragraph IV acknowledgment 
letter'' to confirm the date on which the ANDA was received and to 
establish the timeframe within which an ANDA applicant must send notice 
of a paragraph IV certification contained in the original ANDA (see 
section II.D.1). The letter also provides ANDA applicants with an 
overview of the notice requirements associated with submission of a 
paragraph IV certification to a listed patent for the RLD.
    For 505(b)(2) applications that rely on the Agency's finding of 
safety and/or effectiveness for a listed drug and include a paragraph 
IV certification for a listed patent, the Notification of Issues 
Identified during the Filing Review (filing communication), sometimes 
referred to as the ``74-day letter,'' would constitute the ``paragraph 
IV acknowledgment letter'' defined in Sec.  314.3. Unlike the paragraph 
IV acknowledgment letter for ANDAs, the OND filing communication is 
typically sent in a franked envelope that may not bear a postmark made 
by the U.S. Postal Service. For purposes of Sec.  314.52(b) and (c) (21 
CFR 314.52(b) and (c)) only, the ``date of the postmark'' on the 
``paragraph IV acknowledgment letter'' will be considered to be 4 
calendar days after the date on which the filing communication is 
signed by the signatory authority (generally the Division Director or 
designee in the OND review division), which generally reflects the date 
on which the document is received by the U.S. Postal Service (see 
definition of ``postmark'' in proposed Sec.  314.3). For example, if 
the filing communication is electronically signed by the Division 
Director or designee on Thursday, April 7th, the date of the postmark 
on the paragraph IV acknowledgment letter for the 505(b)(2) 
application, for purposes of Sec.  314.52(b), would be Monday, April 
11th. If OND sends the filing communication via electronic transmission 
in the future, then our proposed definition of ``postmark'' in Sec.  
314.3(b) would apply.
    As noted previously, the paragraph IV acknowledgment letter 
triggers the

[[Page 6815]]

requirements in proposed Sec. Sec.  314.52(b) and 314.95(b) for sending 
notice of the paragraph IV certification. The proposed difference in 
interpreting the term ``postmark'' as applied to paragraph IV 
acknowledgment letters for 505(b)(2) applications reflects current OND 
practice regarding the mailing of filing communications, which should 
occur no later than 74 days after the date of submission of the 
505(b)(2) application. In addition, although an indisputable date of 
mailing is needed for competing ANDAs that may be eligible for a period 
of 180-day exclusivity, a 505(b)(2) application does not raise these 
concerns. We invite comment on this proposed approach or whether an 
alternative approach should be considered.
    II.A.2.v. Paragraph IV certification. We are proposing to define 
``paragraph IV certification'' in Sec.  314.3(b) to mean a patent 
certification of invalidity, unenforceability, or noninfringement 
described in Sec.  314.50(i)(1)(i)(A)(4) or Sec.  
314.94(a)(12)(i)(A)(4) for 505(b)(2) applications and ANDAs, 
respectively. This term is routinely used by the Agency and applicants 
to refer to this type of patent certification. The addition of the term 
``paragraph IV certification'' to Sec.  314.3(b) would provide a 
convenient means of clearly referencing the patent certification 
described in the section 505(b)(2)(A)(iv) and (j)(2)(A)(vii)(IV) of the 
FD&C Act and implementing regulations.
    II.A.2.w. Patent owner. We are proposing to define ``patent owner'' 
as the owner of the patent for which information is submitted for an 
NDA. A patent may be owned by more than one person. If a patent owner 
seeks to have its designated representative receive notice of a 
paragraph IV certification by a 505(b)(2) or ANDA applicant that relies 
upon a listed drug claimed by the patent, the patent owner should 
ensure that current information regarding the correspondence address, 
in accordance with 37 CFR 1.33(d), is submitted to the PTO.
    II.A.2.x. Pharmaceutical alternatives and pharmaceutical 
equivalents. We are proposing to revise the definition of 
``pharmaceutical equivalents'' to clarify that this term is intended to 
refer to drug products in identical dosage forms and route(s) of 
administration that contain identical amounts of the identical active 
ingredient. The requirement for pharmaceutically equivalent products to 
have the same route(s) of administration is consistent with FDA's 
current practice, as described in section 1.2 of the preface to the 
Orange Book (33rd Edition, 2013, at vii). We are not proposing any 
changes to the definition of ``pharmaceutical alternatives.''
    We are proposing to move the definitions of ``pharmaceutical 
alternatives'' and ``pharmaceutical equivalents'' currently in Sec.  
320.1(c) and (d) to Sec.  314.3(b), for ease of reference and 
organizational convenience. The concepts of ``pharmaceutical 
alternatives'' and ``pharmaceutical equivalents'' are relevant to 
matters covered in part 314 (including but not limited to Sec.  314.94 
and proposed Sec. Sec.  314.50(i)(1)(i)(C), 314.93(f), 314.96(c), and 
314.97(b), discussed in section II.G.1-2, II.H, and II.I) in addition 
to matters in part 320 (21 CFR part 320).
    II.A.2.y. Postmark. We are proposing to define the term 
``postmark'' in Sec.  314.3(b) to address the MMA's requirement that a 
505(b)(2) or ANDA applicant send notice of its paragraph IV 
certification within ``20 days after the date of the postmark on the 
notice [i.e., the paragraph IV acknowledgment letter] with which [FDA] 
informs the applicant that the application has been filed'' (see 
section 505(b)(3)(B)(i) and 505(j)(2)(B)(ii)(I) of the FD&C Act). The 
term ``postmark'' is not used elsewhere in section 505 of the FD&C Act 
or in our current regulations in part 314. In light of the transition 
by FDA and regulated industry to electronic communications, an 
interpretation of the term ``postmark'' to mean a postmark made by the 
U.S. Postal Service (``U.S. postmark'') could quickly become outdated. 
The purpose of the postmark in section 505(b)(3)(B)(i) and 
(j)(2)(B)(ii)(I) of the FD&C Act is to establish a verifiable date from 
which the 20-day notice period runs. Accordingly, we are proposing a 
broader definition of a ``postmark'' to mean ``an independently 
verifiable evidentiary record of the date on which a document is 
transmitted, in an unmodifiable format, to another party. For postmarks 
made by the U.S. Postal Service or a designated delivery service, the 
date of transmission is the date on which the document is received by 
the domestic mail service of the U.S. Postal Service or by a designated 
delivery service. For postmarks documenting an electronic event, the 
date of transmission is the date (in a particular time zone) that FDA 
sends the electronic transmission on its host system as evidenced by a 
verifiable record. If the sender and the intended recipient are located 
in different time zones, it is the sender's time zone that provides the 
controlling date of electronic transmission.'' This proposed definition 
of ``postmark'' is adapted from the definition of ``electronic 
postmark'' in regulations issued by the Internal Revenue Service (IRS) 
with respect to electronic filing of documents required under 26 U.S. 
C. 7502 (see 26 CFR 301.7502-1(d)(3)(ii)).
    We invite comment on our proposed interpretation of the term 
``postmark'' in the context of a paragraph IV acknowledgment letter 
from FDA to an applicant for a 505(b)(2) application or ANDA, and 
whether our regulations should be amended to define differently the 
specific date from which the 20-day notice period runs.
    II.A.2.z. Reference standard. We are proposing to define 
``reference standard'' as the drug product selected by FDA that an 
applicant seeking approval of an ANDA must use in conducting an in vivo 
bioequivalence study required for approval. This proposed definition 
reflects the Agency's longstanding use of this term, as described in 
the preamble to our 1992 final rule implementing the Hatch-Waxman 
Amendments (``FDA intends the reference listed drug to be the same drug 
product selected by the agency as the reference standard for 
bioequivalence determinations'' (57 FR 17950 at 17954). By generally 
designating a single drug product as the standard to which generic 
versions must be shown to be bioequivalent, FDA seeks to avoid possible 
significant variations among generic drugs, which could result if such 
drugs were compared to different drug products.
    The reference standard is identified in the Orange Book by the word 
``yes'' in the ``RLD'' column. In certain circumstances, a drug product 
approved in an ANDA (including a petitioned ANDA) may be designated as 
the reference standard for bioequivalence studies intended to support 
approval of an ANDA. For example, if the RLD is a drug product approved 
in an NDA that has been withdrawn from marketing (for reasons other 
than safety or effectiveness), a therapeutically equivalent drug 
product approved in an ANDA may be designated as the reference 
standard.
    We recognize that the term ``reference standard'' has other 
meanings, including in the context of part 314 (see Sec.  
314.50(e)(1)(C)) regarding submission of representative samples of 
reference standards used in analytical studies, excluding 
pharmacopoeial reference standards). The proposed definition of 
``reference standard'' applies solely to the product used in conducting 
an in vivo bioequivalence study required for approval.
    II.A.2.aa. Same drug product formulation. We are proposing to move 
the definition of ``same drug product formulation'' currently in Sec.  
320.1(g) to Sec.  314.3(b), without changes, for ease of reference and 
organizational

[[Page 6816]]

convenience. The term ``same drug product formulation'' is relevant to 
matters covered in part 314 (including but not limited to Sec. Sec.  
314.94 and 314.96) in addition to matters in part 320.
    II.A.2.bb. Strength. We are proposing to define the term 
``strength'' in Sec.  314.3(b) to mean the amount of drug substance 
contained in, delivered, or deliverable from a drug product. The amount 
of drug substance contained in, delivered, or deliverable from a drug 
product includes: (i)(A) The total quantity of drug substance in mass 
or units of activity in a dosage unit or container closure (e.g., 
weight/unit dose, weight/volume or weight/weight in a container 
closure, or units/volume or units/weight in a container closure) and/
or, as applicable (i)(B) the concentration of the drug substance in 
mass or units of activity per unit volume or mass (e.g., weight/weight, 
weight/volume, or units/volume). If these weights and measures are not 
applicable to a type of drug product or dosage form, then the strength 
of the drug product may be described by such other criteria the Agency 
establishes for determining the amount of drug substance contained in, 
delivered, or deliverable from the drug product. For example, the 
strength of certain drug-device combination products (such as a 
transdermal delivery system) may be expressed as the amount of drug 
substance delivered per unit time.
    This proposed definition is intended to codify FDA's interpretation 
of the term ``strength'' in the context of section 505(j)(2)(A)(iii) of 
the FD&C Act. This proposed definition also will facilitate 
implementation of certain statutory provisions added by the MMA 
regarding amendments and supplements that seek approval of a 
``different strength'' (see section 505(b)(4)(B) and (j)(2)(D)(ii) of 
the FD&C Act). Different strengths of a drug product constitute 
different drug products.
    The amount of the drug substance ``delivered'' from a drug product 
is intended to describe the mass of drug substance delivered to the 
patient either per unit time (e.g., as in transdermal delivery system) 
or per actuation (e.g., as in metered dose inhalers) and excludes 
excess drug substance that although not available for labeled use, is 
necessary to allow for the specified total delivery (e.g., a specified 
number of hours for a transdermal delivery system or a specified number 
of actuations for a metered dose inhaler).
    The amount of drug substance ``deliverable from'' a drug product is 
intended to exclude the excess volume allowed by the U.S. Pharmacopeia 
(USP) (to permit withdrawal and administration of the labeled volume of 
an injectable product) from the description of the ``strength'' of the 
drug product (see 21 CFR 201.51(g)).
    FDA has a longstanding history of considering a difference in the 
total quantity of drug substance of a parenteral product (e.g., a 
single or multiple dose vial) or a difference in the concentration of a 
parenteral product to be a difference in the ``strength'' of the 
product for purposes of section 505(j)(2)(A)(iii) of the FD&C Act. FDA 
considers it important to review proposed differences in the total drug 
content or the concentration of a parenteral product because such 
changes can result in medication errors and incorrect dosing of 
patients. Accordingly, the strength of a parenteral drug product is 
determined by both criteria in paragraph (i) of the proposed 
definition--i.e., the total quantity of drug substance in a container 
closure and the concentration of the drug substance.
    For other dosage forms, the strength of the drug product is 
determined based only on the criteria in paragraph (i)(A) or (i)(B) of 
the proposed definition. For example, the strength of a solid oral 
dosage form is determined only by the total quantity of drug substance 
in a dosage unit (e.g., a 25-milligram (mg) tablet). In contrast, the 
strength of a semisolid dosage form is typically determined by the 
concentration of the drug substance. For example, the strength of a 
cream is generally expressed by the concentration as a weight/weight 
percentage reflecting the mass of the drug substance per unit mass of 
the drug product.
    We recognize that the weights and measures described in paragraph 
(i) of the proposed definition may not be applicable to all types of 
drug product or dosage forms. Accordingly, paragraph (ii) of the 
proposed definition provides that the strength of the drug product may 
be described by such other criteria as the Agency establishes for 
determining the amount of drug substance contained in, delivered, or 
deliverable from the drug product.
    It should be emphasized that the proposed definition of strength 
refers to the amount of the drug substance (active ingredient), and not 
the amount of the active moiety, in the drug product. However, we 
recognize that approved drug products formulated with a salt of an acid 
or a base (commonly referred to as ``salt drug products'') may use the 
active moiety in the name rather than the drug substance to conform 
with a drug product naming policy established by the USP. Although the 
USP naming policy describes the ``strength'' of a drug product as the 
amount of active moiety present in the product, the strength of the 
drug product for purposes of section 505(j)(2)(A)(iii) of the FD&C Act 
is the amount of the drug substance. These approaches to describing the 
strength of the drug product do not conflict because if two drug 
products containing the same drug substance are demonstrated to have 
the same ``strength'' in terms of active moiety, they will always have 
the same strength in terms of drug substance. For example, a tablet 
drug product that contains 125 mg of the drug substance ``novelpril 
maleate'' equivalent to 100 mg of the active moiety ``novelpril'' would 
be expressed as ``novelpril tablet 100 mg.'' Based on the proposed 
definition in Sec.  314.3(b), the strength of the drug product is 125 
mg of the drug substance ``novelpril maleate.'' The label for this 
product would describe both the ``strength'' expressed in terms of 
active moiety and the strength expressed in terms of drug substance. 
The Agency recognizes that this naming policy will result in situations 
in which the ``strength'' that directly follows the drug product name 
for such products will be expressed in terms of active moiety and not 
in terms of drug substance, and that this might be confusing. FDA seeks 
comment on this approach to the proposed definition of strength in 
light of these considerations.
    We also generally invite comment on whether this proposed 
definition adequately encompasses the broad range of dosage forms and 
drug products to which a proposed definition of ``strength'' in Sec.  
314.3(b) would apply.
    II.A.2.cc. Substantially complete application. The MMA defines the 
term ``substantially complete application'' for purposes of section 
505(j)(5) of the FD&C Act (see section 505(j)(5)(B)(iv)(II)(cc) of the 
FD&C Act). We are proposing to define ``substantially complete 
application'' in Sec.  314.3(b) to incorporate this statutory 
definition with minor editorial revisions. As proposed, a 
``substantially complete application'' would mean an ANDA that on its 
face is sufficiently complete to permit a substantive review and 
contains all the information required under section 505(j)(2)(A) of the 
FD&C Act and Sec.  314.94. For an application to be substantially 
complete, any information referenced in the application must have been 
provided to the Agency. For example, FDA will refuse to receive an ANDA 
for which a referenced Drug Master File has not been submitted or that 
omitted relevant stability or bioequivalence data as of the date of 
submission of the ANDA. There may be other bases for finding that an 
application is not substantially

[[Page 6817]]

complete--for example, electronic submissions that are not readable or 
do not follow FDA's recommendations for electronic application format 
may be determined to be not substantially complete and refused for 
receipt.
    In addition, we are proposing conforming revisions to Sec.  
314.101(b) to clarify that receipt of an ANDA means that FDA has made a 
threshold determination that the ANDA is substantially complete (see 
section II.J). Our proposed replacement of the current criterion 
``sufficiently complete to permit a substantive review'' with the 
synonymous term ``substantially complete application'' is not intended 
to alter the meaning. Rather, we are seeking to use defined terms 
consistently throughout our regulations.
    II.A.2.dd. Tentative approval. The MMA defines the term ``tentative 
approval'' for purposes of section 505(j)(5) of the FD&C Act to mean 
``notification to an applicant by the Secretary that an [ANDA] meets 
the requirements of [section 505(j)(2)(A)], but cannot receive 
effective approval because the application does not meet the 
requirements of [section 505(j)(5)(B)], there is a period of 
exclusivity for the listed drug under [section 505(j)(5)(F)] or section 
505A, or there is a 7-year period of exclusivity for the listed drug 
under section 527'' (section 505(j)(5)(B)(iv)(II)(dd)(AA) of the FD&C 
Act). We are proposing to define ``tentative approval'' in Sec.  
314.3(b) to incorporate the statutory text and extend this general 
definition, with appropriate conforming revisions, to include tentative 
approval of an NDA (including a 505(b)(2) application).
    Proposed Sec.  314.3(b) defines ``tentative approval'' to mean the 
notification that an NDA (including a 505(b)(2) application) or ANDA 
otherwise meets the requirements for approval under the FD&C Act, but 
cannot be approved because there is unexpired orphan drug exclusivity 
for a listed drug, or that a 505(b)(2) application or ANDA otherwise 
meets the requirements for approval under the FD&C Act, but cannot be 
approved until the conditions in Sec.  314.107(b)(1)(iii), (b)(3), or 
(c) are met, because there is a period of exclusivity for the listed 
drug under Sec.  314.108 or section 505A of the FD&C Act (21 U.S. C. 
355a), or because a court order pursuant to 35 U.S. C. 271(e)(4)(A) 
orders that the application may be approved no earlier than the date 
specified. Proposed Sec.  314.107(b)(4) describes the circumstances in 
which FDA will issue a tentative approval letter (see section 
II.M.2.d).
    The proposed definition of ``tentative approval'' clarifies that a 
drug product that is granted tentative approval is not an approved drug 
and will not be approved until FDA issues an approval letter after any 
necessary additional review of the NDA or ANDA (compare section 
505(j)(5)(B)(iv)(II)(dd)(BB) of the FD&C Act). We have proposed minor 
editorial revisions to the limitation described in the statute to 
replace references to ``effective approval'' of an NDA or ANDA with 
language reflecting our current practice. As discussed in section II.K, 
the Agency does not issue approval letters with delayed effective 
dates.
    II.A.2.ee. The list. We are proposing to revise the definition of 
``the list'' to mean the list of approved drug products published in 
FDA's current ``Approved Drug Products With Therapeutic Equivalence 
Evaluations,'' available electronically on FDA's Web site (http://www.fda.gov/cder). These clarifying revisions reflect our longstanding 
practice of relying upon the electronic version of the Orange Book 
(currently available at http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm), which is updated on a regular basis and can be accessed 
from FDA's Web site. We are proposing to delete the words ``current 
edition,'' ``any current supplement,'' and ``publication'' from the 
definition as these phrases imply reference to a printed version. As 
discussed in section II.B.3, the Agency no longer arranges for 
publication of an annual printed edition or monthly printed supplements 
to the Orange Book.
    Although the format of the electronic version of the Orange Book 
may change with advances in technology, FDA intends to maintain a 
publicly available version of the list that includes, among other 
things: Approved NDAs and ANDAs; therapeutic equivalence evaluations 
(as applicable); exclusivity granted to a listed drug; patents 
submitted for listing by the NDA holder; use codes for method-of-use 
patents; requests to remove a patent from the list; and, upon request 
on a prospective basis, the date on which patents are received by FDA 
for listing.
    II.A.2.ff. Therapeutic equivalents. We are proposing to define 
``therapeutic equivalents'' as approved drug products that are 
pharmaceutical equivalents and for which bioequivalence has been 
demonstrated. Therapeutic equivalents can be expected to have the same 
clinical effect and safety profile when administered to patients under 
the conditions of use specified in the labeling. This proposed 
definition reflects the Agency's longstanding interpretation of this 
term as set forth in section 1.2 of the preface to the Orange Book 
(33rd Edition, 2013, at vii).
II.A.3. Proposed Amendments to Definitions in Current Sec.  314.108
    As discussed in sections II.A.1, II.A.2.f, and II.A.2.n, we are 
proposing to move the definitions of the terms ``active moiety'' and 
``date of approval'' from Sec.  314.108(a) to Sec.  314.3(b). We are 
proposing to amend Sec.  314.108 to state that the definitions in Sec.  
314.3 (in addition to other definitions in Sec.  314.108) apply to 
Sec.  314.108.
    We also are proposing to add a definition of ``bioavailability 
study'' to Sec.  314.108(a) to clarify the scope of this term as used 
in section 505(c)(3)(E)(iii), (c)(3)(E)(iv), (j)(5)(F)(iii), and 
(j)(5)(F)(iv) of the FD&C Act and Sec.  314.108(b)(4) and (b)(5) 
regarding certain exclusivity determinations. The FD&C Act provides 
that a ``bioavailability study'' is not a type of ``new clinical 
investigations . . . essential to the approval of the application [or 
supplement] and conducted or sponsored by the applicant'' eligible for 
a 3-year period of exclusivity during which a 505(b)(2) application or 
ANDA may not be approved for the same conditions of approval (see 
section 505(c)(3)(E)(iii), (c)(3)(E)(iv), (j)(5)(F)(iii), and 
(j)(5)(f)(iv) of the FD&C Act; see also Sec.  314.108(b)(4) and 
(b)(5)).
    The proposed definition of ``bioavailability study'' means a study 
to determine the bioavailability or the pharmacokinetics of a drug. 
This definition incorporates by reference the revised definition of 
``bioavailability'' proposed in Sec.  314.3. This proposed revision is 
intended to clarify that a pharmacokinetic study, which generally is 
conducted in the same manner as a bioavailability study, also is not 
eligible for 3-year exclusivity. Although not specifically defined in 
part 314, the term ``pharmacokinetics'' is generally understood to 
refer to the way a drug is handled by the body, which is described by 
pharmacokinetic measures (such as area under the curve and 
concentration at the maximum) and other derived measures (such as 
clearance, half-life, and volume of distribution). The values of these 
measures reflect the absorption (A), distribution (D), and elimination 
(E) of a drug from the body. A drug can be eliminated by both 
metabolism (M) to one or more active and inactive metabolites and 
excretion of the unchanged drug. The overall set of processes is often 
referred to as ADME, which ultimately controls systemic exposure to a 
drug and its metabolites after drug administration.

[[Page 6818]]

II.A.4. Definitions in Current Sec.  320.1
    We are proposing to move the definitions in current Sec.  320.1(a) 
through (g) to Sec.  314.3(b). We are proposing this change for ease of 
reference because certain terms defined in current Sec.  320.1 already 
are set forth in other parts of our regulations (e.g., 
``bioequivalence''). Proposed Sec.  320.1 would simply state that the 
definitions in Sec.  314.3(b) apply to part 320.

II.B. Submission of Patent Information (Proposed Sec.  314.53)

II.B.1. General Requirements for Submission of Patent Information 
(Proposed Sec.  314.53(b) and (c))
    Section 314.53(b) of our regulations requires that an applicant 
submitting an NDA (including a 505(b)(2) application), an amendment to 
an NDA, or, except as provided in Sec.  314.53(d)(2), a supplement to 
an approved application, submit the patent information described in 
Sec.  314.53(c) on Forms FDA 3542a and 3542 with the filing or upon and 
after approval, respectively. The information provided in Form FDA 3542 
for any patent which claims the drug or a method of using the drug and 
with respect to which a claim of patent infringement could reasonably 
be asserted if a person not licensed by the owner engaged in the 
manufacture, use, or sale of the drug is published in the Orange Book 
after approval of the NDA or the supplement.
    In the Federal Register of April 30, 2007 (72 FR 21266), we 
responded to comments submitted to FDA regarding FDA's request for an 
extension of approval of the collection of information related to 
patent submission and listing requirements involving Forms FDA 3542a 
and 3542 (April 2007 notice). At that time, we made certain revisions 
to Forms FDA 3542a and 3542 and the instructions for completing those 
forms to clarify acceptable practices in accordance with our existing 
regulations. Other proposed changes to Forms FDA 3542a and 3542 would 
have required revisions to the regulations upon which the requirements 
in Forms FDA 3542a and 3542 are based. In sections II.B.1.a and 
II.B.2.a, we propose certain revisions to the content of patent 
information submitted to FDA and the circumstances under which 
submission of patent information is required. These changes to the 
required submission of patent information are intended to clarify the 
basis for requiring certain information, revise and streamline our 
requirements, and describe acceptable approaches to compliance with 
applicable regulations.
    Table 2 summarizes the proposed changes related to reporting 
requirements for submission of patent information:

   Table 2--Highlights of Proposed Changes Regarding Patent Reporting
                            Requirements \1\
------------------------------------------------------------------------
                                                Proposed revisions to
            Current regulations                      regulations
------------------------------------------------------------------------
General Requirements (Sec.   314.53(c)(1))  General Requirements (Sec.
                                             314.53(c)(1))
Patent information will not be accepted      Patent information
 unless it is complete and submitted on      will not be accepted unless
 the appropriate forms (Form FDA 3542a or    it is submitted on the
 3542).                                      appropriate forms (Form FDA
                                             3542a or 3542) and contains
                                             the information required in
                                             Sec.   314.53(c)(2).
Reporting Requirements (Sec.                Reporting Requirements (Sec.
 314.53(c)(2))                                 314.53(c)(2))
The required information and verification   The required information and
 in Sec.   314.53(c)(2)(i) and (c)(2)(ii)    verification in Sec.
 includes:                                   314.53(c)(2)(i) and
                                             (c)(2)(ii) includes:
     Information on whether the         Information on
     patent has been submitted previously       whether the drug
     for the NDA.                               substance patent claims
     Information on whether the         a polymorph that is the
     patent is a re-issued patent of a          same active ingredient
     patent submitted previously for            that is described in the
     listing for the NDA or supplement.         pending NDA or
                                                supplement, and, if so,
                                                has test data described
                                                in Sec.   314.53(b)(2).
                                                Information on
                                                whether the drug
                                                substance patent claims
                                                only a polymorph that is
                                                the same active
                                                ingredient that is
                                                described in the pending
                                                NDA or supplement, and,
                                                if so, has test data
                                                described in Sec.
                                                314.53(b)(2).
Method-of-Use Patents (Sec.                 Method-of-Use Patents (Sec.
 314.53(c)(2)(i)(O) and (c)(2)(ii)(P))        314.53(c)(2)(i)(O) and
                                             (c)(2)(ii)(P))
The required information and verification   The required information and
 in Sec.   314.53(c)(2)(i) and (c)(2)(ii)    verification in Sec.
 includes:                                   314.53(c)(2)(i) and
                                             (c)(2)(ii) includes:
     Information on each method-of-     Information on
     use patent including the following:        each method-of-use
                                                patent including the
                                                following:
        (2) Identification of the specific       (2) Identification of
         section of the proposed labeling         the specific
         for the drug product that                section(s) of the
         corresponds to the method of use         proposed labeling for
         claimed by the patent submitted          the drug product that
        (3) The description of the                corresponds to the
         patented method of use as                method of use claimed
         required for publication.                by the patent
                                                  submitted (if the
                                                  scope of the method-of-
                                                  use claim(s) of the
                                                  patent does not cover
                                                  every use of the drug,
                                                  the applicant must
                                                  identify only the
                                                  specific portion(s) of
                                                  the indication or
                                                  other condition of use
                                                  claimed by the
                                                  patent);
                                                 (3) The description of
                                                  the patented method of
                                                  use as required for
                                                  publication (which
                                                  must contain adequate
                                                  information to assist
                                                  505(b)(2) and ANDA
                                                  applicants in
                                                  determining whether a
                                                  listed method-of-use
                                                  patent claims a use
                                                  for which the
                                                  505(b)(2) or ANDA
                                                  applicant is not
                                                  seeking approval).
[No corresponding regulation]               Exceptions to Required
                                             Submission of Patent
                                             Information (Sec.
                                             314.53(c)(2)(i)(S) and
                                             314.53(c)(2)(ii)(T))
                                             If the applicant
                                             submits information for a
                                             patent that claims the drug
                                             substance (active
                                             ingredient) and meets the
                                             requirements for listing on
                                             that basis, then the
                                             applicant is not required
                                             to provide information on
                                             whether that patent also
                                             claims the drug product
                                             (composition/formulation).
                                             If the applicant
                                             submits information for a
                                             patent that claims the drug
                                             product (composition/
                                             formulation) and meets the
                                             requirements for listing on
                                             that basis, then the
                                             applicant is not required
                                             to provide information on
                                             whether that patent also
                                             claims the drug substance
                                             (active ingredient).

[[Page 6819]]

 
                                             However, an
                                             applicant that submits
                                             information for a method-of-
                                             use patent must also submit
                                             information regarding
                                             whether that patent also
                                             claims either the drug
                                             substance or the drug
                                             product.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
  regulations, but should not be relied upon in place of the proposed
  regulation.

    II.B.1.a. Drug substance (active ingredient) and drug product 
(formulation or composition) patents. We are proposing to revise Sec.  
314.53(c)(1) to clarify that FDA accepts patent information submitted 
on Form FDA 3542a or 3542, as appropriate, as long as the form contains 
the information required in Sec.  314.53(c). The statement in our 
current regulations that FDA ``will not accept the patent information 
unless it is complete . . .'' has generated confusion in some cases, 
particularly where a portion of the specific information requested in a 
section on FDA Form FDA 3542a or 3542 was not applicable to the patent 
for which the form was submitted. By proposing to revise Sec.  
314.53(c)(1) to state that we will not accept the patent information 
unless it ``contains the information required in paragraph (c)(2) of 
this section,'' we are clarifying that FDA will accept a submission of 
patent information on Form FDA 3542a or 3542, as appropriate, that 
omits patent information requested on the form where that omission is 
permitted under an exception in Sec.  314.53(c)(2).
    We are proposing to add Sec.  314.53(c)(2)(i)(S) and (c)(2)(ii)(T) 
to describe exceptions to the required submission of patent 
information. Proposed Sec.  314.53(c)(2)(i)(S)(1) and (c)(2)(ii)(T)(1) 
state that if a patent claims the drug substance that is the active 
ingredient in the drug product for which approval is sought or has been 
granted, respectively, and is eligible for listing in the Orange Book, 
it is not necessary for an applicant to provide information on whether 
the patent also claims the drug product. Similarly, we are proposing to 
add Sec.  314.53(c)(2)(i)(S)(2) and (c)(2)(ii)(T)(2) to provide that if 
a patent claims the drug product for which approval is sought or has 
been granted, respectively, and is eligible for listing in the Orange 
Book, it is not necessary for an applicant to provide information on 
whether the patent also claims the drug substance that is the active 
ingredient in the drug product. These proposed revisions to our 
regulations provide that an applicant need only satisfy the 
requirements for patent listing set forth in section 505(b)(1) and 
(c)(2) of the FD&C Act and, subject to Sec.  314.53(c)(2)(i)(O)(3) and 
(c)(2)(ii)(P)(4), discussed in this section of the document, need not 
identify each basis on which the patent claims the drug. The 
designation of a patent as claiming the drug substance and/or drug 
product for purposes of listing in the Orange Book is not intended to 
define the scope of the patent claims that an NDA holder or patent 
owner may assert against a 505(b)(2) or ANDA applicant based on a 
listed patent.
    Whether or not the applicant provides information stating that the 
patent claims the drug substance or the drug product, an applicant must 
submit information regarding whether the patent claims one or more 
methods of using the drug product for which approval is sought or has 
been granted (method-of-use patent). We are proposing to add Sec.  
314.53(c)(2)(i)(O)(3) and (c)(2)(ii)(P)(4) to confirm that the proposed 
exceptions to required submission of patent information do not alter 
the requirements for submission of method-of-use patent information. 
The information regarding method-of-use patents is required for 
implementation of the patent certification and statement provisions of 
the FD&C Act. Section 505(b)(2)(B) and (j)(2)(A)(viii) of the FD&C Act 
provide that a 505(b)(2) and ANDA applicant, respectively, may submit a 
statement for a method-of-use patent which does not claim a use for 
which the applicant is seeking approval, instead of a patent 
certification under section 505(b)(2)(A)(iii) or 505(j)(2)(A)(vii)(III) 
of the FD&C Act (paragraph III certification) or a paragraph IV 
certification to the listed patent. Information on whether a patent 
claims the drug substance or drug product in addition to whether the 
patent claims one or more methods of use is required because a 
505(b)(2) or ANDA applicant that avails itself of the statutory 
provision that permits it to not seek approval of a method of use 
claimed by the patent (and carve out from product labeling the method-
of-use information claimed by the patent) would still be required to 
submit a patent certification with respect to any drug substance or 
drug product claims covered by the same listed patent (see Letter from 
Janet Woodcock, M.D., Director, CDER, to Rosemarie R. Wilk-Orescan, 
Novo Nordisk Inc., and James F. Hurst, Winston & Strawn LLP, dated 
December 4, 2008, regarding Docket Nos. FDA-2008-P-0343-0009 and FDA-
2008-P-0411-0006, available at http://www.regulations.gov) (Repaglinide 
Citizen Petition Response). For example, a 505(b)(2) or ANDA applicant 
may submit a statement under section 505(b)(2)(B) or 
505(j)(2)(A)(viii), respectively, of the FD&C Act for a method-of-use 
patent that does not claim a use for which the applicant is seeking 
approval and a paragraph IV certification for any remaining drug 
substance, drug product, or other method-of-use claims covered by the 
same patent. This approach is sometimes described as a ``split 
certification'' to the patent.
    We note that a 505(b)(2) or ANDA applicant that submitted a 
paragraph IV certification in addition to a statement under section 
505(b)(2)(B) or 505(j)(2)(A)(viii) of the FD&C Act must comply with the 
notice requirements for a paragraph IV certification and may be subject 
to a 30-month stay of approval if patent infringement litigation is 
initiated within the statutory timeframe. An ANDA applicant that 
submitted a paragraph IV certification and a statement pursuant to 
section 505(j)(2)(A)(viii) of the FD&C Act to a listed patent also may 
be eligible for 180-day exclusivity based on its paragraph IV 
certification if the applicant is a ``first applicant'' and meets other 
statutory and regulatory requirements.
    II.B.1.b. Drug substance patents that claim only a polymorph of the 
active ingredient. Section 314.53(c)(2)(i)(M)(2) and (c)(2)(ii)(N)(2) 
currently require submission of information on whether the patent 
claims a polymorph (generally, a drug substance with a different 
crystalline (including solvates and hydrates) or amorphous form of the 
same drug substance) that is the same active ingredient as that 
described in the pending NDA, amendment, or supplement. We explained in 
the preamble to the June 2003 final rule that ``it would be consistent 
to interpret `drug substance' for patent submission and listing 
purposes as including certain drug substances having different physical 
forms if they would be

[[Page 6820]]

considered the same active ingredient for ANDA approval purposes'' (68 
FR 36676 at 36678).
    We are proposing to revise these regulations to state that an 
applicant is only required to provide information on whether the patent 
claims a polymorph that is the same active ingredient described in the 
pending NDA, amendment, or supplement if the only basis on which the 
patent is eligible for listing is that it claims the polymorph. Based 
on comments received from industry on this issue (see April 2007 
notice) and inquiries from applicants regarding completion of Forms FDA 
3542a and 3542, we have tentatively concluded that our regulations need 
to be modified. With respect to a patent that claims the drug substance 
or drug product described in the pending NDA, amendment, or supplement 
and one or more polymorphic forms of the drug substance, an applicant 
is not required to provide information on whether the patent claims a 
polymorph if the patent otherwise meets the statutory requirements for 
submission of patent information regarding the drug substance or drug 
product.
    Similarly, we are proposing to make conforming revisions to Sec.  
314.53(b)(1), (b)(2), (c)(2)(i)(M)(3), and (c)(2)(ii)(N)(3) to provide 
that the applicant certification regarding test data required by Sec.  
314.53(b) applies only to patents that claim only a polymorph. This 
provision also had generated confusion, and we are proposing revisions 
for clarification.
    II.B.1.c. Method-of-use patents. Section 314.53(b)(1) currently 
states that an applicant ``shall separately identify each pending or 
approved method of use and related patent claim.'' This text has been 
subject to differing interpretations by applicants as to whether our 
regulations require submission of patent information (and completion of 
Forms FDA 3542a and 3542) on a claim-by-claim basis. In the June 2003 
final rule, we explained that we require identification of individual 
patent claims for method-of-use patents to assist 505(b)(2) and ANDA 
applicants in determining whether a listed method-of-use patent claims 
a use for which the 505(b)(2) or ANDA applicant is not seeking approval 
(see 68 FR 36676 at 36682 and 36685). In the April 2007 notice, we 
clarified that ``consistent with our regulations at Sec.  314.53(b)(1), 
. . . an applicant may list together multiple patent claims for each 
pending or approved method of use. However, each pending or approved 
method of use must be separately identified and therefore will require 
separate listing(s) of method-of-use information in section 4 of Forms 
FDA 3542a and 3542. Therefore, if a patent claims one or more methods 
of use that apply to a pending application or approved product, each 
pending or approved method of use would need to be listed separately 
along with the patent claim number(s) for the patent claim(s) for the 
pending or approved method of use. A single Form FDA 3542a or Form FDA 
3542, as appropriate, may be used to list a patent claiming more than 
one method of use, provided that each method of use is listed 
separately along with the patent claim number(s) for the patent 
claim(s) for the pending or approved method of use. This regulatory 
approach accomplishes the statutory objective of providing adequate 
information to permit ANDA and 505(b)(2) applicants to file statements 
which assert that the method-of-use patent does not claim a use for 
which the applicant is seeking approval'' (72 FR 21266 at 21268).
    We are proposing to revise Sec.  314.53(b)(1) by replacing the word 
``claim'' with ``claim(s)'' in the phrase ``shall separately identify 
each pending or approved method of use and related patent claim.'' This 
proposed revision is intended to further clarify that an applicant may 
list together multiple patent claims for a pending or approved method 
of use on Forms FDA 3542a and 3542, respectively. However, each pending 
or approved method of use must be separately identified and therefore 
will require separate listing(s) of method-of-use information in 
section 4 of Forms FDA 3542a and 3542.
    We also are proposing to revise Sec.  314.53(b)(1), 
(c)(2)(i)(O)(2), (c)(2)(ii)(P)(2) and (c)(2)(ii)(P)(3) to enhance 
compliance by NDA applicants with the requirements for identifying the 
specific section(s) of product labeling that correspond to the method 
of use claimed by the patent and, upon approval, describing the 
approved method of use claimed by the patent, as required for 
publication in the Orange Book. Proposed Sec.  314.53(b)(1) would 
expressly require that if the scope of the method-of-use claim(s) of a 
patent does not cover every use of the drug, the applicant must 
identify only the specific sections of product labeling that correspond 
to the specific portion(s) of the indication or other condition of use 
claimed by the patent. The specific product labeling that corresponds 
to the protected use may appear in sections of the labeling other than 
``Indications and Usage.'' This proposed revision and conforming 
revisions to proposed Sec.  314.53(c)(2)(i)(O)(2) and (c)(2)(ii)(P)(2) 
would address situations in which the scope of the method of use 
claimed by the patent is narrower than the indication or other 
condition of use described in product labeling. In such cases, the NDA 
applicant must identify only the specific sections of product labeling 
that correspond to the portion(s) of the indication or other condition 
of use claimed by the patent and not the broader indication or other 
condition of use in the product labeling which may include, but not be 
limited to, the use claimed by the patent. Accurate identification of 
the specific sections of product labeling that correspond to the use 
claimed by the patent is necessary to enable FDA to implement section 
505(b)(2)(B) and (j)(2)(A)(viii) of the FD&C Act, which permit 
505(b)(2) and ANDA applicants to omit protected conditions of use from 
labeling. This information regarding product labeling also is necessary 
for FDA to evaluate whether the omission of aspects of the listed 
drug's labeling protected by patent would render the proposed drug 
product less safe or effective than the listed drug for all remaining 
non-protected conditions of use and preclude approval (see Sec.  
314.127(a)(7); see also Sec.  314.94(a)(8)(iv)).
    Proposed Sec.  314.53(c)(2)(ii)(P)(3) would codify our longstanding 
requirement that the NDA applicant's description of the patented method 
of use (the ``use code'') required for publication in the Orange Book 
must contain adequate information to assist FDA and 505(b)(2) and ANDA 
applicants in determining whether a listed method-of-use patent claims 
a use for which the 505(b)(2) or ANDA applicant is not seeking 
approval. If the scope of the method-of-use claim(s) of the patent does 
not cover every approved use of the drug, the NDA holder's ``use code'' 
must contain only the specific portion(s) of the indication or other 
method of use claimed by the patent. This requirement is necessary to 
effectively implement the statutory provisions that permit 505(b)(2) 
and ANDA applicants to submit a statement that the applicant is not 
seeking approval for the use claimed in the listed patent instead of a 
patent certification to the listed patent with respect to the method of 
use claim(s) (see section 505(b)(2)(B) and (j)(2)(C)(viii) of the FD&C 
Act, respectively). We require the NDA holder to submit an accurate 
description, subject to the verification requirements in Sec.  
314.53(c)(2)(ii)(R), of the method of use within the scope of the 
patent that claims an approved use of the drug to implement these 
statutory provisions. As the U.S. Supreme Court noted in Caraco Pharm. 
Labs. v. Novo

[[Page 6821]]

Nordisk A/S: ``An overbroad use code . . . throws a wrench into the 
FDA's ability to approve generic drugs as the statute contemplates'' 
(132 S. Ct. 1670, at 1684 (2012)).
    II.B.1.d. Patents previously submitted for listing. We are 
proposing to revise Sec. Sec.  314.53(c)(2)(i)(J) and (c)(2)(ii)(K) to 
remove the requirement that an applicant provide information regarding 
whether the patent has been submitted previously for the NDA or 
supplement. This requirement was intended to assist the Orange Book 
staff with their administrative listing responsibilities (see 68 FR 
36676 at 36686). In response to a request for clarification of the 
purpose of this inquiry (see 72 FR 21266 at 21269) and to streamline 
the patent information submission requirements, we are proposing to 
revise Sec. Sec.  314.53(c)(2)(i)(J) and (c)(2)(ii)(K) to request 
information on whether the patent is a reissuance of a patent submitted 
previously for listing in the Orange Book for the NDA or supplement, 
including the original patent number of the listed patent (see section 
II.B.1.e).
    If a patent has been submitted previously for listing in the Orange 
Book, we currently request information on whether the expiration date 
is a new expiration date (Sec.  314.53(c)(2)(i)(K) and (c)(2)(ii)(L)). 
For example, a patent expiration date may be extended after NDA 
approval in response to a request for patent term restoration pursuant 
to 35 U.S.C. 156 (see proposed Sec.  314.53(f)(2)(ii), discussed in 
section II.B.4.b). We are continuing to request this information.
    We note that our proposed revisions to the patent information 
submission requirements for supplements to an approved NDA (see section 
II.B.2.a) are designed to identify, among other things, whether patents 
previously submitted for listing for the underlying NDA continue to 
claim the changed product as approved in the supplement.
    II.B.1.e. Reissued patents. We are proposing certain revisions to 
our regulations to describe our requirements regarding submission of 
information related to patents that have been reissued by the PTO. 
Generally, a patent may be reissued to correct certain errors in the 
scope of claims or defects in a specification or drawing that otherwise 
would have invalidated, in whole or in part, the patent (see 35 U.S.C. 
251). Accordingly, a reissued patent may affect both the patent 
certification or statement submitted by a 505(b)(2) or ANDA applicant 
and the infringement claims that could be asserted by the patent owner 
or NDA holder.
    Although we recognize that the original patent is surrendered upon 
patent reissuance (see 37 CFR 1.178(a)), we are proposing to treat the 
original patent and the reissued patent as a ``single bundle'' of 
patent rights, albeit patent rights that may have changed with 
reissuance, for purposes of administering the patent certification 
requirements of the FD&C Act and any 30-month stay of approval or 180-
day exclusivity that relates to a paragraph IV certification to the 
original patent (see discussion in section II.E.4). FDA's role in 
listing patents remains ministerial (see 59 FR 50338 at 50349, October 
3, 1994 (1994 final rule); 68 FR 36676 at 36687 (June 2003 final 
rule)); however, we are mindful of the implications of reissued patents 
in fulfilling our statutory obligations regarding implementation of the 
patent certification and statement, 30-month stay, 180-day exclusivity, 
and tentative approval provisions of the FD&C Act. We are proposing 
these revisions to describe the responsibilities of an NDA applicant 
associated with listing a reissued patent. The requirements for a 
505(b)(2) or ANDA applicant to provide an appropriate patent 
certification or statement to a reissued patent are discussed in 
section II.E.4).
    We currently receive submissions of patent information for reissued 
patents and list those patents that are eligible for listing in the 
Orange Book. Reissued patents are identified by the PTO with the 
letters ``RE'' preceding the patent number and, because a patent is 
reissued for the unexpired part of the term of the original patent, 
have the same expiration date as the original patent. If the scope of 
claims was narrowed or broadened upon reissuance, the NDA applicant or 
holder may submit a reissued patent for listing in the Orange Book with 
a revised designation of whether the patent claims the drug substance, 
drug product, and/or a method or use, or with a revised use code.
    Proposed Sec.  314.53(c)(2)(i)(J) and (c)(2)(ii)(K) would provide 
that an NDA applicant or holder is required to include information on 
whether a patent submitted for listing is a reissuance of a patent 
previously submitted for listing for the NDA or supplement. Submission 
of patent information for reissued patents is subject to the 30-day 
timeframe for timely filed patent information set forth in section 
505(c)(2) of the FD&C Act. As discussed further in section II.B.2.b, 
the timely filing of patent information for a reissued patent 
(including a reissued patent with a broadened scope of claims) does not 
alter the patent certification obligations of a 505(b)(2) or ANDA 
applicant whose application was pending when the original patent was 
filed by the holder of an approved application for listing more than 30 
days after patent issuance (``late listed''). In other words, if a 
505(b)(2) or ANDA applicant is not required to provide a patent 
certification or statement to the original patent pursuant to Sec.  
314.50(i)(4) or Sec.  314.94(a)(12)(vi) because the patent was late 
listed, the 505(b)(2) or ANDA applicant would not be required to 
provide a patent certification or statement to the reissued patent even 
if timely filed following reissuance. This approach recognizes that the 
original and reissued patents comprise a ``single bundle'' of patent 
rights, which first became relevant to approval of 505(b)(2) 
applications and ANDAs with the submission of the patent information 
prior to reissuance. As described in section II.E.3, the date of 
submission of the original patent information also determines the 
availability of a 30-month stay arising from patent infringement 
litigation resulting from notice of a paragraph IV certification to the 
original or reissued patent (see section 505(c)(3)(C) and 
(j)(5)(B)(iii) of the FD&C Act).
    An original patent that has been reissued would remain listed in 
the Orange Book until FDA determined that any first ANDA applicant is 
no longer eligible for 180-day exclusivity or the 180-day exclusivity 
period has expired (see section II.E.4). We intend to designate 
original patents that have been reissued and remain listed in the 
Orange Book for this reason with the suffix ``*RE'' based on 
information submitted by the NDA applicant or holder in accordance with 
Sec.  314.53(c)(2)(ii)(K). In the absence of this designation, an 
applicant that submits an ANDA after a reissued patent is listed in the 
Orange Book may not provide a patent certification or statement with 
respect to the original patent. Instead, the ANDA applicant must 
provide a patent certification or statement to the reissued patent.

[[Page 6822]]

    Should the scope of a reissued patent be narrowed such that it is 
no longer eligible for listing under section 505(b)(1) or 505(c)(2) of 
the FD&C Act, the NDA holder is required to request that the patent or 
patent information be removed from listing in the Orange Book (``patent 
delisting''), subject to the exceptions set forth in proposed Sec.  
314.53(f)(2) (see discussion in section II.B.4.b).
II.B.2. When and Where To Submit Patent Information (Proposed Sec.  
314.53(d))
    Table 3 summarizes the proposed changes regarding when and where to 
submit patent information:

 Table 3--Highlights of Proposed Changes Regarding Submission of Patent
                             Information \1\
------------------------------------------------------------------------
                                              Proposed revisions to
          Current regulations                      regulations
------------------------------------------------------------------------
Supplements (Sec.   314.53(d)(2)(i))...  Supplements (Sec.
                                          314.53(d)(2)(i)).
 Applicant must submit patent     Applicant must submit
 information required under Sec.          patent information required
 314.53(c) for a patent that claims the   under Sec.   314.53(c) for a
 drug, drug product, or method of use     patent that claims the drug
 for which approval is sought in a        substance, drug product, or
 supplement:                              method of use for which
(A) to change the formulation;.........   approval is sought in a
(B) to add a new indication or other      supplement:
 condition of use;.                      (A) to change the dosage form
(C) to change the strength;............   or route of administration;
(D) to make any other patented change    (B) to change the strength; or
 regarding the drug, drug product, or    (C) to change the drug product
 method of use..                          from prescription to OTC use.
Supplements (Sec.   314.53(d)(2)(ii))..  Supplements (Sec.
If an applicant submits a supplement      314.53(d)(2)(ii)).
 for a change described in Sec.          If an applicant submits a
 314.53(d)(2)(i), the following patent    supplement for a change other
 information submission requirements      than one described in Sec.
 apply:.                                  314.53(d)(2)(i), the following
                                          patent information submission
                                          requirements apply:
     If previously submitted      If previously
     patent information claims the        submitted patent information
     changed product, the applicant       claims the changed product,
     must submit a certification with     the applicant is not required
     the supplement identifying the       to resubmit this patent
     patents that claim the changed       information unless the
     product.                             description of the patented
                                          method of use would change
                                          upon approval of the
                                          supplement, and FDA will
                                          continue to list this patent
                                          information for the product;
     If no patents, including     If previously
     previously submitted patents,        submitted patent information
     claim the changed product, it must   no longer claims the changed
     so certify.                          product, the applicant must
                                          submit a request to remove
                                          that patent information from
                                          the list at the time of
                                          approval of the supplement;
                                          If one or more
                                          existing drug substance, drug
                                          product, or method-of-use
                                          patents claim the changed drug
                                          product for which approval is
                                          sought in the supplement and
                                          such patent information has
                                          not been submitted to FDA, the
                                          applicant must submit the
                                          patent information required
                                          under Sec.   314.53(c).
Patent information deadline (Sec.        Newly issued patents (Sec.
 314.53(d)(3)).                           314.53(d)(3)).
     If a patent is issued for    If a patent is issued
     a drug, drug product, or method of   for a drug substance, drug
     use after an application is          product, or method of use
     approved, the applicant must         after an NDA is approved, the
     submit to FDA the required patent    applicant must submit to FDA
     information within 30 days of the    the required patent
     date of patent issuance.             information within 30 days of
                                          the date of patent issuance.
                                          If the required patent
                                          information is not submitted
                                          within 30 days of patent
                                          issuance, FDA will list the
                                          patent, but patent
                                          certifications will be
                                          governed by the provisions
                                          regarding untimely filed
                                          patents at Sec.  Sec.
                                          314.50(i)(4) and (i)(6) and
                                          314.94(a)(12)(vi) and
                                          (a)(12)(viii).
Late submission of patent information    Untimely filing of patent
 (Sec.  Sec.   314.50(i)(4) and           information (Sec.  Sec.
 314.94(a)(12)(vi)).                      314.50(i)(4) and
                                          314.94(a)(12)(vi)).
     [Provision directed to       Except as provided in
     submission of required patent        Sec.   314.53(f)(1), an NDA
     information in general.].            holder's amendment to the
                                          description of the approved
                                          method(s) of use claimed by
                                          the patent will be considered
                                          untimely filing of patent
                                          information if:
                                         --the amendment is submitted
                                          more than 30 days after patent
                                          issuance and it is not related
                                          to a corresponding change in
                                          approved product labeling; or
                                         --the amendment is submitted
                                          more than 30 days after a
                                          corresponding change in
                                          approved product labeling.
Copies (Sec.   314.53(d)(4))...........  Submission of Forms FDA 3542a
                                          and 3542 (Sec.
                                          314.53(d)(4)).
     Applicant must submit an     Applicant must submit
     archival copy and a copy for the     patent information required by
     chemistry, manufacturing, and        Sec.   314.53(c)(1) and
     controls (CMC) section of the        (c)(2)(i), Sec.   314.50(h),
     review copy to the CDER Central      or Sec.   314.70(f) on Form
     Document Room.                       FDA 3542a to the CDER Central
                                          Document Room at the address
                                          identified on FDA's Web site.
                                         [cir] Form FDA 3542a should not
                                          be submitted to the Orange
                                          Book Staff in the Office of
                                          Generic Drugs.
     Applicant must submit        Applicant must submit
     patent information by letter         patent information required by
     separate from, but at the same       Sec.   314.53(c)(1) and
     time as, submission of the           (c)(2)(ii) on Form FDA 3542 to
     supplement.                          the Office of Generic Drugs,
                                          Document Room, Attention:
                                          Orange Book Staff.
Submission date (Sec.   314.53(d)(5))..  Submission date (Sec.
                                          314.53(d)(5)).
     Patent information will be   Patent information
     considered submitted to FDA as of    will be considered submitted
     the date the information is          to FDA for purposes of Sec.
     received by the Central Document     314.53(d)(3) as of the earlier
     Room.                                of the date the information
                                          submitted on Form FDA 3542 is
                                          date-stamped by the Office of
                                          Generic Drugs, Document Room,
                                          or officially received
                                          electronically by FDA through
                                          the Electronic Submissions
                                          Gateway.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
  regulations, but should not be relied upon in place of the proposed
  regulation.


[[Page 6823]]

    II.B.2.a. Submission of patent information for NDA supplements 
(proposed Sec.  314.53(d)(2)). We are proposing to revise the 
requirements for submission of patent information for NDA supplements 
to reduce duplicative submissions of patent information and enhance 
efficiency.
    Section 314.53(c) requires submission of patent information for 
certain types of supplements that relate to the drug product or a 
method of using the drug product, namely those supplements that seek 
approval to change the formulation, add a new indication or other 
condition of use, change the strength, or make any other patented 
change regarding the drug, drug product, or any method of use (see 
Sec.  314.53(d)(2)(i)(A) through (d)(2)(i)(D)). This approach avoided 
unnecessary resubmission of patent information with supplements that 
did not involve a change to the drug product or a method of using the 
product or involved a change that could not be patented (see 54 FR 
28872 at 28910, July 10, 1989; and 59 FR 50338 at 50344). We are 
proposing to eliminate certain of these patent information submission 
requirements for supplements that seek approval for a change to an 
approved product and for which existing patents listed in the Orange 
Book for the specific drug product that is the subject of the 
supplement continue to claim the changed product (see proposed Sec.  
314.53(d)(2)(ii)(A)). These proposed revisions to our regulations also 
address a comment submitted by an association representing research-
based pharmaceutical and biotechnology companies that ``submission of 
Forms FDA 3542a and 3542 with submission and upon approval, 
respectively, of an NDA supplement is redundant where the information 
has not changed since the form last was filed, imposes a burden on 
sponsors, and serves no statutory purpose'' (72 FR 21266 at 21270).
    Our proposed revisions to Sec.  314.53(d)(2) would create two broad 
categories of supplements for purposes of patent information submission 
based on whether the supplement is a type for which approval would 
result in a new entry in the Orange Book. For supplements that seek 
approval for a change that will result in a new entry in the Orange 
Book (e.g., a change to the dosage form, route of administration, 
strength (including changes to concentration or total drug content), or 
prescription drug status (i.e., change the drug product from 
prescription use to over-the-counter (OTC) use)), an applicant must 
continue to submit patent information required under Sec.  314.53(c) 
with submission of the supplement and following approval, respectively. 
Although these types of changes may not necessarily result in a 
submission of different patent information, by requiring an NDA holder 
to submit complete patent information for a supplement that, if 
approved, would result in a new entry in the Orange Book, we ensure 
that patent information listed for the new entry clearly expresses the 
NDA holder's view regarding which patent(s) claim the drug or a method 
of using the drug as approved in the supplement. For example, different 
strengths of a drug product may have different patent coverage with 
respect to method-of-use patents that claim a dosing regimen or 
indication. In such a case, patent information would be required to be 
submitted with the filing of the NDA supplement and would be required 
to be submitted upon approval of the NDA supplement. This submission of 
patent information on Forms FDA 3542a and 3542 would, among other 
things, identify with specificity the new method of use claimed by the 
patent with reference to the proposed or approved labeling, 
respectively, for the drug product. If the patents listed for the 
approved NDA also claim the drug or method of using the drug for which 
approval is sought in the NDA supplement, we will permit an applicant 
to submit a statement declaring that the patents currently listed for a 
specific NDA (identified by NDA number and product number as listed in 
the Orange Book) also claim the drug or method of using the drug for 
which approval is sought in the NDA supplement, if this statement is 
accompanied by the signed patent declaration verification required by 
Sec.  314.53(c)(2)(i)(Q) and (c)(2)(ii)(R) and if patent information 
required by Sec.  314.53(c)(2)(ii) previously was submitted (see June 
2003 final rule (68 FR 36676 at 36681)). This proposed approach 
fulfills the statutory requirements for patent listing set forth in 
section 505(b)(1) and (c)(2) of the FD&C Act and ensures that patents 
listed for separate entries for drug products in the Orange Book are 
supported by an unambiguous submission of applicable patent 
information.
    It should be noted that proposed Sec.  314.53(d)(2)(i)(A) is 
intended to encompass only the types of changes in dosage form or route 
of administration that may be submitted as an NDA supplement and does 
not apply to proposed changes in dosage form or route of administration 
that should be submitted as a separate application (see guidance for 
industry entitled ``Submitting Separate Marketing Applications and 
Clinical Data for Purposes of Assessing User Fees'' (December 2004), 
available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM079320.pdf) 
(Separate Marketing Application Guidance). Similarly, we note that 
proposed Sec.  314.53(d)(2)(i)(C) describes supplements to change the 
drug product from prescription use to OTC status for all conditions of 
use, because a separate marketing application would be required for a 
change to OTC status for fewer than all conditions of use.
    Our proposal would eliminate the automatic requirement for 
submission of patent information with a supplement seeking approval for 
a change in formulation or new indication or other condition of use 
(except for those conditions of use described in Sec.  
314.53(d)(2)(i)). However, new submission of patent information would 
still be required if the patent(s) that claim the product as changed by 
the supplement differ from the patent(s) currently listed for the drug 
product. For supplements that seek approval for a change to a listed 
product that would not result in a new entry in the Orange Book (i.e., 
a change other than one of the changes described in proposed Sec.  
314.53(d)(2)(i)), an applicant needs to evaluate whether each patent 
for which information is currently listed in the Orange Book for the 
drug product continues to claim the changed product. If existing 
patents listed for the product approved in the original application 
claim the product as changed by the supplement, the applicant is not 
required to resubmit this patent information unless the description of 
the method of use claimed by a patent would change upon approval of the 
supplement (see proposed Sec.  314.53(d)(2)(ii)(A)). (In this regard, 
we note that an untimely filed patent that claims the product approved 
in the original application cannot be transformed into a timely filed 
patent with submission of a supplement.)
    If, however, a listed patent no longer claims the product as 
changed by the supplement (e.g., a new formulation is no longer claimed 
by a patent listed for the original formulation of the drug product), 
then the applicant must submit a request to correct or remove the 
patent information from the list in accordance with proposed Sec.  
314.53(f)(2) at the time of approval of the supplement. 
Correspondingly, if one or more existing patents claim the product

[[Page 6824]]

as changed by the supplement (e.g., a supplement seeking approval for a 
new indication) and this patent information has not been submitted to 
FDA, the applicant must submit the patent information with the 
supplement and following approval. The requirement in proposed Sec.  
314.53(d)(2)(ii)(C) also would apply to submission of patent 
information for a patent currently listed for the drug as approved in 
the original application that claims the drug approved in the 
supplement in a new way (e.g., a new or additional method of use) and 
for which the patent information would be required to be submitted 
under Sec.  314.53(c). In this case, the applicant would be required to 
comply with Sec.  314.53(c) and submit patent information describing 
the new or additional method of use claimed by the patent with the 
supplement and following approval.
    As noted previously in this section of the document, the Agency has 
received comments criticizing as redundant the requirement for 
submission of Forms FDA 3542a and 3542 with submission and upon 
approval, respectively, of an NDA supplement where the information has 
not changed since the form last was filed (see April 2007 notice). 
Section 505(b)(1) of the FD&C Act requires the submission of patent 
information with the filing of a supplement to an NDA. To the extent 
that patents currently listed for the drug product continue to claim 
the product as changed by the supplement, we interpret the statute to 
not require resubmission of duplicative patent information. In 
circumstances other than those described in proposed Sec.  
314.53(d)(2)(ii)(A), an applicant or sponsor must submit required 
patent information with submission and upon approval of a supplement. 
This requirement facilitates the prompt listing of patent information 
postapproval by requiring applicants to complete their initial 
assessment of relevant patents with submission of their application and 
during the pendency of its review.
    We are proposing a conforming revision to Sec.  314.70(f) to 
clarify that an applicant that submits a supplement to an NDA 
(including a 505(b)(2) application) also must comply with the patent 
information requirements under Sec.  314.53.
    II.B.2.b. Untimely filing of patent information (proposed 
Sec. Sec.  314.53(d)(3), 314.50(i)(4), and 314.94(a)(12)(vi)). We are 
proposing to supplement Sec.  314.53(d)(3) to expressly describe our 
longstanding practice with respect to listing untimely filed patents. 
Proposed Sec.  314.53(d)(3) states that if the required patent 
information is not submitted within 30 days of the issuance of the 
patent, FDA will list the patent, but patent certifications will be 
governed by the provisions regarding untimely filed patents in 
Sec. Sec.  314.50(i)(4) and (i)(6) and 314.94(a)(12)(vi) and 
(a)(12)(viii) of this part. We also are proposing to revise Sec. Sec.  
314.50(i)(4) and 314.94(a)(12)(vi) to include certain amendments to the 
description of the approved method(s) of use claimed by the patent 
within the category of untimely filed patent information.
    Section 505(c)(2) of the FD&C Act requires an NDA holder to file 
patent information for a patent issued after the date of approval of 
the application within 30 days of patent issuance. (As clarified in 
proposed Sec.  314.53(c)(2)(ii), this statutory requirement for timely 
filing does not apply to patent information submitted prior to approval 
of an NDA or supplement, even if the patent information is submitted to 
FDA more than 30 days after the patent is issued by the PTO.)
    Section 505(c)(2) of the FD&C Act further directs the Agency to 
publish information on the newly-issued patent upon its submission, and 
we have interpreted this statutory provision to require listing in the 
Orange Book irrespective of whether the patent information has been 
timely filed. Although we list untimely filed patents pursuant to 
section 505(c)(2) of the FD&C Act, we generally do not require an 
applicant with a pending 505(b)(2) application or ANDA to provide a 
patent certification to a patent for which the NDA holder failed to 
comply with the statutory timeframe for submission of patent 
information after approval. Accordingly, the untimely filed patent will 
neither delay approval of a pending 505(b)(2) application or ANDA until 
patent expiration nor necessitate a carve-out of information related to 
a patented method of use.
    Although an applicant with a pending 505(b)(2) application or ANDA 
that references the drug product generally would not be required to 
submit a patent certification to an untimely filed patent that was 
late-listed as to the pending 505(b)(2) application or ANDA, we would 
permit an applicant to submit and maintain a patent certification 
(including a paragraph IV certification) or a statement pursuant to 
section 505(b)(2)(B) or 505(j)(2)(B)(viii) of the FD&C Act, if desired. 
For example, a 505(b)(2) or ANDA applicant may wish to submit a 
paragraph IV certification to challenge the late-listed patent and 
obtain patent certainty (i.e., determine whether the NDA holder or 
patent owner will initiate a patent infringement action against the 
applicant) instead of possibly marketing at risk.
    We also are proposing to revise Sec. Sec.  314.50(i)(4) and 
314.94(a)(12)(vi) to state that, except as provided in Sec.  
314.53(f)(1), an NDA holder's amendment to the description of the 
approved method(s) of use claimed by the patent will be considered 
untimely filing of patent information if:
     The amendment is submitted more than 30 days after patent 
issuance and it is not related to a corresponding change in approved 
product labeling or
     the amendment is submitted more than 30 days after a 
corresponding change in approved product labeling.

This proposed revision is consistent with the objective of ensuring 
that prospective 505(b)(2) and ANDA applicants have timely notice of 
changes to the asserted patent coverage for a listed drug. In addition, 
proposed Sec. Sec.  314.50(i)(4) and 314.94(a)(12)(vi) would complement 
proposed revisions to Sec.  314.53 that are intended to enhance NDA 
holders' compliance with the requirement to accurately identify the 
specific sections of product labeling that correspond to the use 
claimed by the patent (see section II.B.1.c). If an amendment to change 
the patent use code is not related to a corresponding change in 
approved product labeling and is submitted more than 30 days after 
patent issuance (or patent reissuance), then the patent information is 
properly considered untimely filed. In accordance with Sec. Sec.  
314.50(i)(4) and 314.94(a)(12)(vi), an untimely filed method-of-use 
patent does not require a patent certification or statement and would 
not delay approval of a pending 505(b)(2) application or ANDA. 
Similarly, if an amendment to change the patent use code is submitted 
more than 30 days after a corresponding change in approved product 
labeling, then the amendment lacks a clear temporal or substantive link 
to the specific section(s) of approved product labeling claimed by the 
patent, and the patent information is untimely filed.
    An applicant with a pending 505(b)(2) application or ANDA that 
seeks to confirm that a newly listed patent was untimely filed (and may 
not require a patent certification in accordance with Sec.  
314.50(i)(4) or Sec.  314.94(a)(12)(vi)) should contact the Orange Book 
staff. Irrespective of whether the patent was untimely filed (and thus 
late-listed as to the pending 505(b)(2) application or ANDA) or timely 
filed (and thus ``later listed'' as to the pending 505(b)(2) 
application or ANDA), a paragraph IV certification submitted for a 
patent filed with FDA after the date on which a

[[Page 6825]]

505(b)(2) application or ANDA (that is later determined to be 
substantially complete) was submitted will not give rise to a 30-month 
stay (see section 505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act and 
section II.G).
    We note, however, that a 505(b)(2) application or ANDA submitted 
after the untimely filed patent is listed in the Orange Book is 
required to submit an appropriate patent certification or statement to 
the patent. As we explained in the 1994 final rule, ``[t]he approach 
adopted by the Agency as best embodying the compromise adopted by 
Congress requires that if an NDA applicant submits required patent 
information on an approved drug product more than 30 days after 
issuance of the patent, FDA will publish the untimely information, but 
will not require ANDA and 505(b)(2) applicants with pending 
applications that have previously submitted a certification, i.e. those 
applicants that would be prejudiced by the late submission, to 
recertify to the new patent. Only applicants that initially submit 
ANDA's or 505(b)(2) applications after the submission of the patent 
information or whose pending applications do not contain a valid 
certification at the time of submission would be required to submit a 
certification as to that patent. . . . While this could result in two 
categories of ANDA's for a pioneer drug, those without certifications 
for the late-filed patent and those with certifications for that 
patent, this approach is the best means for discouraging manipulation 
of the patent filing scheme and providing optimum notice of applicable 
patents'' (59 FR 50338 at 50340, response to comment 7).
    We remind NDA holders that patents issued after approval of a drug 
under section 505(c) of the FD&C Act include reissued patents (see 
section II.B.1.e) as well as patents that claim a drug product listed 
in the discontinued section of the Orange Book. With reference to the 
latter category, we note that a 505(b)(2) or ANDA applicant may rely 
upon a drug product listed in the discontinued section of the Orange 
Book to the extent that the product was not withdrawn for reasons of 
safety or effectiveness (see Sec.  314.151 with respect to ANDAs). 
Accordingly, we encourage NDA holders to ensure that they continue to 
comply with the statutory requirements for patent listing for products 
that have been discontinued from marketing.
    We also are proposing to revise Sec.  314.50(i)(4) to remove an 
incorrect reference to the possible submission of a certification under 
Sec.  314.50(i)(1)(ii) after the NDA holder's untimely filing of patent 
information. If a 505(b)(2) applicant is required to submit a patent 
certification to untimely filed patent information as provided in 
proposed Sec.  314.50(i)(4), a ``no relevant patents'' statement under 
Sec.  314.50(i)(1)(ii) would not be an acceptable patent certification.
    Finally, we are proposing to revise the heading for Sec.  
314.53(d)(3) to ``newly issued patents'' to better characterize the 
text and emphasize its applicability to patents issued after approval 
of an NDA or supplement. We also are proposing to revise the heading 
for proposed Sec. Sec.  314.50(i)(4) and 314.94(a)(12)(vi) to 
``untimely filing of patent information'' and to make conforming 
revisions to the text of these sections for consistent use of 
terminology.
    II.B.2.c. Where to send submissions of Forms FDA 3542a and 3542 
(proposed Sec.  314.53(d)(4)). We are proposing to require that patent 
information filed on Form FDA 3542 upon and after approval of an NDA or 
supplement be submitted directly to the Orange Book staff through the 
OGD Document Room. The Orange Book staff will send an archival copy of 
this patent information to CDER's Central Document Room for filing with 
the NDA.
    Our proposal to require that NDA holders submit post-approval 
patent information directly to the Orange Book staff is intended to 
facilitate prompt listing of patent information in the Orange Book 
after Form FDA 3542 has been officially received by the Agency. 
Currently, many NDA holders submit a duplicate or courtesy copy of Form 
FDA 3542 to the Orange Book staff electronically or via facsimile at 
the time of their submission of Form FDA 3542 to CDER's Central 
Document Room. This patent information is listed in the Orange Book 
upon receipt by the Orange Book staff, and the Orange Book explains 
that the date on which patent information is published ``may not 
reflect the official receipt date as described in 21 CFR 
314.53(d)(5).'' However, this practice may result in publication of 
patent information prior to receipt by the official repository 
identified in our regulations and cause confusion for prospective first 
applicants and applicants with a pending 505(b)(2) application or ANDA 
seeking to determine whether or not the patent is late-listed. Proposed 
Sec.  314.53(d)(4) designates the OGD Document Room as an official 
repository for submissions of Form FDA 3542, and proposed Sec.  
314.53(d)(5) (see section II.B.2.d) clarifies that the submission date 
of patent information provided by an NDA holder after approval of an 
application is the earlier of the date on which Form FDA 3542 is date-
stamped by the OGD Document Room or officially received electronically 
by FDA though the Electronic Submissions Gateway. These proposed 
revisions to the regulations are intended to enhance efficiency and 
ensure that patent information is promptly listed after its receipt.
    We note, however, that patent information submitted on Form FDA 
3542a with the filing of an NDA, amendment, or supplement, and prior to 
approval of the application must continue to be submitted directly to 
the NDA as required by Sec.  314.50(h) or Sec.  314.70(f), as 
appropriate. An applicant should not submit a copy of Form FDA 3542a to 
the Orange Book staff; the Orange Book staff should only receive patent 
information submitted after approval of the NDA or supplement. An 
applicant should not submit a copy of the patent to FDA with submission 
of Form FDA 3542a or 3542.
    II.B.2.d. Submission date of patent information (proposed Sec.  
314.53(d)(5)). We are proposing to revise Sec.  314.53(d)(5) to 
clarify, for purposes of Sec.  314.53(d)(3), that the submission date 
of patent information provided by an NDA holder after approval of an 
application is the earlier of the date on which Form FDA 3542 is date-
stamped by the OGD Document Room or officially received electronically 
by FDA though the Electronic Submissions Gateway (i.e., at the 
completion of electronic transmission). Our current regulations state 
that the information shall be considered submitted to FDA on the date 
it is received by the Central Document Room. We note that patent 
information sent to another location at FDA is not considered received 
by FDA for purposes of Sec.  314.53(d)(3) on timely filing and a 
505(b)(2) or ANDA applicant's patent certification obligations pursuant 
to Sec.  314.50(i)(4) and (i)(6) or Sec.  314.94(a)(12)(vi) and 
(a)(12)(viii), respectively, unless it is sent to the official 
repository identified in the regulation.
    These proposed revisions are intended to remove any ambiguity about 
the date of submission in light of the implications of untimely filing 
of patent information on the patent certification obligations of 
505(b)(2) applicants and ANDA applicants that rely upon the listed drug 
(see Sec. Sec.  314.50(i)(4) and 314.94(a)(12)(vi)). In this regard, we 
note that the patent certification obligations of a 505(b)(2) or ANDA 
applicant arise upon the receipt by the official repository at FDA of 
the NDA holder's submission of patent information for a listed drug 
rather than the timing of publication of the patent

[[Page 6826]]

information in the Orange Book (see section 505(b)(2)(A) and 
(j)(2)(A)(vii) of the FD&C Act; see also Teva Pharms., USA, Inc. v. 
Leavitt, 548 F.3d 103, at 108 (D.C. Cir. 2008) (noting that FDA ``has 
consistently required ANDA applicants to certify to patents recently 
submitted to FDA, even if FDA had not yet published the patent in any 
version of the Orange Book'')).
    However, for purposes of eligibility for 180-day exclusivity, an 
ANDA applicant is not permitted to submit a paragraph IV certification 
to a patent (e.g., a recently issued patent that claims the RLD) before 
the first working day after the day the patent is listed in the Orange 
Book (see section II.D.1.b.ii and II.E.4).
    In addition, proposed Sec.  314.53(d)(5) would change the addressee 
to whom submission of Form FDA 3542 should be sent from the Central 
Document Room to the OGD Document Room or the Electronic Submissions 
Gateway, consistent with proposed Sec.  314.53(d)(4) discussed in 
section II.B.2.c.
II.B.3. Public Disclosure of Patent Information (Proposed Sec.  
314.53(e))
    We are proposing to delete the reference in Sec.  314.53(e) to 
monthly supplements to the Orange Book because the Agency no longer 
arranges for publication of monthly printed supplements to the Orange 
Book. Patent information listed in the Orange Book, which may be 
accessed from the Agency's Web site, has been updated on a daily basis 
for several years. This correction to Sec.  314.53(e) is consistent 
with our proposed revision of the definition of ``the list'' in Sec.  
314.3(b) to mean the list of approved drug products published in FDA's 
current ``Approved Drug Products With Therapeutic Equivalence 
Evaluations'' available electronically on FDA's Web site at http://www.fda.gov/cder.
    Section 314.53(e) provides that copies of the patent information 
submitted on Form FDA 3542 may be requested from FDA's Freedom of 
Information Staff. We are proposing to revise Sec.  314.53(e) to 
replace the reference to a request for copies of the ``file'' to copies 
of the ``submitted patent information.'' This revision is proposed for 
clarity and does not represent a substantive change. We note, for 
example, that some prospective 505(b)(2) or ANDA applicants have 
requested copies of the patent information submitted on Form FDA 3542 
for patents listed for a listed drug in the Orange Book to determine 
the scope of the labeling identified by the NDA holder as relating to 
the use claimed by the patent. Copies of Form FDA 3542 also have been 
requested to obtain address information for the agent or representative 
authorized to receive notice of patent certification if the patent 
owner or NDA holder does not reside or have a place of business in the 
United States. We anticipate additional requests for the information 
submitted on Form FDA 3542 and may elect to proactively post on FDA's 
Web site a copy of Form FDA 3542 for patents listed in the Orange Book 
in advance of a request under the Freedom of Information Act (see 
Presidential Documents, Memorandum for the Heads of Executive 
Departments and Agencies on Transparency and Open Government (January 
21, 2009) (74 FR 4685, January 26, 2009); see also Office of the 
Attorney General, Memorandum for the Heads of Executive Departments and 
Agencies on The Freedom of Information Act (March 19, 2009), available 
at http://www.usdoj.gov/ag/foia-memo-march2009.pdf).
II.B.4. Correction or Change of Patent Information (Proposed Sec.  
314.53(f))
    We are proposing to revise Sec.  314.53(f) to differentiate the 
procedure for correction or change of patent information by the NDA 
holder (proposed Sec.  314.53(f)(2)) from the procedure for requests by 
persons other than the NDA holder. Proposed Sec.  314.53(f) also would 
address certain issues that have arisen regarding method-of-use patents 
and enhance FDA's response to challenges to the accuracy or relevance 
of submissions of this patent information to the Agency. We are 
proposing to redesignate the current text of Sec.  314.53(f) as Sec.  
314.53(f)(1). We are proposing to add new Sec.  314.53(f)(2) to 
implement section 505(j)(5)(D)(i)(I)(bb)(CC) of the FD&C Act, as added 
by the MMA, and to make other changes for the efficient enforcement of 
the FD&C Act.
    Table 4 summarizes the proposed changes related to correction or 
change of patent information:

 Table 4--Highlights of Proposed Changes Regarding Correction or Change
                        of Patent Information \1\
------------------------------------------------------------------------
                                              Proposed revisions to
          Current regulations                      regulations
------------------------------------------------------------------------
Correction of patent information errors  Correction or change of patent
 (Sec.   314.53(f)).                      information--Requests by
                                          persons other than the NDA
                                          holder (Sec.   314.53(f)(1)).
 If any person disputes the       If any person disputes
 accuracy or relevance of patent          the accuracy or relevance of
 information submitted to FDA under       patent information submitted
 Sec.   314.53 and published by FDA in    to FDA under Sec.   314.53 and
 the list, that person must first         published by FDA in the list,
 notify FDA (OGD Document Room, Attn:     that person must first notify
 Orange Book Staff) in writing stating    FDA (OGD Document Room, Attn:
 the grounds for disagreement. FDA then   Orange Book Staff) in a
 will request that the NDA holder         written or electronic
 confirm the correctness of the patent    communication titled
 information..                            ``314.53(f) Patent Listing
                                          Dispute'' that states the
                                          grounds for disagreement. FDA
                                          then will request that the NDA
                                          holder confirm the correctness
                                          of the patent information
                                          within 30 days.
                                          For listed patents
                                          that claim an approved method
                                          of using the drug product, FDA
                                          will request that the NDA
                                          holder confirm the correctness
                                          of the ``Use Code'' in the
                                          Orange Book, and provide
                                          information on the specific
                                          approved use claimed by the
                                          patent that enables FDA to
                                          make a determination in
                                          accordance with section
                                          505(b)(2)(B) or
                                          (j)(2)(C)(viii) of the FD&C
                                          Act.
 Unless the NDA holder            Unless the NDA holder
 withdraws or amends its patent           withdraws or amends its patent
 information in response to FDA's         information in response to
 request to confirm the correctness of    FDA's request to confirm the
 the patent information, FDA will not     correctness of the patent
 change the patent information in the     information, FDA will not
 list.                                    change the patent information
                                          in the list.
                                         --If there is insufficient
                                          information to make a
                                          determination in accordance
                                          with section 505(b)(2)(B) or
                                          (j)(2)(C)(viii) of the FD&C
                                          Act and the NDA holder has
                                          confirmed the correctness of
                                          its description of the
                                          specific approved use claimed
                                          by the patent, the Agency will
                                          review the proposed labeling
                                          for the 505(b)(2) application
                                          or ANDA with deference to the
                                          505(b)(2) or ANDA applicant's
                                          interpretation of the scope of
                                          the patent.

[[Page 6827]]

 
                                         Correction or change of patent
                                          information--Requests by the
                                          NDA holder (Sec.
                                          314.53(f)(2)).
                                          If the NDA holder
                                          determines that a patent or
                                          patent claim no longer meets
                                          the statutory requirements for
                                          listing, the NDA holder must
                                          promptly notify FDA to
                                          withdraw the patent
                                          information and request that
                                          the patent information be
                                          removed from the list.
                                          If the NDA holder is
                                          required by court order to
                                          amend patent information or
                                          withdraw a patent from the
                                          list, it must submit a copy of
                                          the order to FDA (OGD Document
                                          Room, Attn: Orange Book Staff)
                                          within 14 days of order entry.
                                          FDA will remove a patent from
                                          the list if there is no first
                                          applicant eligible for 180-day
                                          exclusivity or upon the
                                          expiration of the 180-day
                                          period.
                                          If the term of a
                                          listed patent is extended
                                          under 35 U.S.C. 156(e), the
                                          NDA holder must submit on Form
                                          FDA 3542 a correction to the
                                          patent expiration date within
                                          30 days of receipt of a
                                          certificate of extension or
                                          documentation of an extension
                                          of the patent term.
                                          Corrections or changes
                                          to previously submitted patent
                                          information, other than
                                          withdrawal of a patent and
                                          requests to remove a patent
                                          from the list (delisting
                                          requests), must be submitted
                                          on Form FDA 3542 or 3542a, as
                                          appropriate.
                                          Withdrawal of a patent
                                          and delisting requests must be
                                          submitted as described in Sec.
                                            314.53(d)(4), except it need
                                          not be submitted on Form FDA
                                          3542. The patent withdrawal
                                          and delisting request must
                                          contain the NDA number, each
                                          product to which the request
                                          applies, and the patent
                                          number.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
  regulations, but should not be relied upon in place of the proposed
  regulation.

    II.B.4.a. Requests by persons other than the NDA holder--patents 
that claim an approved method of using the drug product (proposed Sec.  
314.53(f)(1)). To efficiently implement the statutory provisions in 
section 505(b)(2)(B) and (j)(2)(C)(viii) of the FD&C Act, we are 
proposing to enhance the mechanism for challenging the accuracy or 
relevance of information with respect to method-of-use patents 
submitted to the Agency under Sec.  314.53 and listed in the Orange 
Book.
    In the preamble to the June 2003 final rule on patent submission 
and listing requirements, we discussed our longstanding position, 
codified in Sec.  314.53(b) and (c)(2), that ``only method-of-use 
patents that claim a use of the drug product in the pending or approved 
application must be submitted'' (68 FR 36676 at 36681). The June 2003 
final rule further explained: ``The declarant must describe each 
individual method of use for which a patent is submitted for listing, 
and identify the corresponding language found in the labeling of the 
approved NDA that corresponds to that method of use. This information 
will expedite our review of ANDA and 505(b)(2) applications that do not 
seek approval for all the approved uses. In determining whether an ANDA 
applicant can `carve out' the method of use, rather than certify to the 
listed patent, we will rely on the description of the approved use 
provided by the NDA holder or patent owner in the patent declaration 
and listed in the Orange Book'' (68 FR 36676 at 36682).
    An NDA holder or patent owner must provide adequate information in 
its submission of patent information to enable potential 505(b)(2) and 
ANDA applicants to avail themselves of the statutory provision that 
permits a 505(b)(2) or ANDA applicant to not certify to a patent by 
stating that it is not seeking approval for the method of use claimed 
by the listed patent (see section 505(b)(2)(B) and (j)(2)(C)(viii) of 
the FD&C Act, respectively) and carving out from product labeling the 
corresponding use information. Our July 2007 revision of Forms FDA 
3542a and 3542 clarifies, in its instructions, that ``[t]he use code 
designates a method of use patent that claims the approved indication 
or use of a drug product. Each approved use claimed by the patent 
should be separately identified in this section and contain adequate 
information to assist 505(b)(2) and ANDA applicants in determining 
whether a listed method of use patent claims a use for which the 
505(b)(2) or ANDA applicant is not seeking approval'' (Form FDA 3542, 
section 4.2b).
    Section 314.53(f) currently provides that, upon notification of the 
grounds for a disagreement with the accuracy or relevance of the patent 
submission, FDA will request that the NDA holder confirm the 
correctness of the patent information or omission of patent 
information. Proposed Sec.  314.53(f)(1) would establish a 30-day 
timeframe in which the NDA holder is required to respond to FDA's 
request in order to facilitate timely resolution of the patent listing 
dispute.
    Proposed Sec.  314.53(f)(1) also would further specify that, in 
response to notification of a patent listing dispute for a listed 
patent that claims an approved method of using the drug product, FDA 
will request that the NDA holder confirm the correctness of its 
description of the approved indication or method of use that has been 
included as the ``use code'' in the Orange Book, and provide 
information on the specific approved use claimed by the patent that 
enables the Agency to make a determination in accordance with section 
505(b)(2)(B) or (j)(2)(C)(viii) of the FD&C Act. If the patent has been 
listed and the NDA holder confirms the accuracy of the patent 
information, fails to timely respond to FDA's request under Sec.  
314.53(f), or submits a revision to the use code that does not provide 
adequate clarity for FDA to determine whether the scope of the proposed 
labeling carve-out would be appropriate based on the NDA holder's use 
code and approved labeling, FDA is proposing to review a proposed 
labeling carve-out(s) for the 505(b)(2) application or ANDA with 
deference to the 505(b)(2) or ANDA applicant's interpretation of the 
scope of the patent. In determining whether a proposed omission of use 
information

[[Page 6828]]

from labeling is appropriate, the Agency will consider the use code and 
labeling information submitted by the NDA holder on Form FDA 3542, the 
history of labeling changes related to approval of an indication(s) for 
the drug product, the 505(b)(2) or ANDA applicant's interpretation of 
the scope of the patent, the need for consistent labeling among 
products approved under section 505(j) of the FD&C Act, and the 
requirements of Sec. Sec.  314.94(a)(8)(iv) and 314.127(a)(7), as 
appropriate.
    The following hypothetical example illustrates our approach under 
proposed Sec.  314.53(f)(1) to determining whether an ANDA applicant's 
proposed labeling carve-out would be appropriate: The NDA holder 
submits Form FDA 3542 to the Office of Generic Drugs, Document Room, 
Attention: Orange Book Staff, within 30 days after issuance of the '321 
patent claiming a method of using the drug product Gaindrolone. The NDA 
holder provided the use code ``to promote weight gain after weight loss 
in certain types of patients'' for each patent that it submitted for 
listing in the Orange Book, but did not specifically identify the 
approved use(s) (e.g., patient population(s)) claimed by the patent. In 
section 4.2a of Form FDA 3542, the NDA holder further identified the 
patented method of use claimed in patent claims 8, 9, and 10 of the 
'321 patent with specific reference to the following sections of the 
approved labeling for the drug product: Indications and Usage 
(``indicated as adjunctive therapy to promote weight gain after weight 
loss following extensive surgery, chronic infections, or severe 
trauma'') and Dosage and Administration. Applicant A submits an ANDA 
that cites Gaindrolone as the basis for ANDA submission and contains a 
505(j)(2)(A)(viii) statement with respect to the '321 patent. Applicant 
A also notifies the Agency in a written communication titled 
``314.53(f) Patent Listing Dispute'' that the use code listed in the 
Orange Book for the '321 patent is overbroad as Applicant A interprets 
the scope of the '321 patent to be limited to ``adjunctive therapy to 
promote weight gain after weight loss following chronic infections.'' 
Applicant A contends that other approved patient populations are not 
within the scope of the '321 patent. FDA subsequently provides the NDA 
holder with the Applicant A's basis for disagreement with the accuracy 
of the listed patent information and requests that the NDA holder 
confirm the correctness of the description of the specific approved use 
claimed by the patent or revise the description within 30 days. The NDA 
holder confirms the use code ``to promote weight gain after weight loss 
in certain types of patients'' and thus does not provide adequate 
clarity for the Agency to make a determination in accordance with 
section 505(j)(2)(A)(viii) of the FD&C Act on whether Applicant A could 
carve out the patented use in ``certain types of patients'' and seek 
approval for the remaining uses. Accordingly, FDA reviews the proposed 
ANDA labeling with deference to Applicant A's interpretation of the 
scope of the patent and approves the ANDA for ``adjunctive therapy to 
promote weight gain after weight loss following extensive surgery or 
severe trauma.'' As noted in the June 2003 final rule, ``the claim-by-
claim listing of method-of-use patents will permit ANDA and 505(b)(2) 
applicants to assess whether they are seeking approval for a use 
claimed in the listed patent, and thus determine whether to submit a 
patent certification or a section viii statement. Additionally, we 
[FDA] can verify that the certification or statement is correct, and 
that only the appropriate methods of use are included in the proposed 
labeling for the ANDA or 505(b)(2) drug product'' (68 FR 36676 at 
36685). Applicant A has a strong incentive to interpret the scope of 
the patent correctly to avoid being subject to patent infringement 
litigation following ANDA approval and potentially enjoined from 
marketing its product. The use code submitted by the NDA holder remains 
listed in the Orange Book (compare June 2003 final rule (68 FR 36676 at 
36683) (``[u]se codes are intended to alert ANDA and 505(b)(2) 
applicants to the existence of a patent that claims an approved use. 
They are not meant to substitute for the applicant's review of the 
patent and the approved labeling'').
    In the same example above, we note that if the NDA holder had 
responded to FDA's request by revising the description of the specific 
approved use claimed by the patent in a manner that provided sufficient 
information for the Agency to make a determination in accordance with 
section 505(j)(2)(A)(viii) of the FD&C Act on whether Applicant A could 
carve out the patented use, FDA would have no occasion to review the 
proposed ANDA labeling with deference to Applicant A's interpretation 
of the scope of the patent. For example, if the NDA holder submitted a 
revised Form 3542 that provided a revised use code (hypothetically ``to 
promote weight gain after weight loss following chronic infections or 
severe trauma'') and specifically referred to the corresponding portion 
of the approved labeling, there would be sufficient information for the 
Agency to make a determination in accordance with section 
505(j)(2)(A)(viii) of the FD&C Act. Accordingly, there would be no 
ambiguity that would warrant review of the proposed ANDA labeling with 
deference to Applicant A's interpretation of the scope of the patent, 
even if Applicant A's interpretation differed from that of the NDA 
holder.
    As previously discussed in the June 2003 final rule, we reiterate 
that the Agency's role in patent listing is ministerial and does not 
involve substantive review of patents (see 68 FR 36676 at 36683). 
Rather, our proposed revisions to the regulations in 314.53(f) are 
intended to provide the Agency with the information necessary to 
implement section 505(b)(2)(B) and (j)(2)(C)(viii) of the FD&C Act. FDA 
believes that enhancing the mechanism for challenging overbroad use 
codes listed in the Orange Book may cause NDA holders to be more 
circumspect in their original submission of patent information to FDA. 
Accordingly, we expect that there will rarely be a need for the Agency 
to review the proposed labeling for the 505(b)(2) application or ANDA 
with deference to the 505(b)(2) or ANDA applicant's interpretation of 
the scope of the patent. However, we invite comment on this proposed 
approach to enhancing FDA's response to challenges to the accuracy or 
relevance of submissions of patent information to the Agency, while 
maintaining the Agency's ministerial role in patent listing.
II.B.4.b. Requests by NDA Holder To Remove Patent Information From the 
List (Proposed Sec.  314.53(f)(2))
    II.B.4.b.i. Patents or patent claims that no longer meet the 
statutory requirements for listing. Section 1102(a)(2) of the MMA 
amends section 505(j)(5)(D)(i)(I) of the FD&C Act to define certain 
events that constitute forfeiture of 180-day exclusivity. As noted in 
section I, we are implementing the 180-day exclusivity provisions of 
the MMA directly from the statute and will determine if additional 
rulemaking is necessary in the future. Where a novel issue of 
interpretation is raised by a particular factual scenario regarding 
forfeiture of 180-day exclusivity, we may open a public docket or 
otherwise seek comment from affected parties in advance of taking 
action (see section I.D). However, we are proposing at this time to add 
Sec.  314.53(f)(2) regarding requests by an NDA holder to remove patent 
information from the list to implement section 
505(j)(5)(D)(i)(I)(bb)(CC) of the FD&C

[[Page 6829]]

Act (forfeiture of 180-day exclusivity due to failure to market where 
the patent or patent information that qualified the first applicant for 
180-day exclusivity is withdrawn by the NDA holder), and to clarify our 
current practice with respect to withdrawal of a patent or patent 
information by an NDA holder.
    Under proposed Sec.  314.53(f)(2), if the NDA holder determines 
that a patent or patent claim (e.g., a method-of-use claim) no longer 
meets the statutory requirements for listing, the NDA holder is 
required to promptly notify FDA to withdraw the patent or patent 
information and request that the patent or patent information be 
removed from the list. Circumstances under which a patent or patent 
claim no longer meets the statutory requirements for listing include, 
but are not limited to, a judicial finding of invalidity or 
unenforceability for a listed patent, from which no appeal has been or 
can be taken, or a court order to amend patent information or withdraw 
a patent from the list. We note that an NDA applicant that determined 
that a patent or patent claim submitted on Form FDA 3542a no longer met 
the statutory requirements for listing prior to NDA approval would 
``withdraw'' the patent or patent claim by not including the patent or 
patent claim in its submission of Form FDA 3542 upon approval of the 
NDA or NDA supplement. There is no need to submit a request to remove 
the patent or patent claim from the list because such patent 
information is listed in the Orange Book only upon approval of the NDA 
or NDA supplement.
    The FD&C Act does not provide an independent cause of action for a 
505(b)(2) or ANDA applicant seeking an order requiring an NDA holder to 
correct or delete patent information listed in the Orange Book (see 
section 505(c)(3)(D)(ii)(II) and (j)(5)(C)(ii)(II) of the FD&C Act; see 
also Mylan Pharmaceuticals, Inc. v. Thompson, 268 F.3d 1323 (Fed. Cir. 
2001) (holding that the pre-MMA statutory scheme did not recognize a 
cause of action for delisting a patent from the Orange Book, and that 
``such an action would be a private right of action barred by the 
[act]'')). If a 505(b)(2) or ANDA applicant successfully asserts a 
counterclaim to a patent infringement action to obtain an order 
requiring the NDA holder to amend or withdraw patent information from 
the list (see section 505(c)(3)(D)(ii)(I) and (j)(5)(C)(ii)(I) of the 
FD&C Act), the NDA holder must withdraw the patent or patent 
information and request that the patent or patent information be 
removed from the list. The Agency will not remove the patent or patent 
information in response to a request, accompanied by a copy of the 
court order, from the 505(b)(2) or ANDA applicant or on its own. We are 
proposing to require an NDA holder to submit a copy of a court order 
requiring amendment or withdrawal of patent information to the Orange 
Book Staff through the Office of Generic Drugs Document Room within 14 
calendar days of the date on which the order was entered. By providing 
a 14-day timeframe within which an NDA holder must notify FDA of this 
type of court order, the proposed regulation would facilitate the NDA 
holder's compliance with obligations under the FD&C Act and applicable 
regulations and ensure that pending 505(b)(2) applications or ANDAs 
that have provided a patent certification to the amended or withdrawn 
patent are not inappropriately delayed if they are otherwise eligible 
for approval. The Orange Book Staff subsequently will forward a copy of 
the court order to the NDA through the CDER Central Document Room.
    We recognize that for patents that meet the statutory criteria for 
listing in the Orange Book, fewer than all of the patent claims may be 
the subject of litigation against a particular 505(b)(2) or ANDA 
applicant. In such a case, a judicial finding of invalidity for certain 
patent claims and withdrawal of that patent information by submission 
of an amended Form FDA 3542 may not necessarily be reflected in the 
Orange Book (unless, for example, all drug product claims were 
invalidated and only a method-of-use claim remained). Accordingly, it 
would be prudent for current and prospective 505(b)(2) and ANDA 
applicants to be aware of relevant court decisions in patent litigation 
(see also the 1994 final rule (59 FR 50338 at 50346) (noting the 
prudence of conducting patent searches to identify patents that may be 
ineligible for listing in the Orange Book but that may be infringed by 
a proposed product)).
    Consistent with our current practice, proposed Sec.  314.53(f)(2) 
states that we will remove a patent from the Orange Book when the NDA 
holder has informed us that the patent no longer meets the statutory 
requirements for listing if there is no first applicant eligible for 
180-day exclusivity or upon the expiration of the 180-day exclusivity 
period of a first applicant.
    Proposed Sec.  314.53(f)(2) also applies to amendment of the patent 
information to remove a claim (drug substance, drug product, or method 
of use) from the list. For example, if a patent is listed in the Orange 
Book as claiming the drug product and a method of use, and an NDA 
holder withdrew only the drug product claim and requested that the drug 
product claim be removed from the list, we would remove the drug 
product claim from the Orange Book if there is no first applicant 
eligible for 180-day exclusivity or upon the expiration of the 180-day 
exclusivity period of a first applicant. This provision is intended to 
address scenarios in which an ANDA applicant has submitted a paragraph 
IV certification with respect to the drug substance or drug product 
claim and a 505(j)(2)(C)(viii) statement with respect to a method-of-
use claim for a single patent.
    When an NDA holder has withdrawn a patent and submitted to FDA a 
request to remove the patent from the Orange Book, we currently 
identify this request in a separate column in the Orange Book titled 
``Delist Requested.'' If an NDA holder withdraws a patent claim (e.g., 
a method-of-use claim in a patent that also claims the drug product) 
and submits to FDA a request to remove the patent claim from the Orange 
Book, we intend to identify this request with a symbol (e.g., an 
asterisk) in the column for that claim. These notations signal that the 
patent or patent claim remains listed in the Orange Book only to 
preserve a first applicant's eligibility for 180-day exclusivity for 
their pending ANDA or during the period of 180-day exclusivity after 
approval of the first applicant's ANDA. While the patent or patent 
claims remain listed in the Orange Book, subsequent ANDA applicants 
must submit or maintain an appropriate patent certification or 
statement with respect to the patent or patent claims for which the 
delisting request has been submitted. This requirement is consistent 
with preservation of a first applicant's eligibility for 180-day 
exclusivity because the 180-day exclusivity period bars approval of 
subsequent ANDAs for the same drug product that also contain a 
paragraph IV certification to the patent (see section 
505(j)(5)(B)(iv)(I) of the FD&C Act). However, a 505(b)(2) applicant is 
not required to certify or maintain a previous certification to the 
patent for which a request to remove the patent from the list has been 
submitted, because such a patent remains listed in the Orange Book only 
for purposes of preserving a first ANDA applicant's eligibility for 
180-day exclusivity.
    An applicant can determine that a patent or patent claim has been 
removed from the Orange Book if it no longer appears in the Orange Book 
patent listings for the drug product at issue. In addition, FDA 
maintains a separate Web page linked from the ``search by patent''

[[Page 6830]]

option on the Orange Book Web page that identifies patents that have 
been recently delisted (currently located at http://www.accessdata.fda.gov/scripts/cder/ob/docs/delist.cfm).
    II.B.4.b.ii. Patent term restoration. Proposed Sec.  
314.53(f)(2)(ii) directs NDA holders to submit a correction to the 
expiration date of their listed patent if the term of the patent is 
extended under the patent term restoration provisions of 35 U.S.C. 156, 
and sets a timeframe for compliance. With respect to patents eligible 
for listing in the Orange Book, the Hatch-Waxman Amendments generally 
provide that the terms of certain patents may be extended for a period 
of up to 5 years if the patent claims a product or method of using a 
product that has been subject to a defined regulatory review period 
before commercial marketing or use (see 35 U.S.C. 156(a)). We are 
proposing to require the NDA holder to submit the correction to the 
patent expiration date on Form FDA 3542 within 30 calendar days of 
receipt of a certificate of extension as described in 35 U.S.C. 
156(e)(1) or documentation of an extension of the term of the patent as 
described in 35 U.S.C. 156(e)(2). The 30-day timeframe within which an 
NDA holder must notify FDA of the patent term extension is consistent 
with the statutory timeframe set forth in section 505(c)(2) of the FD&C 
Act for filing with FDA the patent number and patent expiration date of 
any patent that claims the drug or method of using the drug and is 
issued after NDA approval. Although extension of the patent term of a 
previously issued patent is not explicitly within the scope of section 
505(c)(2) of the FD&C Act, the proposed 30-day timeframe for submission 
of a correction of the patent expiration date is consistent with the 
objective of ensuring that prospective 505(b)(2) and ANDA applicants 
have timely notice of changes to the asserted patent coverage for a 
listed drug.
    II.B.4.b.iii. Submissions to FDA. Proposed Sec.  314.53(f)(2)(iii) 
would require that corrections or changes to previously submitted 
patent information (other than withdrawal of a patent or requests to 
remove a patent from the list) must be submitted on Form FDA 3542a or 
3542, as appropriate. This proposed requirement is intended to 
facilitate listing of patent information in the Orange Book and ensure 
that patent information is accompanied by the patent declaration 
verification required by Sec.  314.53(c)(2)(i)(Q) and (c)(2)(ii)(R) and 
set forth in the certification requirements of Form FDA 3542a or 3542, 
respectively. We note that we will not accept corrections or changes 
that are not submitted on the appropriate forms. However, an NDA holder 
may elect to submit a cover letter highlighting the corrections or 
changes made in the accompanying Form FDA 3542. An NDA holder's 
withdrawal of fewer than all of a previously submitted patent's claims 
(e.g., withdrawal of the method of use claim(s) for a patent that also 
claims the drug product) would be considered a correction or change to 
patent information for purposes of proposed Sec.  314.53(f)(2)(iii) 
because the patent would remain listed in the Orange Book.
    However, proposed Sec.  314.53(f)(2)(iv) clarifies that an NDA 
holder's withdrawal of a patent and request to remove a patent from the 
Orange Book is not required to be submitted on Form FDA 3542a (with 
respect to pre-approval withdrawal of a patent) or FDA Form FDA 3542. 
The withdrawal of a patent must be submitted as an amendment to the NDA 
if the application has not been approved. After NDA approval, the 
withdrawal of a patent must be submitted to the Orange Book Staff 
through the OGD Document Room and must specify the patent number, the 
application number, and each product(s) approved in the application to 
which the request applies. The Orange Book Staff subsequently will 
forward a copy of the patent withdrawal to the NDA through the CDER 
Central Document Room.

II.C. Patent Certification (Proposed Sec. Sec.  314.50(i) and 
314.94(a)(12))

II.C.1. Method-of-Use Patents (Proposed Sec. Sec.  314.50(i)(1)(iii) 
and 314.94(a)(12)(iii))
    We are proposing to revise Sec. Sec.  314.50(i)(1)(iii) and 
314.94(a)(12)(iii) to clarify that a 505(b)(2) or ANDA applicant that 
is not seeking approval for any indications or other conditions of use 
that are covered by a method-of-use patent for the listed drug(s) 
relied upon or RLD, respectively, and has omitted corresponding 
labeling from its proposed product may submit a statement under section 
505(b)(2)(B) or 505(j)(2)(A)(viii), respectively, instead of a patent 
certification with respect to any method-of-use claims. The proposed 
addition of the phrase ``or other conditions of use'' to Sec. Sec.  
314.50(i)(1)(iii) and 314.94(a)(12)(iii) reflects that a method-of-use 
patent that claims a use other than an indication may be submitted for 
listing in the Orange Book and may be the subject of a statement under 
section 505(b)(2)(B) or 505(j)(2)(A)(viii) with an accompanying 
labeling carve-out. This proposed revision is intended to conform with 
current Agency practice.
II.C.2. Method-of-Manufacturing Patents (Proposed Deletion of 
Sec. Sec.  314.50(i)(2) and 314.94(a)(12)(iv))
    The current regulations in Sec. Sec.  314.50(i)(2) and 
314.94(a)(12)(iv) state that a 505(b)(2) or ANDA applicant, 
respectively, is not required to make a patent certification with 
respect to any patent that claims only a method of manufacturing the 
drug product (method-of-manufacturing patent). This has been 
incorrectly interpreted by certain applicants to mean that a 
manufacturer could elect to submit such a patent for listing. In 2003, 
Sec.  314.53(b) was amended to state, among other things, that process 
patents (i.e., method-of-manufacturing patents) must not be submitted 
to FDA (68 FR 36676 at 36679). Therefore, we are proposing that current 
Sec. Sec.  314.50(i)(2) and 314.94(a)(12)(iv) be removed (and reserved) 
to ensure consistency and clarity in our regulations.
II.C.3. Licensing Agreement (Proposed Sec.  314.50(i)(3))
    We are proposing to revise Sec.  314.50(i)(3) regarding licensing 
agreements to remove the references to an ``immediate effective date'' 
and clarify that the patent owner with whom the applicant has a 
licensing agreement may consent to approval of the 505(b)(2) 
application (if otherwise justified) as of a specific date. These 
proposed revisions reflect that there may be barriers to approval other 
than the patent that is the subject of the licensing agreement. In 
addition, the proposed revision acknowledges that a patent owner may 
consent to approval as of a specific date.
    This proposed revision does not alter the current requirements for 
a 505(b)(2) (or ANDA) applicant that submits a paragraph IV 
certification to a patent that claims the listed drug relied upon and 
for which the applicant has a licensing agreement with the patent owner 
(see proposed Sec. Sec.  314.50(i)(3) and 314.94(a)(12)(v)). A 
505(b)(2) or ANDA applicant must comply with the statutory requirements 
for sending notice of paragraph IV certification under section 
505(b)(3) and (j)(2)(B) of the FD&C Act, respectively, with respect to 
each listed patent for which it has submitted a paragraph IV 
certification notwithstanding the applicant's statement that it has 
been granted a patent license.

[[Page 6831]]

II.D. Notice of Paragraph IV Certification (Proposed Sec. Sec.  314.52 
and 314.95)

II.D.1. Timing of Notice
    A 505(b)(2) or ANDA applicant submitting a paragraph IV 
certification is required to give notice of the patent challenge to the 
holder of the NDA for the listed drug(s) relied upon or RLD, 
respectively, and each owner of the patent that is the subject of the 
certification within a specified timeframe (see section 505(b)(3) and 
(j)(2)(B) of the FD&C Act). We are proposing to revise our regulations 
to clearly delineate the two limitations on the timeframe within which 
notice can be provided to the NDA holder and each patent owner of a 
paragraph IV certification to a listed patent: (1) The date before 
which notice may not be given and (2) the date by which notice must be 
given. The MMA amended the FD&C Act to establish the date by which 
notice of a paragraph IV certification must be given to the NDA holder 
and each patent owner. Table 5 summarizes the proposed changes related 
to the timing of providing notice of a paragraph IV certification.

  Table 5--Highlights of Proposed Changes Regarding Timing of Notice of
                     Paragraph IV Certification \1\
------------------------------------------------------------------------
                                                Proposed revisions to
            Current regulations                      regulations
------------------------------------------------------------------------
Sending the notice (Sec.  Sec.   314.52(b)  Sending the notice (Sec.
 and 314.95(b))                              Sec.   314.52(b)(1) and
                                             (b)(2) and 314.95(b)(1) and
                                             (b)(2))
 505(b)(2) applicant must send       Except as provided
 notice required by Sec.   314.52(a) when    in Sec.   314.52(d), a
 it receives from FDA an acknowledgment      505(b)(2) applicant must
 letter stating that its 505(b)(2)           send notice required by
 application has been filed.                 Sec.   314.52(a) on or
                                             after the date it receives
                                             from FDA a paragraph IV
                                             acknowledgment letter, but
                                             not later than 20 days
                                             after the date of the
                                             postmark on the paragraph
                                             IV acknowledgment letter.
                                             Any required notice
                                             is invalid if it is sent
                                             before the 505(b)(2)
                                             applicant's receipt of a
                                             paragraph IV acknowledgment
                                             letter. The applicant will
                                             not have complied with Sec.
                                               314.52(b) until it sends
                                             valid notice.
 ANDA applicant must send notice     Except as provided
 required by Sec.   314.95(a), when it       in Sec.   314.95(d), an
 receives from FDA an acknowledgment         ANDA applicant must send
 letter stating that its ANDA is             notice required by Sec.
 sufficiently complete to permit a           314.95(a) on or after the
 substantive review.                         date it receives from FDA
                                             an acknowledgment letter or
                                             a paragraph IV
                                             acknowledgment letter, but
                                             not later than 20 days
                                             after the date of the
                                             postmark on the
                                             acknowledgment letter or
                                             paragraph IV acknowledgment
                                             letter.
                                             Any required notice
                                             is invalid if it is sent
                                             before the ANDA applicant's
                                             receipt of an
                                             acknowledgment letter or a
                                             paragraph IV acknowledgment
                                             letter, or before the first
                                             working day after the day
                                             the patent is published in
                                             the list. The applicant
                                             will not have complied with
                                             Sec.   314.95(b) until it
                                             sends valid notice.
                                             The 20-day clock
                                             begins on the day after the
                                             date of the postmark on the
                                             paragraph IV acknowledgment
                                             letter. When the 20th day
                                             falls on Saturday, Sunday,
                                             or a Federal holiday, the
                                             20th day will be the next
                                             day that is not a Saturday,
                                             Sunday, or Federal holiday.
Sending the notice (Sec.  Sec.   314.52(b)  Sending the notice (Sec.
 and 314.95(b))                              Sec.   314.52(b)(3) and
                                             314.95(b)(3)
 At the same time, the 505(b)(2)     At the same time
 or ANDA applicant must amend its            the 505(b)(2) or ANDA
 application to include a statement          applicant sends the notice
 certifying that notice of paragraph IV      required by Sec.
 certification has been provided to each     314.52(a) or Sec.
 person identified under Sec.   314.52(a)    314.95(a), respectively, it
 or Sec.   314.95(a), respectively, and      must submit an amendment to
 that notice met the content requirement     its 505(b)(2) application
 under Sec.   314.52(c) or Sec.              that includes a statement
 314.95(c), respectively.                    certifying that the notice
                                             of paragraph IV
                                             certification has been
                                             provided to each person
                                             under Sec.   314.52(a) or
                                             Sec.   314.95(a),
                                             respectively, and that
                                             notice met the content
                                             requirement under Sec.
                                             314.52(c) or Sec.
                                             314.95(c), respectively.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
  regulations, but should not be relied upon in place of the proposed
  regulation.

    II.D.1.a. Date before which notice may not be given. We are 
proposing to clarify the text of our regulations to reflect our 
longstanding practice that notice of a paragraph IV certification may 
not be sent by a 505(b)(2) or ANDA applicant unless and until we have 
notified the applicant that its application has been filed or received, 
as appropriate, in an acknowledgment letter or a paragraph IV 
acknowledgment letter (see proposed Sec. Sec.  314.52(b)(1) and 
314.95(b)(1)).
    Sections 314.52(b) and 314.95(b) currently require that a 505(b)(2) 
and ANDA applicant, respectively, send notice of a paragraph IV 
certification when it receives from FDA an acknowledgment letter 
stating that the application is sufficiently complete to permit a 
substantive review. An NDA, including a 505(b)(2) application, is 
deemed sufficiently complete to permit a substantive review if it is 
filed by the 60th day after submission (see Sec.  314.101(a)(1) and 
proposed Sec.  314.101(a)(2)). An ANDA is received when FDA has made a 
threshold determination that the ANDA is substantially complete and has 
sent the ANDA applicant an acknowledgment letter or paragraph IV 
acknowledgment letter (see Sec.  314.101(b)). We previously have 
explained that notice of a paragraph IV certification is to be sent 
only after the 505(b)(2) or ANDA applicant has received acknowledgment 
from FDA that its application has been determined to be acceptable for 
review because such notice subjects the 505(b)(2) or ANDA applicant to 
the risk that it will be sued for patent infringement (see 
``Abbreviated New Drug Application Regulations''; proposed rule (54 FR 
28872; July 10, 1989) (1989 proposed rule); see also 35 U.S.C. 
271(e)(2)). The receipt of notice of a paragraph IV certification by a 
patent owner or the NDA holder (or their representatives) begins a 45-
day period within which the NDA holder or patent owner must initiate a 
patent infringement action against the 505(b)(2) or ANDA applicant in 
order to obtain, in certain cases, a statutory 30-month stay of 
approval of the application while the patent infringement litigation is 
pending (section 505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act).
    The FD&C Act requires that a notice of paragraph IV certification 
must state

[[Page 6832]]

that the 505(b)(2) application or ANDA containing the certification 
``has been submitted'' (see section 505(b)(3)(D)(i) and 
(j)(2)(B)(iv)(I) of the FD&C Act). As we noted in the preamble to the 
1989 proposal to implement the Hatch-Waxman Amendments, however, 
``[t]he statute and legislative history of Title I [of the Hatch-Waxman 
Amendments] demonstrate that Congress did not intend incomplete 
application submissions to trigger legal action by a patent owner or 
approved application holder'' (1989 proposed rule, 54 FR 28872 at 
28887). By requiring that a 505(b)(2) application has been filed or an 
ANDA has been received before notice of a paragraph IV certification 
can be given, we ensure that the NDA holder and patent owner do not 
needlessly expend resources to initiate litigation with respect to an 
application that is incomplete and therefore may not be reviewed by the 
Agency (see 1989 proposed rule, 54 FR 28872 at 28887 and 1994 final 
rule, 59 FR 50338 at 50349-50350). Accordingly, our current regulations 
require that a 505(b)(2) or ANDA applicant's notice of a paragraph IV 
certification must include a statement that FDA has filed the NDA (in 
the case of a 505(b)(2) application) or has received the ANDA (see 
Sec. Sec.  314.52(c)(1) and 314.95(c)(1)).
    Despite the language in our existing regulations and the preamble 
to the 1989 proposed rule, we have continued to receive inquiries from 
the public regarding whether notice of paragraph IV certification may 
be sent before the filing of a 505(b)(2) application or receipt of an 
ANDA. Some have expressed uncertainty after enactment of the MMA 
because the FD&C Act requires that notice be sent ``not later than 20 
days after the date of the postmark on the notice with which [FDA] 
informs the applicant'' that its 505(b)(2) application or ANDA has been 
filed, without explicitly establishing a date earlier than which notice 
may not be provided (see section 505(b)(3)(B)(i) and (j)(2)(B)(ii)(I) 
of the FD&C Act).
    We are proposing to amend Sec. Sec.  314.52(b) and 314.95(b) by 
revising and redesignating the current text as paragraphs (b)(1) and 
(b)(3) and adding a new paragraph (b)(2). Proposed Sec.  Sec.  
314.52(b)(2) and 314.95(b)(2) state that any notice sent before the 
receipt of an FDA acknowledgment letter or paragraph IV acknowledgment 
letter is invalid (and thus does not trigger either the 45-day period 
in which the NDA holder and each patent owner may initiate a patent 
infringement action and obtain a 30-month stay or the beginning of any 
related 30-month period) and will not be considered to comply with the 
FD&C Act's notice requirement until valid notice is sent. We also are 
proposing to revise Sec.  314.95(b)(2) to state that any notice sent 
before the first working day after the day the patent is published in 
the Orange Book (the list) is invalid and will not be considered to 
comply with the FD&C Act's notice requirement (see discussion in 
section II.D.1.b.ii).
    An applicant that prematurely sends notice of a paragraph IV 
certification must resend notice within the required timeframe in order 
to satisfy the notice requirement of the FD&C Act and, in the case of a 
first applicant, qualify for 180-day exclusivity. To help ensure that 
notices of paragraph IV certifications are not sent prematurely, we 
also are proposing to amend Sec.  Sec.  314.52(c)(3) and 314.95(c)(3) 
to require that each 505(b)(2) or ANDA applicant include, in any notice 
of paragraph IV certification related to its application, a statement 
that it has received an acknowledgment letter or paragraph IV 
acknowledgment letter. We recognize that this proposed requirement may 
have the effect of delaying the provision of notice of paragraph IV 
certification by a 505(b)(2) applicant (but not an ANDA applicant) by 
approximately 2 weeks after the 505(b)(2) application is filed, because 
an NDA is considered filed 60 days after submission, but our proposed 
definition of a ``paragraph IV acknowledgment letter'' for a 505(b)(2) 
application is the filing communication that is generally mailed by the 
74th day after the date of submission of the 505(b)(2) application in 
accordance with the performance goal established under the current 
reauthorization of the prescription drug user fee program in FDASIA 
(see section II.D.3.b). We recognize that this would potentially delay 
the initiation of patent infringement litigation by an NDA holder or 
patent owner and any corresponding 30-month stay of approval of the 
505(b)(2) application by approximately 2 weeks. We invite comment on 
this approach to premature notice of a paragraph IV certification for a 
505(b)(2) application, especially with respect to notice sent after a 
505(b)(2) application is filed (60th day after submission) and before a 
paragraph IV acknowledgment letter (generally sent by the 74th day 
after submission) is received.
    There have been some instances in which an applicant seeks to 
submit an amendment containing a paragraph IV certification to its 
505(b)(2) application or ANDA prior to filing or receipt of the 
application as described in Sec.  314.101(a) and (b), respectively, and 
receipt of an acknowledgment letter or a paragraph IV acknowledgment 
letter. For example, an applicant may seek to amend its ANDA to add a 
new strength of the drug product (see Sec.  314.95(d)(3)). We are 
proposing to revise Sec. Sec.  314.52(d)(2) and 314.95(d)(2) to clarify 
that an applicant submitting an amendment containing a paragraph IV 
certification must comply with the timeframes set forth in Sec. Sec.  
314.52(b) and 314.95(b) and wait until it has received an 
acknowledgment letter or a paragraph IV acknowledgment letter before 
sending notice of its paragraph IV certification to the NDA holder and 
each patent owner. This approach ensures that a notice of paragraph IV 
certification is not sent before we have accepted for substantive 
review the underlying application to which the notice relates (i.e., 
before we have filed the 505(b)(2) application or received the ANDA). 
As one Federal district court observed in upholding FDA's 
interpretation of the statute in this scenario, ``[i]f an ANDA 
applicant could send Paragraph IV notice when amending an ANDA that has 
not yet been accepted as received, the applicant could accelerate the 
timing provisions and litigation process well beyond the framework that 
Congress intended'' (SB Pharmco Puerto Rico, Inc. v. Mutual 
Pharmaceutical Co., 552 F. Supp. 2d 500, 510 (E.D. Pa.), appeal 
dismissed, 2008 U.S. App. LEXIS 27672 (Fed. Cir. 2008) (holding that 
notice of a paragraph IV certification sent concurrent with submission 
of an amendment to an ANDA that had not yet been accepted for filing 
``was not valid or timely'' under section 505(j)(2)(B)(ii)(II) of the 
FD&C Act)).
    Thus, if an ANDA applicant submits an amendment containing a 
paragraph IV certification before it has received an acknowledgment 
letter or a paragraph IV acknowledgment letter advising that the ANDA 
has been received for substantive review, the applicant is required to 
send notice of its paragraph IV certification within 20 days after the 
date of the postmark on the acknowledgment letter or paragraph IV 
acknowledgment letter, as applicable. It is important to note that the 
relevant date for purposes of determining first applicant eligibility 
for 180-day exclusivity based upon submission of a paragraph IV 
certification contained in an amendment is the date of submission of 
the amendment (i.e., the date on which the amendment was officially 
received (date-stamped) by the OGD Document Room) even though the 
acknowledgment letter or paragraph IV acknowledgment letter may state 
that the ANDA was received for substantive review on the date on which 
the original ANDA was submitted (i.e., the date on

[[Page 6833]]

which the ANDA was officially received (date-stamped) by the OGD 
Document Room) or, in the case of an ANDA that OGD initially refused to 
receive under Sec.  314.101(d) or (e), the date on which the 
deficiencies were resolved.
    II.D.1.b. Date by which notice must be given. The MMA amended the 
FD&C Act to require that 505(b)(2) and ANDA applicants provide notice 
of a paragraph IV certification to the NDA holder and each patent owner 
in accordance with the following timeframes:
     If the paragraph IV certification is included in an 
original 505(b)(2) application or ANDA, or in an amendment to such 
application that is submitted before the applicant receives an 
acknowledgment letter or paragraph IV acknowledgment letter, not later 
than 20 days after the date of the postmark on the notice from FDA 
informing the applicant that its application has been filed or received 
(see section 505(b)(3)(B)(i) and (j)(2)(B)(ii)(I) of the FD&C Act), or
     If the paragraph IV certification is included in any other 
amendment or in a supplement, at the time the applicant submits the 
amendment or supplement (see section 505(b)(3)(B)(ii) and 
505(j)(2)(B)(ii)(II) of the FD&C Act).
    II.D.1.b.i. Determining the timeframe for sending notice after 
receipt of an acknowledgment letter or a paragraph IV acknowledgment 
letter. We are proposing to revise Sec. Sec.  314.52(b)(1) and 
314.95(b)(1) to require that an applicant must send notice of a 
paragraph IV certification contained in a 505(b)(2) application or ANDA 
on or after the date on which it receives an acknowledgment letter or a 
paragraph IV acknowledgment letter, but not later than 20 days after 
the date of the ``postmark'' (see proposed definition below) on the 
acknowledgment letter or paragraph IV acknowledgment letter. As 
discussed in sections II.A.2.u and II.A.2.y, we are proposing a broader 
definition of the term ``postmark'' and, as applied to paragraph IV 
acknowledgment letters for 505(b)(2) applications, an alternate 
interpretation of the term ``postmark'' to reflect current OND practice 
regarding the mailing of filing communications. For purposes of 
proposed Sec.  314.52(b) and (c) only, the ``date of the postmark'' on 
the paragraph IV acknowledgment letter for a 505(b)(2) application is 
considered to be 4 calendar days after the date on which the filing 
communication is signed by the signatory authority (generally the 
Division Director or designee in OND) unless OND sends the filing 
communication to the applicant via electronic transmission. If OND 
sends the filing communication via electronic transmission, then our 
proposed definition of ``postmark'' in Sec.  314.3(b) would apply. We 
recognize that issuance of the filing communication within 14 days 
after the 60-day filing date described in Sec.  314.101(a)(1) and 
(a)(2) represents a performance goal under the current reauthorization 
of the prescription drug user fee program in FDASIA. Accordingly, an 
applicant that has submitted a 505(b)(2) application containing a 
paragraph IV certification and has received neither a refuse-to-file 
letter within 60 days nor a filing communication within 74 days after 
FDA receives the 505(b)(2) application should contact FDA to request 
issuance of the filing communication. We invite comment on whether an 
alternate approach should be taken. With reference to an acknowledgment 
letter or a paragraph IV acknowledgment letter for an ANDA, we 
recognize that there may be scenarios in which the postmark on the 
envelope containing an acknowledgment letter or a paragraph IV 
acknowledgment letter is illegible or inadvertently absent. We invite 
comment on the interpretation of the term ``postmark'' in the context 
of an acknowledgment letter or a paragraph IV acknowledgment letter for 
a 505(b)(2) application or an ANDA, and whether our regulations should 
be amended to define differently the specific date on which the 20-day 
notice period begins.
    The MMA does not specify how the 20-day period for providing notice 
of a paragraph IV certification is to be calculated. We are proposing 
in Sec. Sec.  314.52(b)(1) and 314.95(b)(1) to calculate this notice 
period in the same way that we calculate the 45-day period within which 
each patent owner and NDA holder may initiate a patent infringement 
action (which may, if other applicable requirements are satisfied, 
trigger a 30-month stay of approval of a 505(b)(2) application or ANDA) 
following receipt of notice of a paragraph IV certification (see Sec.  
314.107(f)). Specifically, we propose that the first day of the 20-day 
period begin on the day after the date of the postmark on the 
acknowledgment letter or paragraph IV acknowledgment letter. The 20-day 
period is proposed to include all calendar days, except that if the 
20th day falls on a Saturday, Sunday, or Federal holiday, the last day 
of the 20-day period will be considered to be the next day that is not 
a Saturday, Sunday, or Federal holiday. This approach reflects the most 
conservative interpretation of the statute and is the calculation 
method currently used by most ANDA applicants.
    There will be no regulatory benefit or consequence for applicants 
based on when they provide notice of a paragraph IV certification 
contained in an original application, as long as notice is provided 
within the 20-day timeframe required by the MMA. An ANDA applicant that 
does not comply with the statutory timeframe in section 
505(j)(2)(B)(ii)(I) and (j)(2)(B)(ii)(II) of the FD&C Act for providing 
notice of its paragraph IV certification will be subject to 
administrative consequences (see section II.D.5).
    II.D.1.b.ii. Determining the timeframe for sending notice of a 
paragraph IV certification upon submission of an amendment or 
supplement. We are proposing to revise Sec. Sec.  314.52(d) and 
314.95(d) to implement section 505(b)(3)(B)(i), (b)(3)(B)(ii), 
(j)(2)(B)(ii)(I), and (j)(2)(B)(ii)(II) of the FD&C Act and for the 
efficient enforcement of the FD&C Act. Our proposed revisions clarify 
the applicable timeframe in which a 505(b)(2) or ANDA applicant must 
send notice of a paragraph IV certification submitted in an amendment 
or supplement to its 505(b)(2) application or ANDA, respectively. We 
are proposing to revise and redesignate the current text of Sec. Sec.  
314.52(d) and 314.95(d) as paragraph (d)(1) to accommodate the proposed 
inclusion of additional paragraphs to Sec. Sec.  314.52(d) and 
314.95(d). Table 6 summarizes the proposed changes related to the 
timing of providing notice of paragraph IV certification(s) submitted 
in an amendment or supplement to a 505(b)(2) application or ANDA.

  Table 6--Highlights of Proposed Changes Regarding Timing of Notice of
      Paragraph IV Certification in an Amendment or Supplement \1\
------------------------------------------------------------------------
                                                Proposed revisions to
            Current regulations                      regulations
------------------------------------------------------------------------
Amendment to an application or an           Amendment or supplement to a
 abbreviated application (Sec.  Sec.         505(b)(2) application or an
 314.52(d) and 314.95(d))                    ANDA (Sec.  Sec.
                                             314.52(d)(1) and
                                             314.95(d)(1))

[[Page 6834]]

 
 If an application or abbreviated   After receipt of an
 application is amended to include the       acknowledgment letter or
 certification described in Sec.  Sec.       paragraph IV acknowledgment
 314.50(i) or 314.94(a)(12)(i)(A)(4),        letter:
 respectively, the applicant must send the   If an applicant
 notice required by Sec.  Sec.   314.52(a)   submits an amendment or
 or 314.95(a), respectively, at the same     supplement to its 505(b)(2)
 time the amendment is submitted to FDA      application or ANDA that
                                             includes a paragraph IV
                                             certification, the
                                             applicant must send notice
                                             required by Sec.
                                             314.52(a) or Sec.
                                             314.95(a), respectively, at
                                             the same time the amendment
                                             is submitted to FDA.
                                                Notice of
                                                paragraph IV
                                                certification is
                                                required regardless of
                                                whether notice already
                                                has been provided for
                                                another paragraph IV
                                                certification contained
                                                in the application or in
                                                an amendment or
                                                supplement to the
                                                application.
                                            Amendment to a 505(b)(2)
                                             application or an ANDA
                                             (Sec.  Sec.   314.52(d)(2)
                                             and 314.95(d)(2))
                                            Before receipt of an
                                             acknowledgement letter or
                                             paragraph IV acknowledgment
                                             letter:
                                                If an applicant
                                                submits a paragraph IV
                                                certification in an
                                                amendment to a 505(b)(2)
                                                application or ANDA, the
                                                applicant must send
                                                notice required by Sec.
                                                 314.52(a) or Sec.
                                                314.95(a), respectively,
                                                in accordance with the
                                                procedures in Sec.
                                                314.52(b) or Sec.
                                                314.95(b).
                                                If an ANDA
                                                applicant timely
                                                provides notice of
                                                paragraph IV
                                                certification in
                                                accordance with Sec.
                                                314.95(b), FDA will base
                                                its determination of
                                                whether the applicant is
                                                a first applicant on the
                                                date of submission of
                                                the amendment containing
                                                the paragraph IV
                                                certification.
                                            Amendment to a 505(b)(2)
                                             application or an ANDA
                                             (Sec.  Sec.   314.52(d)(3)
                                             and 314.95(d)(3))
                                             An applicant that
                                             submits an amendment or
                                             supplement to its 505(b)(2)
                                             application or ANDA to seek
                                             approval of a new strength
                                             must provide notice of any
                                             paragraph IV certification
                                             in accordance with Sec.
                                             Sec.   314.52(d)(1) and
                                             (d)(2) or Sec.  Sec.
                                             314.95(d)(1) and (d)(2), as
                                             applicable.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
  regulations, but should not be relied upon in place of the proposed
  regulation.

    We are proposing to revise Sec. Sec.  314.52(d) and 314.95(d) 
(redesignated as Sec. Sec.  314.52(d)(1) and 314.95(d)(1), 
respectively) to require that an applicant send notice of a paragraph 
IV certification contained in an amendment to an application that has 
been received for substantive review or in a supplement to an approved 
application at the same time that the amendment or supplement is 
submitted to FDA. Our proposed revisions clarify the requirement in our 
current regulations for an applicant to send notice of a paragraph IV 
certification at the same time that the amendment is submitted to FDA 
by distinguishing between: (1) Amendments submitted after the 
application has been received for substantive review as indicated by 
the receipt of an acknowledgment letter (if, as to an ANDA, the 
original application did not contain a paragraph IV certification) or 
paragraph IV acknowledgment letter and (2) amendments submitted before 
an application has been received for substantive review (see proposed 
Sec. Sec.  314.52(d)(2) and 314.95(d)(2) and section II.D.1.b.i.). The 
MMA amended the FD&C Act to require that notice of a paragraph IV 
certification contained in a supplement to an approved 505(b)(2) 
application or ANDA be sent at the same time that the supplement is 
submitted to FDA, and our proposed revision to Sec. Sec.  314.52(d)(1) 
and 314.95(d)(1) incorporates this requirement (see section 
505(b)(3)(B)(ii) and (j)(2)(B)(ii)(II) of the FD&C Act).
    In proposed Sec. Sec.  314.52(d)(1) and 314.95(d)(1), we reiterate 
the statutory requirement that notice of a paragraph IV certification 
in an amendment or supplement must be provided regardless of whether 
the applicant has already given notice with respect to another 
paragraph IV certification contained in the 505(b)(2) application or 
ANDA or in an amendment or supplement to the 505(b)(2) application or 
ANDA. The phrase ``another paragraph IV certification'' may refer to a 
previous paragraph IV certification to a different listed patent for 
the listed drug relied upon or RLD or, for certain amendments and 
supplements (see section II.F), a previous paragraph IV certification 
to the same listed patent. For example, if an ANDA applicant submitted 
a paragraph IV certification to the '246 patent (a listed patent 
claiming the drug product for the listed drug relied upon) in its 
original application, and subsequently submitted an amendment to its 
pending ANDA to change the formulation, the ANDA applicant would be 
required to provide a new patent certification to the '246 patent (see 
proposed Sec.  314.96(d)(1) and section II.F.1). If this ANDA applicant 
submitted a paragraph IV certification to the '246 patent in its 
amendment, the ANDA applicant would be required to send notice of its 
second paragraph IV certification to the '246 patent to the NDA holder 
and each patent owner at the same time the amendment to the ANDA is 
submitted to FDA.
    If an applicant submits an amendment containing a paragraph IV 
certification to its 505(b)(2) application or ANDA before the applicant 
has received an acknowledgment letter (if, as to an ANDA, the original 
application did not contain a paragraph IV certification) or a 
paragraph IV acknowledgment letter, proposed Sec. Sec.  314.52(d)(2) 
and 314.95(d)(2) require that the applicant send notice of its 
paragraph IV certification in accordance with the procedures described 
in Sec. Sec.  314.52(b) and 314.95(b), respectively. In this 
circumstance, the 505(b)(2) or ANDA applicant must send notice of the 
paragraph IV certification contained in

[[Page 6835]]

its amendment on or after the date it receives an acknowledgment letter 
or paragraph IV acknowledgment letter, but not later than 20 days after 
the date of the postmark on the letter. This requirement reflects our 
longstanding policy that notice of a paragraph IV certification may not 
be sent unless and until we have notified the applicant that its 
application has been filed or received, as appropriate (see section 
II.D.1.a).
    It should be noted that a paragraph IV certification submitted in 
an amendment after the 505(b)(2) application or ANDA is submitted but 
before the applicant receives a paragraph IV acknowledgment letter is 
considered part of the original 505(b)(2) application or ANDA solely 
for the purpose of determining the appropriate timeframe for sending 
notice of paragraph IV certification. The availability of a 30-month 
stay for patent infringement litigation initiated within the statutory 
timeframe in response to a paragraph IV certification submitted in an 
amendment to a 505(b)(2) application or an ANDA continues to be 
determined by whether the patent at issue was filed with FDA before the 
date on which the original 505(b)(2) application or ANDA (excluding an 
amendment or supplement) was submitted (see section 505(c)(3)(C) and 
(j)(5)(B)(iii) of the FD&C Act; see also proposed Sec.  314.107(b)(2) 
and section II.M.2.b). For purposes of determining an ANDA applicant's 
eligibility for 180-day exclusivity and the date from which a first 
ANDA applicant's compliance with section 505(j)(5)(D)(i)(IV) of the 
FD&C Act is assessed, the date of the submission of the paragraph IV 
certification is the date on which the amendment was submitted. An 
amendment seeking approval for a different strength of a drug product 
thus may have a different submission date than the original ANDA 
submission for purposes of evaluating an ANDA applicant's eligibility 
for 180-day exclusivity for that new drug product and the date from 
which a first ANDA applicant's compliance with section 
505(j)(5)(D)(i)(IV) of the FD&C Act is assessed.
    Proposed Sec. Sec.  314.52(d)(3) and 314.95(d)(3) require that an 
applicant that submits an amendment or supplement to a 505(b)(2) 
application or ANDA that contains a paragraph IV certification and 
seeks approval for a different strength of the drug product must adhere 
to the timing requirements for notice in Sec. Sec.  314.52(d)(1) or 
(d)(2) and 314.95(d)(1) or (d)(2), as applicable. Unlike other 
amendments and supplements to a 505(b)(2) application or ANDA, an 
amendment or supplement seeking approval of a different strength may 
refer to a different listed drug than the listed drug identified in the 
original 505(b)(2) application or ANDA (see section 505(b)(4)(B) and 
(j)(2)(D)(ii) of the FD&C Act). Accordingly, we have separately 
described this type of amendment or supplement to clarify applicable 
regulatory requirements.
    There are a few situations in which the relationship between an 
acknowledgment letter or paragraph IV acknowledgment letter and the 
timing of notice for a paragraph IV certification contained in an 
amendment or supplement to a 505(b)(2) application or ANDA may seem 
complicated. For example, in the case of a 505(b)(2) or ANDA applicant 
that submits an original application containing a paragraph III 
certification to a listed patent and receives an acknowledgment letter 
(as distinguished from a paragraph IV acknowledgment letter) indicating 
that the 505(b)(2) application or ANDA has been received for 
substantive review, if the applicant subsequently submits an amendment 
containing a paragraph IV certification to a listed patent, the 
applicant need not wait to receive a paragraph IV acknowledgment letter 
before sending notice in accordance with Sec.  314.52(d)(1) or Sec.  
314.95(d)(1).
    Also, we note that FDA may send an acknowledgment letter for 
certain types of supplements (e.g., a supplement to an ANDA seeking 
approval for a new strength of a drug product; a 505(b)(2) supplement 
to an NDA seeking approval for a new indication, new dosage regimen, 
new route of administration, or a change from prescription use to OTC 
status for all conditions of use). However, this practice would not 
alter the 505(b)(2) or ANDA applicant's statutory obligation to send 
notice of a paragraph IV certification at the time the supplement is 
submitted to FDA (and not at the time the paragraph IV acknowledgment 
letter for the supplement may be received).
    We interpret the requirement in proposed Sec.  314.52(d)(1) or 
Sec.  314.95(d)(1) to send notice of a paragraph IV certification at 
the same time that the amendment or supplement to the application is 
submitted to FDA to mean that notice to the NDA holder and each patent 
owner must be sent on the same day that the amendment or supplement to 
the application is submitted to FDA. It should be noted that the 
controlling date for purposes of first applicant eligibility is the 
date on which the amendment or supplement to the ANDA containing a 
paragraph IV certification is submitted (i.e., officially received 
(date-stamped) by the OGD Document Room) as long as notice is timely 
provided in accordance with the statute. Due to a technical difference 
in the method by which FDA determines the date of submissions to FDA 
(using a date of receipt rule) and the date on which an applicant sends 
notice of a paragraph IV certification to the NDA holder and each 
patent owner (using a date of mailing rule), these dates may differ. 
For example, Applicant A submits an amendment containing a paragraph IV 
certification to its ANDA on August 2 and sends notice of the paragraph 
IV certification to the NDA holder and each patent owner on that same 
day. The amendment to the ANDA is date-stamped by the OGD Document Room 
on August 3. Applicant A has complied with the statutory requirement to 
send notice of its paragraph IV certification at the same time the 
amendment or supplement to the ANDA is submitted despite the difference 
in the date on which the amendment was officially received and the date 
on which the notice of paragraph IV certification was sent because both 
the amendment and notice(s) were actually sent on the same day.
    If an ANDA applicant does not provide notice of a paragraph IV 
certification on the same day that an amendment or supplement is 
submitted, FDA will consider the paragraph IV certification to be 
effective only as of the date that the applicant has both submitted the 
amendment or supplement containing the paragraph IV certification and 
sent the notice (see Purepac Pharmaceutical Co. v. Thompson, 354 F.3d 
877 (D.C. Cir. 2004)).
    To qualify as a first applicant eligible for 180-day exclusivity 
under section 505(j)(5)(B)(iv)(II)(bb) of the FD&C Act, an applicant 
must, among other things, submit a paragraph IV certification on the 
``first day on which a substantially complete application containing a 
[paragraph IV certification] is submitted.'' Because daily electronic 
updates to the Orange Book generally do not occur until the afternoon 
(Eastern Standard Time), the opportunity to be a first applicant with 
respect to a patent that is newly listed in the Orange Book (i.e., to 
submit an amendment to the ANDA containing a paragraph IV certification 
and send notice of the paragraph IV certification on that same day) 
could be affected by, among other things, the time zone in which the 
ANDA applicant resides. To ensure that all ANDA applicants 
(irrespective of time zone) have a reasonable opportunity to be a first 
applicant with respect to a newly listed patent, we are proposing that 
any notice of paragraph

[[Page 6836]]

IV certification is invalid if it is sent before the first working day 
after the day the patent is listed in the Orange Book (see proposed 
Sec. Sec.  314.95(b)(2) and 314.94(a)(12)(viii)(C)(1)(ii), discussed in 
section II.E.4). The term ``working day'' has the meaning provided in 
21 CFR 1.377 (``any day from Monday through Friday, excluding Federal 
holidays''). This approach is intended to promote equity among ANDA 
applicants and reduce the burden on industry and on the Agency 
associated with serial submissions of amendments and multiple notices 
of paragraph IV certifications related to a newly-issued patent. When a 
new patent is issued by the PTO, the NDA holder has 30 days within 
which to submit the patent information to FDA for listing. An ANDA 
applicant does not know if or when the patent may be submitted to FDA, 
and when it is submitted, there may be a delay in the patent's 
appearance in the Orange Book. Therefore, if an ANDA applicant 
reasonably believes a patent could be listed for an RLD, it will often 
submit a paragraph IV certification to FDA and send notice to the NDA 
holder and patent owner each day during the 30-day period after 
issuance of the new patent. ANDA applicants have adopted this practice 
in an attempt to satisfy the certification and notice requirements on 
the first date on which the patent is listed in the Orange Book and 
thus qualify as a first applicant. FDA's proposal is intended to 
eliminate the need for these burdensome serial certifications.
    The following example illustrates our approach: The NDA holder 
submits Form FDA 3542 to the Office of Generic Drugs, Document Room, 
Attention: Orange Book Staff, within 30 days after issuance of the '123 
patent claiming the drug product Litigatolol. Form FDA 3542 is date-
stamped by the OGD Document Room on Friday, August 5 and listed in the 
Orange Book, which is updated at 3 p.m. Eastern Standard Time on that 
date. Applicant B and Applicant C have submitted ANDAs for Litigatolol 
and have received acknowledgment letters indicating that their ANDAs 
have been received for substantive review. Applicant B is located in 
California and submits an amendment to its ANDA containing a paragraph 
IV certification to the '123 patent and sends notice to the NDA holder 
and each patent owner late in the afternoon, Pacific Time, on Friday, 
August 5. Applicant C is located in New Jersey and would have been 
unable to submit an amendment to its ANDA containing a paragraph IV 
certification to the '123 patent and send notice to the NDA holder and 
each patent owner before the end of the working day on Friday, August 
5. Applicant C submits the amendment and sends notice on Monday, August 
8. Prior to these amendments, no ANDA had contained a paragraph IV 
certification to a patent listed for Litigatolol. Applicant B 
prematurely submitted its amendment containing a paragraph IV 
certification, and its notice of paragraph IV certification is invalid 
because it was sent before the first full working day after the patent 
is listed in the Orange Book. Only Applicant C has submitted the first 
substantially complete ANDA containing a paragraph IV certification for 
purposes of first applicant eligibility.
    It should be noted that if there is a delay between FDA's receipt 
of new patent information and publication of the patent information in 
the Orange Book, the actual date of publication of the patent 
information in the Orange Book provides the date from which the 
validity of the ANDA applicant's notice of paragraph IV certification 
will be assessed for purposes of first applicant eligibility (compare 
section II.D.3 regarding determination of a 505(b)(2) or ANDA 
applicant's patent certification obligations and the availability of a 
30-month stay based on patent information in FDA's possession).
    II.D.1.c. Certification of provision of notice. We are proposing to 
amend Sec. Sec.  314.52(b) and 314.95(b) by revising and redesignating 
certain text as new paragraph (b)(3). Proposed Sec. Sec.  314.52(b)(3) 
and 314.95(b)(3) describe the current requirement for 505(b)(2) and 
ANDA applicants, respectively, to amend their applications at the time 
that they provide notice of a paragraph IV certification to include a 
statement certifying that notice has been provided to the NDA holder 
and each patent owner as required by Sec. Sec.  314.52(a) and 314.95(a) 
and has met the content requirements for notice of a paragraph IV 
certification as described in Sec. Sec.  314.52(c) and 314.95(c). We 
are proposing to clarify that a copy of the notice of paragraph IV 
certification itself does not need to be submitted to FDA in the 
amendment.
    We describe acceptable methods for delivery of notice of paragraph 
IV certification and documentation of timely delivery and receipt of 
such notice in section II.D.4.
II.D.2. Notice Required for All Paragraph IV Certifications
    The MMA requires applicants submitting 505(b)(2) applications and 
ANDAs to provide notice for all paragraph IV certifications submitted 
to FDA on or after August 18, 2003, regardless of whether the applicant 
had previously given notice of a paragraph IV certification contained 
in its application or an amendment or supplement to the application 
(see section 505(b)(3)(B) and (j)(2)(B)(ii) of the FD&C Act).
    We are proposing to require a 505(b)(2) or ANDA applicant to 
provide a new notice of paragraph IV certification to a patent for 
which it previously had provided notice if the applicant submits an 
amendment or supplement to the 505(b)(2) application or ANDA for 
certain changes to the proposed product that should be accompanied by a 
new patent certification (see section II.F).
II.D.3. Contents of Notice
    We are proposing to revise Sec. Sec.  314.52(c) and 314.95(c) 
regarding the contents of notice of a paragraph IV certification to 
incorporate requirements added by the MMA and to support the efficient 
enforcement of our regulations. We note, however, that the Agency 
neither assesses the adequacy of the contents of a 505(b)(2) or ANDA 
applicant's notice of paragraph IV certification nor the applicant's 
stated basis for certifying that a listed patent is invalid, 
unenforceable, or will not be infringed by its proposed drug product. 
In our final rule implementing the patent and exclusivity provisions of 
the Hatch-Waxman amendments, we stated that ``the agency does not have 
the expertise or the desire to become involved in issues concerning 
patent law and sufficiency of notice. . . . Disputes involving the 
sufficiency of the notice [i.e., the detailed statement of the factual 
and legal basis behind the applicant's opinion that the patent is 
invalid, unenforceable, or not infringed] must be resolved by the 
applicant, patent owner, and holder of the approved application rather 
than by action on the part of FDA'' (59 FR 50338 at 50349, October 3, 
1994).
    We also are revising Sec. Sec.  314.52(c) and 314.95(c) to require 
the 505(b)(2) or ANDA applicant to cite section 505(b)(3)(D) and 
(j)(2)(B)(iv), respectively, as amended by the MMA, in the notice of 
paragraph IV certification.
    Table 7 summarizes the proposed changes related to content of a 
notice of paragraph IV certification.

[[Page 6837]]



Table 7--Highlights of Proposed Changes Regarding Content of a Notice of
                     Paragraph IV Certification \1\
------------------------------------------------------------------------
                                                Proposed revisions to
            Current regulations                      regulations
------------------------------------------------------------------------
Content of a notice (Sec.  Sec.             Content of a notice (Sec.
 314.52(c)) and 314.95(c))                   Sec.   314.52(c)) and
                                             314.95(c))
 The 505(b)(2) or ANDA applicant     The 505(b)(2) or
 must cite section 505(b)(3)(B) or           ANDA applicant must cite
 505(j)(2)(B)(ii) of the FD&C Act, as        section 505(b)(3)(D) or
 appropriate, and the notice must also       505(j)(2)(B)(iv) of the
 include, but not be limited to, the         FD&C Act, as appropriate,
 following information:                      and the notice must also
                                             include, but is not limited
                                             to, the following
                                             information:
    --(1) A statement that a 505(b)(2)         --(1) A statement that a
     application submitted by the               505(b)(2) application
     applicant has been filed by FDA; or a      that contains any
     statement that FDA has received an         required BA or BE data
     ANDA submitted by the applicant            has been submitted by
     containing any required                    the applicant and filed
     bioavailability (BA) or                    by FDA; or a statement
     bioequivalence (BE) data or                that FDA has received an
     information.                               ANDA submitted by the
                                                applicant containing any
                                                required BA or BE data
                                                or information.
    --(2) The NDA or ANDA number.              --(2) The NDA or ANDA
                                                number.
    --(3) The established name, if any, of     --(3) A statement that
     the proposed drug product.                 the applicant has
    --(4) The active ingredient, strength,      received the
     and dosage form of the proposed drug       acknowledgment letter or
     product.                                   paragraph IV
                                                acknowledgment letter
                                                for the 505(b)(2)
                                                application or ANDA.
    --(5) The patent number and expiration     --(4) The established
     date, as submitted to the Agency or        name, if any, of the
     as known to the applicant, of each         proposed drug product.
     patent alleged to be invalid,          --(5) The active ingredient,
     unenforceable, or not infringed.        strength, and dosage form
    --(6) A detailed statement of the        of the proposed drug
     factual and legal basis of the          product.
     applicant's opinion that the patent    --(6) The patent number and
     is not valid, unenforceable, or will    expiration date of each
     not be infringed.                       patent on the list alleged
    --(7) If the applicant does not reside   to be invalid,
     or have a place of business in the      unenforceable, or not
     U.S., the name and address of an        infringed.
     agent in the U.S. authorized to        --(7) A detailed statement
     accept service of process for the       of the factual and legal
     applicant.                              basis of the applicant's
                                             opinion that the patent is
                                             not valid, unenforceable,
                                             or will not be infringed.
                                            --(8) If the applicant
                                             alleges that the patent
                                             will not be infringed and
                                             may later decide to file a
                                             civil action for
                                             declaratory judgment in
                                             accordance with section
                                             505(c)(3)(D) and
                                             505(j)(5)(C) of the FD&C
                                             Act, then the notice must
                                             be accompanied by an offer
                                             of confidential access to
                                             the 505(b)(2) application
                                             or ANDA for the sole and
                                             limited purpose of
                                             evaluating possible
                                             infringement of the patent
                                             that is the subject of the
                                             paragraph IV certification.
                                               --(9) If the applicant
                                                does not reside or have
                                                a place of business in
                                                the U.S., the name and
                                                address of an agent in
                                                the U.S. authorized to
                                                accept service of
                                                process for the
                                                applicant.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
  regulations, but should not be relied upon in place of the proposed
  regulation.

    II.D.3.a. Statement that any required bioavailability or 
bioequivalence studies for a 505(b)(2) application have been submitted. 
The MMA amended the FD&C Act to require that the notice of paragraph IV 
certification for a 505(b)(2) application include a statement that ``an 
application that contains data from bioavailability or bioequivalence 
studies'' has been submitted to FDA (section 505(b)(3)(D)(i) of the 
FD&C Act). This statutory provision parallels the content requirements 
for notice of paragraph IV certification for an ANDA (see section 
505(j)(2)(B)(iv)(I) of the FD&C Act). Consistent with our previous 
implementation of the statutory requirement for ANDAs in Sec.  
314.95(c), proposed Sec.  314.52(c)(1) requires that a notice of a 
paragraph IV certification for a 505(b)(2) application state that data 
from ``any required bioavailability or bioequivalence studies'' 
(emphasis added) have been submitted. This qualifier reflects that FDA 
may exercise its scientific judgment to determine what bioavailability 
and bioequivalence studies may be needed for certain 505(b)(2) 
applications and ANDAs (see, e.g., Sec.  314.54(a)(1) and (a)(2) 
(citing Sec. Sec.  314.50(d)(3) and 320.21(a)(2) and (f)); compare 
Sec.  320.21(b)(2)).
    A 505(b)(2) application may seek to rely upon non-product-specific 
published literature or other studies necessary for approval for which 
the applicant has no right of reference or use. This type of 505(b)(2) 
application generally would not require studies showing relative 
bioavailability or bioequivalence because the 505(b)(2) application is 
not relying upon the Agency's finding of safety and/or effectiveness 
for a listed drug. In the absence of a listed drug, there is not likely 
to be a specific drug for use as a comparator in a relative 
bioavailability or bioequivalence study. However, such a 505(b)(2) 
application must establish that reliance on the studies described in 
the literature is scientifically appropriate. Further, a 505(b)(2) 
application that did not rely upon a listed drug would not require a 
patent certification or statement, and thus there would be no occasion 
for a notice of paragraph IV certification.
    II.D.3.b. Statement confirming receipt of an acknowledgment letter 
or a paragraph IV acknowledgment letter. We are proposing to revise 
Sec. Sec.  314.52(c)(3) and 314.95(c)(3) to add a new requirement for 
505(b)(2) and ANDA applicants, respectively, to facilitate compliance 
with and enforcement of section 505(b)(3)(B)(i), (b)(3)(B)(ii), 
(j)(2)(B)(ii)(I), and (j)(2)(B)(ii)(II) of the FD&C Act regarding the 
timing of notice of paragraph IV certification. Proposed Sec. Sec.  
314.52(c)(3) and 314.95(c)(3) require a 505(b)(2) and ANDA applicant, 
respectively, to include a statement in its notice of paragraph IV 
certification that the applicant has received an acknowledgment letter 
or a paragraph IV acknowledgment letter for its 505(b)(2) application 
or ANDA. This requirement is intended to ensure that a notice of 
paragraph IV certification is not sent before FDA has determined that 
the 505(b)(2) application or ANDA containing the certification is 
acceptable for substantive review and has issued an acknowledgment 
letter or a paragraph IV acknowledgment letter (see section II.D.1.a).
    II.D.3.c. Documentation that paragraph IV certification was 
submitted and notice was sent only for patents listed in the Orange 
Book. We are proposing to revise Sec. Sec.  314.52(c)(6) and 
314.95(c)(6) to specify that notice of a paragraph IV certification 
(and therefore the underlying paragraph IV certification as well) must 
only be sent for a patent that is listed in the Orange Book for the 
listed drug(s) relied upon

[[Page 6838]]

for a 505(b)(2) application or for the RLD for an ANDA. We are 
proposing to add the phase ``on the list'' to proposed Sec. Sec.  
314.52(c)(6) and 314.95(c)(6) to qualify the patents for which a notice 
of paragraph IV certification must be sent.
    As discussed in section II.D.4.b, we are proposing to require an 
ANDA applicant to include a dated printout of the Orange Book entry for 
the RLD that includes the patent that is the subject of the notice of 
paragraph IV certification in its amendment certifying that notice of 
paragraph IV certification has been sent and documenting that notice 
has been received (see proposed Sec.  314.95(e)). A 505(b)(2) applicant 
may elect to submit a copy of the Orange Book patent listing for the 
listed drug(s) relied upon with its 505(b)(2) application, amendment, 
or supplement containing a paragraph IV certification to describe the 
applicant's understanding of the most current patent information listed 
in the Orange Book at the time of submission. We note, however, that a 
505(b)(2) or ANDA applicant's patent certification obligations and the 
availability of a 30-month stay under section 505(c)(3)(C) and 
(j)(5)(B)(iii) of the FD&C Act are determined based on patent 
information in FDA's possession, even if such information is not 
accurately listed in the Orange Book (see Teva Pharms., USA, Inc. v. 
Leavitt, 548 F.3d 103, at 105 (D.C. Cir. 2008) (``FDA insists reality 
matters'')).
    In addition, we are proposing to delete the phrase ``as submitted 
to the agency or as known to the applicant'' from Sec. Sec.  
314.52(c)(6) and 314.95(c)(6), as this phrase is over-inclusive. It 
does not accurately describe the universe of patents for which a 
paragraph IV certification may be submitted and thus is inapplicable to 
the content requirements for notice of a paragraph IV certification. 
Although an applicant may submit a certification pursuant to section 
505(b)(2)(A)(i) or 505(j)(2)(A)(vii)(I) of the FD&C Act (``paragraph I 
certification'') with respect to patent information that has not been 
filed with FDA and is not listed in the Orange Book, such a patent 
could not be the basis for a paragraph IV certification.
    II.D.3.d. Offer of confidential access accompanying notice. The MMA 
established conditions under which a 505(b)(2) or ANDA applicant may 
bring a declaratory judgment action to obtain ``patent certainty'' 
(i.e., obtain a judicial determination of noninfringement, invalidity, 
or unenforceability) with respect to a listed patent for which it has 
given notice of a paragraph IV certification but has not been sued by 
the NDA holder or any patent owner within the statutory timeframe (see 
section 505(c)(3)(D) and (j)(5)(C) of the FD&C Act). As a precondition 
to filing an action for declaratory judgment to establish patent 
noninfringement (as distinguished from patent invalidity or 
unenforceability), the applicant must provide a document offering the 
NDA holder and each patent owner confidential access to the 505(b)(2) 
application or ANDA for the sole and limited purpose of assessing 
patent noninfringement (see section 505(c)(3)(D)(i)(III) and 
(j)(5)(C)(i)(III) of the FD&C Act). Because this offer of confidential 
access, if made, is required to accompany the notice of paragraph IV 
certification, we are proposing to revise Sec. Sec.  314.52(c) and 
314.95(c) to reference the statutory requirement for an offer of 
confidential access (see section 505(c)(3)(D)(i)(I)(cc) and 
(j)(5)(C)(i)(I)(cc) of the FD&C Act). Our proposed regulations do not 
otherwise address the offer of confidential access because the process 
for seeking a declaratory judgment does not involve FDA.
II.D.4. Documentation of Timely Sending and Receipt of Notice
    We are proposing to revise Sec. Sec.  314.52(e) and 314.95(e) to 
clarify the requirements for submission of an amendment to a 505(b)(2) 
application or ANDA, respectively, containing documentation of timely 
sending of notice of paragraph IV certification and confirmation of 
receipt of same by the NDA holder and each patent owner. In addition, 
we are proposing to revise Sec. Sec.  314.52 and 314.95 to expand the 
list of acceptable delivery methods that may be used to send notice of 
paragraph IV certification to the NDA holder and each patent owner. 
These proposed revisions are intended to facilitate compliance with the 
statutory requirements regarding timing of notice of paragraph IV 
certification and related regulatory provisions.
    Table 8 summarizes the proposed changes regarding documentation of 
timely sending and receipt of notice of paragraph IV certification:

   Table 8--Highlights of Proposed Changes Regarding Documentation of
 Timely Sending and Receipt of Notice of Paragraph IV Certification \1\
------------------------------------------------------------------------
        Current regulations           Proposed revisions to regulations
------------------------------------------------------------------------
Notice of certification (Sec.  Sec.  Notice of certification (Sec.  Sec.
   314.52(a) and 314.95(a))             314.52(a) and 314.95(a))
 505(b)(2) or ANDA            505(b)(2) or ANDA
 applicant must send notice of        applicant must send notice of
 paragraph IV certification by        paragraph IV certification by
 registered or certified mail,        registered or certified mail,
 return receipt requested, to each    return receipt requested, or by a
 patent owner and the NDA holder.     designated delivery service, to
                                      each patent owner and the NDA
                                      holder.
                                      505(b)(2) or ANDA
                                      applicant may send notice by an
                                      alternative method only if FDA has
                                      agreed in advance that the method
                                      will produce an acceptable form of
                                      documentation.
Documentation of receipt of notice   Documentation of timely sending and
 (Sec.  Sec.   314.52(e) and          receipt of notice (Sec.  Sec.
 314.95(e))                           314.52(e) and 314.95(e))
 Applicant must amend its     Applicant must amend its
 505(b)(2) application or ANDA to     505(b)(2) application or ANDA to
 document the date of receipt of      provide documentation of the date
 the notice of paragraph IV           of receipt of the notice of
 certification by each patent owner   paragraph IV certification by each
 and NDA holder provided the          patent owner and NDA holder
 notice.                              provided the notice.
 Applicant must include a    --FDA will accept as adequate
 copy of the return receipt or        documentation of the date of
 other similar evidence of the date   receipt a return receipt,
 the notification was received.       signature proof of delivery by a
--FDA will accept as adequate         designated delivery service, or a
 documentation of the date of         letter acknowledging receipt by
 receipt a return receipt or a        the person provided notice.
 letter acknowledging receipt by
 the person provided the notice.
 An applicant may rely on    --Amendment must be submitted to
 another form of documentation only   FDA within 30 days after the last
 if FDA has agreed to such            date on which notice was received
 documentation in advance.            by a patent owner or NDA holder.

[[Page 6839]]

 
                                      Amendment also must
                                      include adequate documentation
                                      that notice was sent on a date
                                      that complies with the timeframe
                                      required by Sec.   314.52(b) or
                                      (d) or Sec.   314.95(b) or (d), as
                                      applicable.
                                     --FDA will accept a copy of the
                                      registered mail receipt, certified
                                      mail receipt, or receipt from a
                                      designated delivery service, as
                                      adequate documentation of the date
                                      of delivery.
                                      An ANDA applicant's
                                      amendment must include a dated
                                      printout of the Orange Book entry
                                      for the RLD that includes the
                                      patent that is the subject of the
                                      paragraph IV certification.
                                      An applicant may rely on
                                      another form of documentation only
                                      if FDA has agreed in advance.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
  regulations, but should not be relied upon in place of the proposed
  regulation.

    II.D.4.a. Acceptable methods of sending notice of paragraph IV 
certification. A 505(b)(2) or ANDA applicant currently is required to 
send notice of a paragraph IV certification to the NDA holder and each 
patent owner by registered or certified mail, return receipt requested, 
unless FDA agrees in advance to another method of delivery (see 
Sec. Sec.  314.52(a) and (e) and 314.95(a) and (e)). We are proposing 
to revise Sec. Sec.  314.52(a) and (e) and 314.95(a) and (e) to provide 
applicants with the option of sending notice of paragraph IV 
certification by a designated delivery service, as defined in proposed 
Sec. Sec.  314.52(g)(1) and 314.95(g)(1). Section 505(b)(2) and ANDA 
applicants often request permission to send notice of a paragraph IV 
certification by a major commercial delivery service instead of the 
U.S. Postal Service (for example, to send notice of a paragraph IV 
certification to a patent owner who resides outside of the United 
States). Because we routinely grant these requests, we are proposing to 
amend our regulations to provide the option to all 505(b)(2) and ANDA 
applicants to send notice of paragraph IV certification by the U.S. 
Postal Service or a designated delivery service. We propose to define a 
``designated delivery service'' in Sec. Sec.  314.52(g)(1) and 
314.95(g)(1) to mean any delivery service provided by a trade or 
business that the Agency determines: (1) Is available to the general 
public throughout the United States; (2) records electronically to its 
database, kept in the regular course of its business, or marks on the 
cover in which any item referred to in this section is to be delivered, 
the date on which such item was given to such trade or business for 
delivery; and (3) provides overnight or 2-day delivery service 
throughout the United States.
    This proposed definition is adapted from definition of ``designated 
delivery service'' in 26 U.S.C. 7502(f)(2) (governing timely mailing 
treated as timely filing and paying by the IRS). As noted in proposed 
Sec. Sec.  314.52(g)(2) and 314.95(g)(2), FDA will periodically issue 
guidance describing designated delivery services that meet these 
criteria.
    Our proposal to revise Sec. Sec.  314.52(a) and (e) and 314.95(a) 
and (e) to provide applicants with the option of sending notice of 
paragraph IV certification by a designated delivery service, as defined 
in proposed Sec. Sec.  314.52(g)(1) and 314.95(g)(1), differs from an 
earlier proposal to provide additional methods of sending notice of 
paragraph IV certification (see ``New Drugs for Human Use; 
Clarification of Requirements for Patent Holder Notification; Proposed 
Rule'' 63 FR 11174; March 6, 1998) (Patent Holder Notification proposed 
rule). The Patent Holder Notification proposed rule would have 
permitted a 505(b)(2) or ANDA applicant to send notice of paragraph IV 
certification ``by mail or personal delivery'' (including overnight 
delivery service, electronic mail, and facsimile) if the applicant 
obtained a verification of receipt. We received comments objecting to 
certain aspects of the Patent Holder Notification Proposed Rule--in 
particular, notice by electronic methods of delivery such as electronic 
mail or facsimile--and withdrew the proposed rule (see ``New Drugs for 
Human Use; Clarification of Requirements for Patent Holder 
Notification; Withdrawal'' 65 FR 12154; March 8, 2000) (Withdrawal of 
Patent Holder Notification proposed rule). With respect to notification 
by overnight delivery service, two comments on the Patent Holder 
Notification proposed rule supported this alternate method of delivery 
if a signed verification of receipt of notice by the NDA holder or each 
patent owner was provided (see Docket No. FDA-1997-P-0417-0011 and FDA-
1997-P-0417-0012, available at http://www.regulations.gov). Another 
comment objected to notification by overnight delivery service because 
receipt of bulk deliveries (containing multiple envelopes and packages) 
to large corporations is acknowledged by a single signature. This 
commenter expressed concern that an overnight delivery service envelope 
containing a notice of paragraph IV certification may not ensure timely 
receipt by a responsible person. Given that receipt of notice of 
paragraph IV certification begins a statutory 45-day period within 
which a patent infringement action must be filed to obtain, under 
certain circumstances, a 30-month stay, a signature acknowledging 
receipt of the specific envelope was preferred by this commenter (see 
Docket No. FDA-1997-P-0417-0010, available at http://www.regulations.gov).
    In light of the frequency with which FDA receives requests to send 
notice by overnight delivery services, we invite comment on our current 
proposal to provide applicants with the option of sending notice of 
paragraph IV certification by a designated delivery service, as defined 
in proposed Sec. Sec.  314.52(g)(1) and 314.95(g)(1).
    We also are proposing to add Sec. Sec.  314.52(a)(4) and 
314.95(a)(4) and revise Sec. Sec.  314.52(e) and 314.95(e) to clarify 
that a 505(b)(2) or ANDA applicant may send notice of paragraph IV 
certification by an alternative method (i.e., a method other than 
registered or certified mail, return receipt requested, or a designated 
delivery service) only if FDA has agreed in advance that the method 
will produce an acceptable form of documentation.
    In addition, we are proposing to revise the introductory text of 
Sec.  314.52(a) to refer to each patent that claims the listed drug or 
drugs relied upon or that claims a use for such listed drug or drugs 
and for which the applicant submits a paragraph IV certification. This 
revision is proposed

[[Page 6840]]

for clarity and does not represent a substantive change.
    II.D.4.b. Amendment documenting timely sending and confirmation of 
receipt of notice of paragraph IV certification. We are proposing to 
revise Sec. Sec.  314.52(e) and 314.95(e) to facilitate implementation 
of section 505(b)(3)(B)(i), (b)(3)(B)(ii), (j)(2)(B)(ii)(I), and 
(j)(2)(B)(ii)(II) of the FD&C Act and for the efficient enforcement of 
the FD&C Act.
    A 505(b)(2) or ANDA applicant that has submitted one or more 
paragraph IV certifications currently must submit an amendment to its 
application documenting the date on which notice of paragraph IV 
certification was received by the NDA holder and each patent owner (see 
Sec. Sec.  314.52(e) and 314.95(e)). As discussed in section II.D.1.b, 
the MMA amended the FD&C Act to require that a 505(b)(2) and ANDA 
applicant provide notice of a paragraph IV certification in accordance 
with the timeframes described in section 505(b)(3)(B)(i), 
(b)(3)(B)(ii), (j)(2)(B)(ii)(I), and (j)(2)(B)(ii)(II) of the FD&C Act 
(see proposed Sec. Sec.  314.52(b) and (d) and 314.95(b) and (d)). Our 
proposed revisions to Sec. Sec.  314.52(e) and 314.95(e) require a 
505(b)(2) and ANDA applicant, respectively, to establish compliance 
with this statutory requirement by also submitting in its amendment 
documentation that the notice of paragraph IV certification was sent on 
a date that complies with the timeframe required by Sec.  314.52(b) or 
(d) or Sec.  314.95(b) or (d), as applicable. For administrative 
efficiency, we are proposing to require that a 505(b)(2) or ANDA 
applicant submit the amendment containing documentation of timely 
sending and receipt of notice of paragraph IV certification within 30 
days after the last date on which notice was received by a person 
described in Sec.  314.52(a) or Sec.  314.95(a), respectively.
    The proposed requirement for documentation that notice of paragraph 
IV certification was timely sent can be satisfied by submitting a copy 
of the registered mail receipt or certified mail receipt issued by the 
U.S. Postal Service that bears a postmark documenting the date of 
mailing or by submitting a copy of the receipt from a designated 
delivery service, as defined in proposed Sec. Sec.  314.52(g) and 
314.95(g). With respect to documentation of the date of receipt of 
notice of paragraph IV certification, we are proposing to revise 
Sec. Sec.  314.52(e) and 314.95(e) to include acceptance of signature 
proof of delivery by a designated delivery service as adequate 
documentation. A single document may be adequate to document both 
timely sending and receipt of notice of paragraph IV certification if 
it contains the information required by proposed Sec. Sec.  314.52(e) 
and 314.95(e).
    In addition, we are proposing to require that ANDA applicants 
include in their amendment a dated printout of the Orange Book entry 
for the RLD that includes the patent that is the subject of the notice 
of paragraph IV certification. This requirement is intended to ensure 
that a paragraph IV certification that may qualify an ANDA applicant 
for 180-day exclusivity is submitted only for a listed patent and is 
not prematurely or inappropriately sent before the first working day 
after the day the patent is listed in the Orange Book (see proposed 
Sec. Sec.  314.95(b)(2) and 314.94(a)(12)(viii)(C)(1)(ii)).
    The following example illustrates our approach: The NDA holder 
timely submits Form FDA 3542 to the Office of Generic Drugs, Document 
Room, Attention: Orange Book Staff, at 4 p.m., Eastern Standard Time, 
on the 30th day after issuance of the '456 patent claiming the drug 
product Procrastinadipine. Form FDA 3542 is date-stamped by the Office 
of Generic Drugs, Document Room on Friday, October 1 and listed in the 
Orange Book on the afternoon of Monday, October 4. Applicant D and 
Applicant E have submitted ANDAs for Procrastinadipine and each has 
received an acknowledgment letter indicating that its ANDA has been 
received for substantive review.
    Applicant D is aware that the '456 patent was issued by the PTO on 
September 1 and understands that for the '456 patent to be timely filed 
under section 505(c)(2) of the FD&C Act, the NDA holder must file the 
patent information with FDA no later than October 1. Applicant D 
submits an amendment to its ANDA containing a paragraph IV 
certification to the '456 patent and sends notice to the NDA holder and 
each patent owner on October 1 in an effort to have submitted the first 
substantially complete ANDA containing a paragraph IV certification to 
a patent listed for Procrastinadipine. However, Applicant D is unable 
to submit the required printout (see proposed Sec.  314.95(b)(2)) of 
the Orange Book entry for the RLD that includes the patent that is the 
subject of the paragraph IV certification because the '456 patent has 
not yet been listed in the Orange Book. Applicant E submits on Tuesday, 
October 5 (i.e., the first working day after the day the patent is 
listed in the Orange Book) an amendment to its ANDA containing a 
paragraph IV certification to the '456 patent and the required printout 
of the Orange Book entry and sends notice to the NDA holder and each 
patent owner on that same day.
    Prior to these amendments, no ANDA had contained a paragraph IV 
certification to a patent listed for Procrastinadipine. Applicant D's 
notice of paragraph IV certification is premature and thus invalid 
because the '456 patent had not yet been listed in the Orange Book. 
Only Applicant E has submitted the first substantially complete ANDA 
containing a paragraph IV certification for purposes of first applicant 
eligibility.
II.D.5. Administrative Consequence for Late Notice
    The MMA does not specify a consequence for 505(b)(2) or ANDA 
applicants that do not send notice of a paragraph IV certification 
within the timeframe required by the FD&C Act (i.e., within 20 days 
after the date of the postmark on the paragraph IV acknowledgment 
letter or on the date that an amendment or supplement containing a 
paragraph IV certification is submitted to FDA). In response to our 
Request for MMA Comments, we received comments suggesting that we 
create an administrative consequence for late notice (see, e.g., PhRMA 
MMA Comment at 1 to 2). In light of the importance of the timing of 
sending notice of paragraph IV certification to the statutory scheme, 
we agree that it is appropriate to propose an administrative 
consequence for ANDA applicants who are late in providing notice.
    After considering several suggestions for administrative 
consequences, including those submitted to us in response to our 
Request for MMA Comments, we are proposing to address ANDA applicants 
that fail to timely provide notice of a paragraph IV certification by 
moving forward the date of submission of the ANDA by the number of days 
beyond the required time frame that the applicant delayed in sending 
its notice (see proposed Sec.  314.101(b)(4)). Consequently, an ANDA 
applicant may lose its first applicant status and thus its eligibility 
for 180-day exclusivity as a result of providing late notice (see 
section 505(j)(5)(B)(iv) of the FD&C Act), if another applicant submits 
a substantially complete ANDA containing a paragraph IV certification 
on the same first day and provides timely notice. Also, an ANDA 
applicant that fails to timely provide notice of paragraph IV 
certification may experience a delay in the review queue for its ANDA 
consistent with the revised date of submission. We note that this 
proposed administrative consequence

[[Page 6841]]

would not reduce the 30-month timeframe set forth in section 
505(j)(5)(D)(i)(I)(aa)(BB) and (j)(5)(D)(i)(IV) of the FD&C Act in the 
forfeiture calculus for a first applicant; rather, the 30-month period 
would begin on the revised date of submission.
    We believe that the proposed administrative consequence for ANDA 
applicants appropriately balances the purposes served by the 
requirement for timely notice of paragraph IV certifications with the 
legislative goal of speeding the availability of lower cost 
alternatives to approved drugs. Certain options we considered as 
alternatives did not seem to provide as measured a balance. For 
example, we considered deeming paragraph IV certifications for which 
notice had been provided after the statutory timeframe to not be 
``lawfully maintained'' (see section 505(j)(5)(B)(iv)(bb) of the FD&C 
Act). Under this interpretation, however, an ANDA applicant would 
certainly lose its eligibility for 180-day exclusivity as a result of 
sending late notice, regardless of the amount of time its notice was 
delayed (e.g., even if its notice were one day late). We decline to 
adopt this approach because it seems disproportionately punitive.
    We are not proposing a similar consequence for 505(b)(2) applicants 
that fail to timely provide notice of a paragraph IV certification 
because 505(b)(2) applicants are not eligible for 180-day exclusivity 
and we are unable to extend the review clock as an administrative 
consequence for an NDA (including a 505(b)(2) application) subject to 
the Prescription Drug User Fee Act Reauthorization Performance Goals 
and Procedures (see http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm119243.htm; see also 21 CFR 314.100). As 
described below, we considered other possible administrative 
consequences for any 505(b)(2) applicants that fail to provide notice 
of a paragraph IV certification within the statutory timeframe; 
however, we are declining to propose an administrative consequence at 
this time.
    The implications of late notice of a paragraph IV certification by 
a 505(b)(2) applicant differ from those of an ANDA applicant that may 
otherwise be eligible for 180-day exclusivity. A 505(b)(2) application 
that contains a paragraph IV certification could not be approved until 
the 505(b)(2) applicant had provided notice of its paragraph IV 
certification to the NDA holder and each patent owner and the 
respective 45-day periods for each recipient of notice had expired 
without the filing of a legal action for patent infringement (see Sec.  
314.107(f)(2)). A 505(b)(2) applicant that provides late notice of a 
paragraph IV certification risks that the NDA holder or patent owner 
will file an action for patent infringement within the 45-day period 
after notice, and that any resultant 30-month stay will delay approval 
by a period of time commensurate with the 505(b)(2) applicant's delay 
in providing notice of its paragraph IV certification. We considered 
the suggestion, submitted in response to our Request for MMA Comments, 
that we ``creat[e] an automatic regulatory presumption which could be 
used by the court hearing the patent infringement action that the ANDA 
or 505(b)(2) applicant `failed to reasonably cooperate in expediting 
the action' within the meaning of [section 505(c)(3)(C) and 
(j)(5)(B)(iii) of the FD&C Act]'' (see PhRMA MMA Comment at 2). 
However, we decline to propose this approach because it is not 
necessary to properly implement the statutory goal of adequate notice 
and opportunity to defend certain intellectual property rights prior to 
approval.

II.E. Amended Patent Certifications (Proposed Sec. Sec.  314.50(i)(6) 
and 314.94(a)(12)(viii))

    We are proposing to revise Sec. Sec.  314.50(i)(6) and 
314.94(a)(12)(viii) regarding submission of amended patent 
certifications by 505(b)(2) and ANDA applicants, respectively, to 
reflect revisions to the FD&C Act made by the MMA and for the efficient 
enforcement of the FD&C Act. A 505(b)(2) or ANDA applicant would be 
required to submit an amended patent certification to provide, for 
example, a certification to a recently issued patent listed by the NDA 
holder after submission of a 505(b)(2) application or ANDA that relies 
upon the listed drug, or to change its certification to a patent for 
which the applicant had previously submitted a patent certification. As 
discussed in this section of the document, submission of an amended 
patent certification also would be required for a reissued patent and 
for a revision to a prior certification in the event that a patent or 
patent information has been withdrawn from listing in the Orange Book.
    We are proposing to revise the introductory text of Sec.  
314.94(a)(12)(viii) to remove the provision that restricts an ANDA 
applicant from amending a paragraph IV certification to a paragraph III 
certification in certain circumstances. Currently, Sec.  
314.94(a)(12)(viii) provides that an ANDA applicant that has submitted 
a paragraph IV certification may not amend its patent certification to 
a paragraph III certification (delaying approval until the date on 
which such patent will expire) if a patent infringement action has been 
filed against another applicant that had submitted a paragraph IV 
certification. The current regulation provides that an ANDA applicant 
is permitted to amend its patent certification to a paragraph III 
certification in these circumstances only if the Agency has determined 
that no applicant is entitled to 180-day exclusivity or the patent 
expired while patent infringement litigation was pending or before the 
end of the 180-day exclusivity period. We have determined, however, 
that it is not necessary to restrict submission of an amended patent 
certification under these circumstances because 180-day exclusivity 
does not extend beyond patent expiry. Accordingly, an applicant that 
amended its paragraph IV certification to a paragraph III certification 
would not be eligible for approval until patent expiration and thus 
would not undermine a first applicant's 180-day exclusivity as to that 
patent. The MMA specifically provides that a first applicant's 180-day 
exclusivity would, in any event, terminate upon expiration of all of 
the patents as to which the applicant submitted a paragraph IV 
certification qualifying it for 180-day exclusivity (see section 
505(j)(5)(D)(i)(VI) of the FD&C Act; see also Sec.  
314.94(a)(12)(viii)).
    There are several circumstances in which amending to a paragraph 
III certification is appropriate, including when an applicant is no 
longer seeking approval before the patent expires or when required by 
the terms of a settlement agreement between parties in patent 
infringement litigation. This proposal would facilitate amendment of 
paragraph IV certifications to paragraph III certifications in such 
circumstances.
    We also are proposing to revise Sec. Sec.  314.50(i)(6)(i) and 
314.94(a)(12)(viii) to require that a 505(b)(2) or ANDA applicant 
submit an amended patent certification as an amendment to its pending 
application (including a supplemental 505(b)(2) application or 
supplemental ANDA (see Sec. Sec.  314.70(i) and 314.97(c), 
respectively)) and not by letter. This requirement will facilitate 
appropriate management of amended patent certifications.
    Table 9 summarizes the proposed changes regarding amended patent 
certifications:

[[Page 6842]]



    Table 9--Highlights of Proposed Changes Regarding Amended Patent
                            Certifications\1\
------------------------------------------------------------------------
                                                Proposed revisions to
            Current regulations                      regulations
------------------------------------------------------------------------
Amended Certifications (Sec.  Sec.          Amended Certifications (Sec.
 314.50(i)(6) and 314.94(a)(12)(viii))        Sec.   314.50(i)(6) and
                                             314.94(a)(12)(viii))
 Amended patent certification must   Amended patent
 be submitted as an amendment to a pending   certification must be
 505(b)(2) application or ANDA or by         submitted as an amendment
 letter to an approved application.          to the 505(b)(2)
                                             application or ANDA and may
                                             no longer be submitted by
                                             letter.
Amended Certifications (Sec.                Amended Certifications (Sec.
 314.94(a)(12)(viii) only)                     314.94(a)(12)(viii) only)
 ANDA applicants restricted from     Deletion of
 amending a paragraph IV certification to    restriction on ANDA
 a paragraph III certification in certain    applicants from amending a
 circumstances when another ANDA applicant   paragraph IV certification
 has been sued for patent infringement.      to a paragraph III
                                             certification.
After a Finding of Infringement (Sec.       After a Finding of
 Sec.   314.50(i)(6)(i) and                  Infringement (Sec.  Sec.
 314.94(a)(12)(viii)(A))                     314.50(i)(6)(i) and
                                             314.94(a)(12)(viii)(A))
                                             Change from
                                             paragraph IV certification
                                             to paragraph III
                                             certification required
                                             after a final judgment is
                                             entered finding the patent
                                             to be infringed.
                                             Provision applies
                                             if patent infringement
                                             action initiated within 45
                                             days of receipt of notice
                                             of paragraph IV
                                             certification.
                                             Change from
                                             paragraph IV certification
                                             to paragraph III
                                             certification required
                                             after court enters final
                                             decision from which no
                                             appeal has been or can be
                                             taken, or signs settlement
                                             order or consent decree
                                             with a finding of
                                             infringement (unless the
                                             patent also is found
                                             invalid). An applicant may
                                             instead provide a statement
                                             under Sec.
                                             314.50(i)(1)(iii) or Sec.
                                             314.94(a)(12)(iii) with
                                             respect to a method-of-use
                                             patent if the 505(b)(2)
                                             application or ANDA is
                                             amended such that the
                                             applicant is no longer
                                             seeking approval for a
                                             method of use claimed by
                                             the patent.
                                             Provision applies
                                             if patent infringement
                                             action initiated after
                                             receipt of notice of
                                             paragraph IV certification,
                                             irrespective of whether the
                                             action is brought within
                                             the 45-day period.
After Removal of a Patent from the List     After Request to Remove a
 (Sec.  Sec.   314.50(i)(6)(ii) and          Patent or Patent
 314.94(a)(12)(viii)(B))                     Information from the List
 If a patent is removed from the     (Sec.  Sec.
 list, any applicant with a pending          314.50(i)(6)(ii) and
 application (including a tentatively        314.94(a)(12)(viii)(B))
 approved application with a delayed         If the list
 effective date) who has made a              reflects that an NDA holder
 certification with respect to such patent   has requested that a patent
 must amend its certification.               be removed from the list
 A patent that is the subject of a   and:
 lawsuit under Sec.   314.107(c) shall not  --no ANDA applicant is
 be removed from the list until FDA          eligible for 180-day
 determines either that no delay in          exclusivity based on a
 effective dates of approval is required     paragraph IV certification
 under that section as a result of the       to that patent, the patent
 lawsuit, that the patent has expired, or    will be removed and any
 that any such period of delay in            applicant with a pending
 effective dates of approval is ended.       505(b)(2) application or
 Applicant must submit a ``no        ANDA (including a
 relevant patents'' certification or, if     tentatively approved
 other relevant patents claim the drug,      505(b)(2) application or
 must amend the patent certification to      ANDA) who has certified to
 refer only to those relevant patents.       that patent must submit an
                                             amendment to withdraw the
                                             certification.
                                            --one or more first
                                             applicants are eligible for
                                             180-day exclusivity based
                                             on a paragraph IV
                                             certification to that
                                             patent, the patent shall
                                             remain listed until any 180-
                                             day exclusivity is
                                             extinguished.
                                             If one or more
                                             first applicants are
                                             eligible for 180-day
                                             exclusivity based on a
                                             paragraph IV certification
                                             to a patent that has been
                                             reissued, then the first
                                             applicant must submit a
                                             paragraph IV certification
                                             to the reissued patent
                                             within 30 days of listing
                                             to have lawfully maintained
                                             its paragraph IV
                                             certification for purposes
                                             of eligibility for 180-day
                                             exclusivity.
                                             A 505(b)(2)
                                             applicant is not required
                                             to provide or maintain a
                                             certification to a patent
                                             that remains listed only
                                             for purposes of a first
                                             applicant's 180-day
                                             exclusivity.
                                             After any
                                             applicable 180-day
                                             exclusivity period has
                                             ended, the patent will be
                                             removed and any pending
                                             ANDA (including a
                                             tentatively approved ANDA)
                                             that contains a
                                             certification to the patent
                                             must be amended to withdraw
                                             the certification.
                                             If removal of a
                                             patent from the list
                                             results in no patents
                                             listed for the listed
                                             drug(s) identified in the
                                             505(b)(2) application or
                                             ANDA, the applicant must
                                             submit an amended
                                             certification reflecting
                                             that there are no listed
                                             patents.
Late submission of patent information       Untimely filing of patent
 (Sec.  Sec.   314.50(i)(4) and              information (Sec.  Sec.
 314.94(a)(12)(vi))                          314.50(i)(4) and
                                             314.94(a)(12)(vi))
     If a patent on the listed       (see Table 3)
     drug is issued and the NDA holder for
     the listed drug does not submit the
     required information on the patent
     within 30 days of patent issuance, an
     applicant who submitted a 505(b)(2)
     application or an ANDA for that drug
     that contained an appropriate patent
     certification before the submission
     of the patent information is not
     required to submit an amended
     certification.

[[Page 6843]]

 
     An applicant whose 505(b)(2)
     application or ANDA is submitted
     after a late submission of patent
     information, or whose pending
     505(b)(2) application or ANDA was
     previously submitted but did not
     contain an appropriate patent
     certification at the time of the
     patent submission, must submit a
     certification under (Sec.
     314.50(i)(1)(i) or Sec.
     314.94(a)(12)(i) or a statement under
     Sec.   314.50(i)(1)(iii) or Sec.
     314.94(a)(12)(iii) as to that patent.
Patents Claiming the Drug Substance, Drug   Patents Claiming the Drug
 Product, or Method of Use (Sec.  Sec.       Substance, Drug Product, or
 314.50(i)(1)(i)(A) and                      Method of Use (Sec.  Sec.
 314.94(a)(12)(i)(A))                        314.50(i)(1)(i)(A) and
                                             314.94(a)(12)(i)(A))
     A 505(b)(2) application and     (No substantive
     ANDA are required to contain a patent   revisions)
     certification or statement for each    ............................
     patent issued by the PTO that, in the  ............................
     opinion of the applicant and to the    ............................
     best of its knowledge, claims the      ............................
     listed drug relied upon or RLD or      ............................
     that claims an approved use for such   ............................
     drug for which the applicant is        Other Amendments (Sec.  Sec.
     seeking approval and for which            314.50(i)(6)(iii)(A)(2)
     information is required to be filed     and
     under section 505(b) and (c) of the     314.94(a)(12)(viii)(C)(1)(i
     FD&C Act and Sec.   314.53.             i))
                                             Except as provided
                                             in Sec.  Sec.
                                             314.50(i)(4) and
                                             (i)(6)(iii)(B) and
                                             314.94(a)(12)(vi) and
                                             (a)(12)(viii)(C)(2)), an
                                             applicant must submit a
                                             patent certification or
                                             statement if, after
                                             submission of the 505(b)(2)
                                             application or ANDA, a new
                                             patent is issued by the PTO
                                             that, in the opinion of the
                                             applicant and to the best
                                             of its knowledge, claims
                                             the listed drug or RLD or
                                             that claims an approved use
                                             for such drug and for which
                                             information is required to
                                             be filed under section
                                             505(b) and (c) of the FD&C
                                             Act and Sec.   314.53.
                                             For a paragraph IV
                                             certification, the
                                             certification must not be
                                             submitted earlier than the
                                             first working day after the
                                             day the patent is published
                                             in the list.
Other Amendments (Sec.  Sec.                Other Amendments (Sec.  Sec.
 314.50(i)(6)(iii)(A) and                      314.50(i)(6)(iii)(A)(1)
 314.94(a)(12)(viii)(C)(1))                  and
                                             314.94(a)(12)(viii)(C)(1)(i
                                             ))
     [Amended patent certification   [Upon patent
     required upon patent expiration under   expiration, FDA will
     existing requirement for submission     consider the 505(b)(2) or
     of amended certification if, at any     ANDA applicant to have
     time before approval, the submitted     constructively changed its
     certification is no longer accurate.]   patent certification to a
                                             paragraph II
                                             certification.]
Other Amendments (Sec.  Sec.                Other Amendments (Sec.  Sec.
 314.50(i)(6)(iii)(B) and                      314.50(i)(6)(iii)(B) and
 314.94(a)(12)(viii)(C)(2))                  314.94(a)(12)(viii)(C)(2))
     An applicant is not required    An applicant is not
     to amend a submitted certification in   required to submit a
     response to patent information          supplement to change a
     submitted after approval of the         submitted certification in
     505(b)(2) application or ANDA (unless   response to patent
     a patent certification is required      information submitted after
     with a supplement to the 505(b)(2)      approval of the 505(b)(2)
     application or ANDA).                   application or ANDA (unless
                                             a patent certification is
                                             required with a supplement
                                             to the 505(b)(2)
                                             application or ANDA).
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
  regulations, but should not be relied upon in place of the proposed
  regulation.

II.E.1. Amended Patent Certifications After a Finding of Infringement
    We are proposing to amend Sec. Sec.  314.50(i)(6)(i) and 
314.94(a)(12)(viii)(A) to reflect changes to the FD&C Act made by the 
MMA that clarify the requirements for a 505(b)(2) or ANDA applicant, 
respectively, to amend their paragraph IV certification after a 
judicial finding of patent infringement. As further discussed in 
section II.M, the MMA amended section 505(c)(3)(C) and (j)(5)(B)(iii) 
of the FD&C Act to specify the types of court decisions that will 
terminate a 30-month stay of approval, given that many patent 
infringement actions previously had been concluded without a ``final 
judgment'' regarding infringement being entered by a court. With 
respect to a 505(b)(2) or ANDA applicant that had submitted a paragraph 
IV certification resulting in a patent infringement action, the FD&C 
Act provides that if, before the expiration of the 30-month stay of 
approval, the district court hearing the patent infringement action 
decides that the patent has been infringed and the district court's 
judgment is either not appealed or is affirmed on appeal, the 505(b)(2) 
application or ANDA may be approved on the date specified by the 
district court that is not earlier than the date of expiration of the 
patent (including any patent extension) and of any applicable 
exclusivity (see section 505(c)(3)(C)(ii)(II) and 
(j)(5)(B)(iii)(II)(bb) of the FD&C Act and 35 U.S.C. 271(e)(4)(A)).
    We are proposing to amend Sec. Sec.  314.50(i)(6)(i) and 
314.94(a)(12)(viii)(A) to require that a 505(b)(2) and ANDA applicant, 
respectively, submit an amendment to change its paragraph IV 
certification to a paragraph III certification (stating that the patent 
will expire on a specific date) or, if appropriate, to a statement 
under section 505(b)(2)(B) or (j)(2)(A)(viii) of the FD&C Act if a 
``court enters a final decision from which no appeal has been or can be 
taken'' that the patent at issue has been infringed. After a final 
court decision of patent infringement from which no appeal has been or 
can be taken, a 505(b)(2) or ANDA applicant can no longer lawfully 
maintain a paragraph IV certification that the patent is invalid or 
will not be infringed by the manufacture, use, or sale of the drug for 
which the 505(b)(2) application or ANDA has been submitted (see, e.g., 
Mylan Labs., Inc. v. Thompson, 389 F.3d 1272, 1281 (D.C. Cir. 2004) 
(concluding that after the district court's finding of patent validity 
and infringement, the ANDA applicant's paragraph IV certification was 
``at variance with the legal reality'' and ``no longer accurate'')). 
These proposed revisions to Sec. Sec.  314.50(i)(6)(i) and

[[Page 6844]]

314.94(a)(12)(viii)(A) reflect a change to the current text requiring a 
505(b)(2) or ANDA applicant to amend its paragraph IV certification if 
a ``final judgment'' has been entered finding the patent to be 
infringed.
    Proposed Sec. Sec.  314.50(i)(6)(i) and 314.94(a)(12)(viii)(A) also 
would require a 505(b)(2) and ANDA applicant, respectively, to submit 
an amendment to change its paragraph IV certification to a paragraph 
III certification or, if appropriate, to a statement under section 
505(b)(2)(B) or 505(j)(2)(A)(viii) of the FD&C Act if a court signs a 
settlement order or consent decree in the action that includes a 
finding that the patent is infringed, unless the final decision, 
settlement order or consent decree also finds the patent to be invalid. 
For a first ANDA applicant, submission of an amendment that changes the 
paragraph IV certification that qualified the applicant for 180-day 
exclusivity to a paragraph III certification or a statement under 
section 505(j)(2)(A)(viii) of the FD&C Act has implications for 
continuing eligibility for 180-day exclusivity (see section 
505(j)(5)(D)(i)(III) of the FD&C Act). We note, however, that if a 
settlement is reached without a finding of patent infringement or 
invalidity, then a paragraph IV certification may continue to be 
appropriate. For example, if the 505(b)(2) or ANDA applicant is granted 
a patent license such that the applicant would be permitted to obtain 
approval and commence marketing prior to patent expiration, the 
505(b)(2) or ANDA applicant would maintain its paragraph IV 
certification with respect to the patent at issue and should submit an 
amendment pursuant to proposed Sec. Sec.  314.50(i)(3) and 
314.94(a)(12)(v) to advise the Agency of the patent licensing 
agreement. Such an amendment must include a written statement by the 
applicant that it has been granted a patent license and a written 
statement from the patent owner confirming the licensing agreement and 
consenting to approval of the application as of a specific date (see 
proposed Sec. Sec.  314.50(i)(3) and 314.94(a)(12)(v)).
    We are proposing to apply the requirement that a 505(b)(2) or ANDA 
applicant must submit an amendment to change its paragraph IV 
certification to a paragraph III certification or, if appropriate, to a 
statement under section 505(b)(2)(B) or 505(j)(2)(A)(viii) of the FD&C 
Act after a judicial finding of patent infringement irrespective of 
whether the patent infringement action was brought within 45 days of 
receipt of the notice of paragraph IV certification (see proposed 
Sec. Sec.  314.50(i)(6)(i) and 314.94(a)(12)(viii)(A)). A patent 
infringement action initiated outside of the 45-day period following 
receipt of a notice of paragraph IV certification is not eligible for a 
30-month stay of approval while the patent infringement litigation is 
pending (see Sec.  314.107(b)(3)). However, the rationale for an 
amended patent certification in the event that the patent is found 
valid and infringed applies with equal force to a legal action for 
infringement of a listed patent that was brought outside of the 45-day 
period (see 35 U.S.C. 271(e)(4)). Thus, we are proposing to remove the 
phrase ``within 45 days of the receipt of notice sent under [Sec.  
314.52 or Sec.  314.95, respectively]'' from the description of the 
patent infringement action to which Sec. Sec.  314.50(i)(6)(i) and 
314.94(a)(12)(viii)(A) apply. This proposed revision would clarify, for 
example, that the approval of a 505(b)(2) application or ANDA that 
contained a paragraph IV certification but was not subject to a 30-
month stay still may be delayed by the intervening grant of pediatric 
exclusivity under section 505A(b)(1)(B) of the FD&C Act after a 
judicial finding of infringement of the patent for which the paragraph 
IV certification had been submitted (see Mylan Labs., Inc. v. Thompson, 
332 F. Supp. 2d 106 (D.D.C.), aff'd, 389 F.3d 1272 (D.C. Cir. 2004); 
see also proposed Sec.  314.107(b)(4) and (e)(1)(vi)).
    As explained in proposed Sec. Sec.  314.50(i)(6)(i) and 
314.94(a)(12)(viii)(A), an applicant may change its paragraph IV 
certification for a method-of-use patent to a statement under section 
505(b)(2)(B) or 505(j)(2)(A)(viii) of the FD&C Act only if the 
applicant amends its 505(b)(2) application or ANDA, respectively, such 
that the applicant is no longer seeking approval for a method of use 
claimed by the patent (see Sec. Sec.  314.50(i)(1)(iii) and 
314.94(a)(12)(iii)).
II.E.2. Amended Certifications After Request by the NDA Holder To 
Remove a Patent or Patent Information From the List
    We are proposing to revise Sec. Sec.  314.50(i)(6)(ii) and 
314.94(a)(12)(viii)(B) to clarify the circumstances and timeframe in 
which a 505(b)(2) or ANDA applicant, respectively, must submit an 
amended patent certification to its 505(b)(2) application or ANDA after 
an NDA holder has requested removal of a patent or patent information 
from the list (``patent delisting''). These proposed revisions also 
describe our current practice regarding patent delisting as it relates 
to the eligibility of one or more first ANDA applicants for 180-day 
exclusivity.
    An NDA holder may request removal of a patent or patent information 
from the list in accordance with a court order or on its own 
initiative, if it determines that the patent or patent information no 
longer meets the statutory criteria for listing (see section 505(b)(1) 
and (c)(2) of the FD&C Act). Since April 18, 2008, FDA has identified 
in the Orange Book (the list) those patents for which an NDA holder has 
withdrawn the patent and submitted a request for removal of the patent 
from the list. We are proposing to revise Sec. Sec.  314.50(i)(6)(ii) 
and 314.94(a)(12)(viii)(B) to state that if an NDA holder has requested 
removal of a patent or patent information from the list, the patent or 
patent information will be removed if no ANDA applicant has submitted a 
paragraph IV certification to the patent or no ANDA applicant is 
eligible for 180-day exclusivity. Upon removal of the patent or patent 
information from the list, any applicant with a pending 505(b)(2) 
application or ANDA (including a tentatively approved 505(b)(2) 
application or ANDA) must submit an amendment to its application to 
withdraw its certification to the patent.
    However, if an NDA holder has requested removal of a patent or 
patent information from the list and one or more first ANDA applicants 
are eligible for 180-day exclusivity, FDA will not remove the patent or 
patent information from the list until we have determined that no first 
applicant still is eligible for 180-day exclusivity (see section 
505(j)(5)(D) of the FD&C Act regarding forfeiture of 180-day 
exclusivity) or the 180-day exclusivity is extinguished (see proposed 
Sec. Sec.  314.50(i)(6)(ii) and 314.94(a)(12)(viii)(B)). Otherwise, if 
the NDA holder withdrew the patent or patent information for which a 
first ANDA applicant had submitted the certification that qualified it 
for 180-day exclusivity and FDA immediately removed the patent or 
patent information from the list, the first applicant would be required 
to withdraw its patent certification and could not ``lawfully 
maintain'' its paragraph IV certification (as the ANDA would no longer 
be considered to be one containing a paragraph IV certification) (see 
section 505(j)(5)(B)(iv)(II)(bb) and (j)(5)(D)(i)(III) of the FD&C 
Act). In addition, if FDA immediately removed a patent or patent 
information from the list upon the NDA holder's request when one or 
more first applicants were eligible for 180-day exclusivity, it could 
result in ANDA applicants withdrawing corresponding patent 
certifications

[[Page 6845]]

prematurely and thus undermining a first applicant's 180-day 
exclusivity. We also are proposing to revise the heading for Sec. Sec.  
314.50(i)(6)(ii) and 314.94(a)(12)(viii)(B) by replacing the phrase 
``after removal of a patent'' with ``after request to remove a patent 
or patent information'' to emphasize that FDA will not remove a patent 
or patent information from the list until we have determined that no 
first applicant is eligible for 180-day exclusivity.
    An NDA holder's withdrawal of a patent or patent information is 
implicitly an acknowledgment that the standard for patent listing set 
forth in section 505(b) and (c) of the FD&C Act can no longer be met. 
Nevertheless, a patent for which the NDA holder has requested removal 
may remain listed for 180-day exclusivity purposes. For a patent that 
remains listed for purposes of 180-day exclusivity after an NDA holder 
has withdrawn the patent or patent information and requested that FDA 
remove the patent or patent information from the list, the requirements 
for providing a patent certification will differ between 505(b)(2) 
applicants and ANDA applicants. A 505(b)(2) applicant is neither 
eligible for nor blocked by 180-day generic drug exclusivity. 
Accordingly, we are proposing to revise Sec.  314.50(i)(6)(ii) to 
exempt a 505(b)(2) applicant from the requirement to provide or 
maintain a certification to a patent that is identified in the Orange 
Book as remaining listed only for purposes of a first applicant's 180-
day generic drug exclusivity. Because one or more ANDA applicants may 
be eligible for 180-day exclusivity, ANDA applicants are required to 
provide an appropriate patent certification to each patent listed in 
the Orange Book (except as provided in Sec.  314.94(a)(12)(vi)), 
including to a patent that is listed with a notation indicating that 
the NDA holder has requested removal of the patent or patent 
information from the Orange Book. Once FDA has determined that no first 
applicant is eligible for 180-day exclusivity, or such exclusivity is 
extinguished, and has removed the patent information from the Orange 
Book, an ANDA applicant must submit an amendment to its pending ANDA to 
withdraw the certification.
    We are proposing to delete the statement in current Sec. Sec.  
314.50(i)(6)(ii) and 314.94(a)(12)(viii)(B) regarding the timing of 
removal of a patent or patent information that is the subject of a 
patent infringement lawsuit under Sec.  314.107(c). This statement 
would be replaced by the broader criterion, discussed earlier in this 
section, that a patent will not be removed from the list until FDA has 
determined that any 180-day exclusivity is extinguished. This proposed 
revision reflects our current practice.
    We also are proposing to add a statement to emphasize that if a 
505(b)(2) or ANDA applicant submits an amendment to withdraw a 
paragraph IV certification, the 505(b)(2) application or ANDA will no 
longer be considered to be one containing a paragraph IV certification 
to the patent. In addition, we are proposing a conforming revision to 
Sec.  314.94(a)(12)(viii) to clarify that once an amendment is 
submitted to change a certification, the ANDA will no longer be 
considered to contain the prior certification. This is consistent with 
the Agency's practice for amended patent certifications for 505(b)(2) 
applications (see Sec.  314.50(i)(6)).
    Finally, we are proposing to relocate within Sec. Sec.  
314.50(i)(6)(ii) and 314.94(a)(12)(viii)(B) and revise the current 
statement regarding submission of an amended patent certification after 
removal of a patent from the list. This proposed revision is intended 
to clarify rather than substantively change our current requirements. 
If removal of a patent from the list results in there being no patents 
listed for the listed drug(s) identified in the 505(b)(2) application 
or the RLD identified in the ANDA, the applicant must submit an amended 
certification under Sec.  314.50(i)(1)(ii) or Sec.  314.94(a)(12)(ii), 
as appropriate, to reflect that there are no listed patents. We note, 
however, that if a 505(b)(2) or ANDA applicant fails to submit an 
amended patent certification after removal of a patent from the list, 
the Agency will consider the 505(b)(2) or ANDA applicant to have 
constructively withdrawn its patent certification to the delisted 
patent (compare Ranbaxy Labs. Ltd. v. FDA, 307 F. Supp. 2d 15, 21 
(D.D.C.), aff'd, 2004 U.S. App. LEXIS 8311 (D.C. Cir. 2004); see also 
section II.E.4). With respect to any patents that remain listed for the 
listed drug(s) identified in the 505(b)(2) application or for the RLD 
identified in the ANDA, it is expected that the applicant would 
maintain an accurate patent certification consistent with current 
regulatory requirements (see Sec. Sec.  314.50(i)(6)(iii) and 
314.94(a)(12)(viii)(C)). We seek comment on this approach.
II.E.3. Amended Certifications Upon Patent Reissuance
    In section II.B.1.e, we describe certain proposed revisions to our 
regulations to clarify our requirements regarding an NDA holder's 
submission of patent information related to reissued patents. Because 
the listing of a reissued patent may require submission of an amended 
patent certification by a 505(b)(2) or ANDA applicant under our current 
regulations, we are describing in this section of the document an 
applicant's patent certification obligations with respect to a reissued 
patent.
    Sections 314.50(i)(6)(iii) and 314.94(a)(12)(viii)(C) require that 
a 505(b)(2) and ANDA applicant submit an amended patent certification 
if, at any time before approval of the 505(b)(2) application or ANDA, 
the applicant learns that the submitted certification is no longer 
accurate. As a general rule, we require a 505(b)(2) or ANDA applicant 
to provide an appropriate patent certification or statement with 
respect to a reissued patent, unless either the original patent or the 
reissued patent was not timely filed by the NDA holder for listing in 
the Orange Book (see Sec. Sec.  314.50(i)(4) and 314.94(a)(12)(vi)). As 
noted in section II.B.1.e, if a 505(b)(2) or ANDA applicant is not 
required to provide a patent certification or statement to the original 
patent because it was untimely filed (and late-listed as to the pending 
505(b)(2) application or ANDA), the 505(b)(2) or ANDA applicant would 
not be required to provide a patent certification or statement to the 
reissued patent even if timely filed following reissuance.
    We require a 505(b)(2) or ANDA applicant to provide an amended 
patent certification or statement to the reissued patent, even though a 
patent certification or statement may already have been submitted for 
the original patent, because the scope of claims may be narrowed or, in 
certain circumstances, broadened upon reissuance of the patent (see 35 
U.S.C. 251). A change in the scope of the patent claims may result in 
the reissued patent being listed in the Orange Book with a revised 
designation by the NDA holder regarding whether the patent claims the 
drug substance, drug product, and/or a method of use, or the reissued 
patent may be listed with a revised use code. Accordingly, submission 
of an amendment to a pending 505(b)(2) application or ANDA is necessary 
to provide an appropriate patent certification or statement to the 
reissued patent, even if the type of patent certification (e.g., a 
paragraph III certification) does not differ from that submitted for 
the original patent.
    If an ANDA applicant submitted a paragraph IV certification to the 
original listed patent and continues to opine that the reissued patent 
is invalid or will not be infringed by the manufacture, use, or sale of 
the drug for which the application is submitted, then we are

[[Page 6846]]

proposing that the applicant must submit an amendment to its pending 
ANDA that contained a paragraph IV certification to the reissued patent 
within 30 days of the date of listing of the reissued patent in the 
Orange Book to lawfully maintain its paragraph IV certification for 
purposes of eligibility for 180-day exclusivity (see proposed Sec.  
314.94(a)(12)(viii)(B)). Both 505(b)(2) and ANDA applicants are 
required to provide notice of the paragraph IV certification to the 
reissued patent and comply with other applicable regulatory 
requirements at the time of submission of the amendment containing the 
paragraph IV certification. We seek comment on this proposal.
    An amended patent certification to the reissuance of an original 
patent for which a paragraph IV certification previously was submitted 
may have implications for the 30-month stay provisions of the FD&C Act:
     If a 505(b)(2) or ANDA applicant submitted a paragraph IV 
certification to the original patent and a patent infringement action 
was initiated within 45 days of its notice of the paragraph IV 
certification to the original patent, the resulting 30-month stay would 
not be affected solely by reissuance of the patent, recertification, 
and renotification and would continue subject to Sec.  314.107.
     If a 505(b)(2) or ANDA applicant submitted a statement 
under section 505(b)(2)(B) or section 505(j)(2)(A)(viii) of the FD&C 
Act, respectively, or a paragraph III certification to the original 
patent and subsequently submitted a paragraph IV certification to the 
reissued patent, a 30-month stay would be available if a patent 
infringement action was initiated within 45 days of its notice of the 
paragraph IV certification to the reissued patent.
     If a 505(b)(2) or ANDA applicant had previously submitted 
a paragraph IV certification to the original patent and no patent 
infringement action was initiated within 45 days of receipt of notice, 
no subsequent patent infringement action with respect to the reissued 
patent can give rise to a 30-month stay.

This approach reflects our proposal to treat the original patent and 
the reissued patent as a ``single bundle'' of patent rights, albeit 
patent rights that have changed with reissuance, such that the patent 
information listed for the reissued patent would have been submitted 
under 505(b)(1) or 505(c)(2) of the FD&C Act at the time of listing of 
the original patent for purposes of section 505(c)(3)(C) and 
(j)(5)(B)(iii) of the FD&C Act. Although we recognize that a reissued 
patent may have a broadened scope of claims if applied for within 2 
years from the grant of the original patent (see 35 U.S.C. 251), our 
proposal to consider the original patent and reissued patent together 
for purposes of administering the patent certification requirements of 
the FD&C Act and any 30-month stay of approval or 180-day exclusivity 
that relates to a paragraph IV certification is intended to provide a 
consistent and predictable approach to implementation of the FD&C Act. 
If FDA were to propose a different approach to the availability of a 
30-month stay based on a paragraph IV certification to a reissued 
patent with broadened claims, the implementation of such an approach 
would require resources and patent expertise that FDA currently does 
not possess and would be inconsistent with the Agency's ministerial 
role in patent listing. In any event, we do not expect that the 
scenario described here will occur frequently.
    An amended patent certification to the reissuance of an original 
patent for which a paragraph IV certification previously was submitted 
also may have implications for the 180-day exclusivity provisions of 
the FD&C Act. As described previously in this section of the document, 
if a one or more first ANDA applicants is eligible for 180-day 
exclusivity based on a paragraph IV certification to the original 
patent and the patent is reissued, the first ANDA applicant would be 
required to submit a paragraph IV certification to the reissued patent 
within 30 days of listing to be considered by FDA to have lawfully 
maintained its paragraph IV certification for purposes of section 
505(j)(5)(B)(iv)(II)(bb) and (j)(5)(D)(i)(III) of the FD&C Act. We note 
that the original patent, which qualified the first applicant for 180-
day exclusivity, would remain listed in the Orange Book until FDA 
determined that any 180-day exclusivity is extinguished. Consistent 
with our current practice regarding requests for patent delisting, the 
original patent that qualified a first applicant for 180-day 
exclusivity also would remain listed in the Orange Book even if the 
scope of the reissued patent is narrowed such that the patent is no 
longer eligible for listing pursuant to section 505(b)(1) or 505(c)(2) 
of the FD&C Act and the NDA holder has requested, as required, that the 
patent be delisted from the Orange Book (see proposed Sec.  
314.53(f)(2) and section II.B.4.b). Given that FDA will continue to 
list a patent that qualified a first applicant for 180-day exclusivity 
under specified circumstances even if the patent has been withdrawn by 
the NDA holder on its own initiative or after a judicial finding of 
invalidity or unenforceability, the fact that the original patent 
technically is surrendered upon reissuance is not relevant to FDA's 
assessment of a first applicant's continued eligibility for 180-day 
exclusivity. However, in recognition of the surrender of the original 
patent upon reissuance, we require a first applicant to maintain a 
paragraph IV certification to the reissued patent. If a first applicant 
submitted only a paragraph III certification or a 505(j)(2)(A)(viii) 
statement to the reissued patent, we would consider the first applicant 
to have amended or withdrawn its paragraph IV certification to the 
patent for which it qualified for 180-day exclusivity under section 
505(j)(5)(D)(i)(III) of the FD&C Act.
    If no applicant had submitted a paragraph IV certification to the 
original patent, the first ANDA applicant to submit a paragraph IV 
certification to the reissued patent could be eligible for 180-day 
exclusivity, if no other applicant already has qualified as a first 
applicant based on an earlier paragraph IV certification to another 
listed patent. However, if a first applicant who qualifies as such 
based on a paragraph IV certification to the original patent forfeits 
180-day exclusivity, 180-day exclusivity would not be available to a 
subsequent applicant that submitted a paragraph IV certification to the 
reissued patent (see section 505(j)(5)(D)(iii)(II) of the FD&C Act).
II.E.4. Other Amended Certifications
    Sections 314.50(i)(6)(iii) and 314.94(a)(12)(viii)(C) require a 
505(b)(2) and ANDA applicant, respectively, to amend a submitted 
certification if, at any time before approval of the application, the 
applicant learns that the submitted certification is no longer 
accurate. In Dr. Reddy's Labs., Inc. v. Thompson, the district court 
held that our regulations ``imposing a duty upon ANDA applicants to 
assure its certifications are accurate until the date of final approval 
is supported by [the] . . . express FDA authority [in section 
505(j)(4)(J) and (K) of the FD&C Act]'' (302 F. Supp. 2d 340, 355 
(D.N.J. 2003)) (see also section 505(e) of the FD&C Act).
    Over the years, many 505(b)(2) and ANDA applicants have neglected 
to amend a previously submitted patent certification after the patent 
has expired. The Agency's longstanding position has been that a patent 
is relevant for purposes of 180-day exclusivity determinations ``until 
the end of the term of the patent or applicable 180-day

[[Page 6847]]

exclusivity period, whichever occurs first'' (1994 final rule, 59 FR 
50338 at 50348). Section 505(j)(5)(D)(i)(VI) of the FD&C Act, added by 
the MMA, is consistent with FDA's longstanding position that 180-day 
exclusivity is extinguished upon expiration of the patent(s) on which 
exclusivity is based (see Docket No. FDA-2004-N-0062-0006 (comment 
submitted by PhRMA) at 5, available at http://www.regulations.gov).
    Accordingly, we are proposing to codify our longstanding position 
that if an applicant that previously submitted a paragraph III 
certification, a paragraph IV certification, or a statement under 
section 505(b)(2)(B) or (j)(2)(A)(viii) of the FD&C Act with respect to 
a listed patent fails to amend its patent certification to a paragraph 
II certification upon patent expiration, the Agency will consider the 
505(b)(2) or ANDA applicant to have constructively changed its patent 
certification to a paragraph II certification (see, e.g., Ranbaxy Labs. 
Ltd. v. FDA, 307 F. Supp. 2d 15, 21 (D.D.C.), aff'd, 2004 U.S. App. 
LEXIS 8311 (D.C. Cir. 2004) (finding that upon patent expiration an 
ANDA applicant's paragraph IV certifications ``became invalid, and 
either converted as a matter of law to Paragraph II certifications or 
became inaccurate, thereby creating both an obligation on [the ANDA 
applicant's] . . . part to amend its ANDAs to reflect patent expiry and 
an inability on the part of the FDA to approve the ANDAs in their 
inaccurate form'')). This approach also will clarify that any pediatric 
exclusivity will delay approval of a 505(b)(2) application or ANDA upon 
patent expiry under section 505A(b)(1)(B) and (c)(1)(B) of the FD&C 
Act, regardless of whether an applicant has amended its certification 
to a paragraph II certification.
    We also are proposing to amend Sec. Sec.  314.50(i)(6)(iii)(A) and 
314.94(a)(12)(viii)(C)(1) by revising and redesignating the current 
text as paragraph (1) and paragraph (i), respectively, and adding a new 
paragraph (2) and paragraph (ii) to expressly codify the requirement 
for a 505(b)(2) and ANDA applicant to submit a patent certification to 
a newly issued patent. Proposed Sec. Sec.  314.50(i)(6)(iii)(A)(2) and 
314.94(a)(12)(viii)(C)(1)(ii) state that, except as provided in 
Sec. Sec.  314.50(i)(4) and (i)(6)(iii)(B) and 314.94(a)(12)(vi) and 
(a)(12)(viii)(C)(2)), an applicant must submit a patent certification 
or statement if, after submission of the 505(b)(2) application or ANDA, 
a new patent is issued by the PTO that, in the opinion of the applicant 
and to the best of its knowledge, claims the listed drug or RLD or that 
claims an approved use for such drug and for which information is 
required to be filed under section 505(b) and (c) of the FD&C Act and 
Sec.  314.53.
    A 505(b)(2) and ANDA applicant currently are required to submit a 
patent certification or statement for each patent issued by the PTO 
that, in the opinion of the applicant and to the best of its knowledge, 
claims the listed drug or RLD or that claims an approved use for such 
drug for which the applicant is seeking approval and for which 
information is required to be filed under section 505(b) and (c) of the 
FD&C Act and Sec.  314.53. Although the general requirement to submit a 
patent certification to a newly issued patent is established by 
Sec. Sec.  314.50(i)(1)(i)(A) and 314.94(a)(12)(i)(A) and implicit in 
the exceptions for late submission of patent information, we are 
proposing to expressly codify the requirement to submit a patent 
certification to a newly issued patent in the section of the 
regulations directed to amended patent certification.
    As discussed in section II.D.1.b.ii, we are proposing that a patent 
certification or statement by an ANDA applicant must not be submitted 
earlier than the first working day after the day the patent is 
published in the Orange Book (see proposed Sec.  
314.94(a)(12)(viii)(C)(1)(ii)). Thus, for a paragraph IV certification, 
the certification must not be submitted earlier than the first working 
day after the day the patent is published in the Orange Book. This 
proposal is intended to discourage burdensome serial submissions of 
paragraph IV certifications and ensure that all ANDA applicants 
(irrespective of time zone) have a reasonable opportunity to be a first 
applicant with respect to a newly listed patent (see also proposed 
Sec.  314.95(b)(2)).
    In addition, we are proposing to revise Sec. Sec.  
314.50(i)(6)(iii) and 314.94(a)(12)(viii)(C) to technically correct, 
but not substantively change, the reference to the lack of a 
requirement to ``amend'' a submitted patent certification after 
approval of a 505(b)(2) application or ANDA, respectively. We are 
proposing to correct this statement to indicate that an applicant is 
not required to submit a supplement solely to change a submitted patent 
certification after approval of the application. This revision also 
reflects that any changes to an application after approval would be 
made in a supplement to the application and not in an amendment, as the 
current regulation describes.

II.F. Patent Certification Requirements for Amendments and Supplements 
to 505(b)(2) Applications and ANDAs (Proposed Sec. Sec.  314.60, 
314.70, 314.96, and 314.97)

    We are proposing to add Sec. Sec.  314.60(f), 314.70(i), 314.96(d), 
and 314.97(c) to clarify and augment the patent certification 
requirements for amendments and supplements described in Sec. Sec.  
314.50(i)(6)(iii) and 314.94(a)(12)(viii)(C). Proposed Sec. Sec.  
314.60(f) and 314.96(d) would require an applicant to also submit a 
patent certification described in Sec. Sec.  314.50(i) or 
314.94(a)(12), as appropriate, if approval is sought for any of the 
following types of amendments to an original 505(b)(2) application or 
ANDA: (1) To add a new indication or other condition of use; (2) to add 
a new strength; (3) to make other than minor changes in product 
formulation; or (4) to change the physical form or crystalline 
structure of the active ingredient.
    Currently, an applicant that submits an amendment to a pending 
505(b)(2) application or supplement or a pending ANDA or supplement is 
required to amend its patent certification if, at any time before 
approval, the applicant learns that the previously submitted patent 
certification is no longer accurate with respect to the pending 
application or supplement, as amended (see Sec. Sec.  314.50(i)(6)(iii) 
and 314.94(a)(12)(viii)(C), respectively, and section II.E.4). For 
example, an amendment to change the formulation of a proposed product 
in a 505(b)(2) application or ANDA would require a revised patent 
certification if, in the applicant's opinion and to the best of its 
knowledge, the new formulation would infringe a listed patent for which 
it previously had filed a paragraph IV certification.
    Some NDA holders have expressed concern that a 505(b)(2) or ANDA 
applicant may change its proposed product in an amendment to a pending 
application, but not update its patent certification to correspond to 
the proposed product as changed by the amendment. For example, in 2003, 
FDA received a citizen petition submitted on behalf of Biovail 
Corporation requesting, among other things, that FDA require submission 
of a new patent certification upon amendment of the chemistry, 
manufacturing, and controls section of an ANDA (Docket No. FDA-2003-P-
0519 (Biovail Petition), available at http://www.regulations.gov; see 
also PhRMA comment to Docket No. FDA-2002-N-0279-0061 at 9 to 10, 
available at http://www.regulations.gov). The

[[Page 6848]]

Biovail Petition recognized that even if the ANDA (or 505(b)(2)) 
applicant continued to assert that a paragraph IV certification was the 
appropriate patent certification for the changed product, the factual 
and legal basis of the applicant's opinion that the patent will not be 
infringed may have changed in light of the changes in product 
formulation (see Biovail Petition at 4 to 5). Biovail maintained that 
``[r]equiring a new patent certification whenever the CMC portion of an 
ANDA is amended will allow the NDA holder and patent owner to ensure 
that the impact of the amendment on patent infringement issues is 
addressed promptly'' (Supplement to Biovail Petition at 1).
    We agree that certain changes to a proposed product submitted in a 
505(b)(2) application or ANDA should be accompanied by a new patent 
certification (see section II.F.2). To address these concerns and 
further clarify our requirements for submission of new patent 
certifications with an amendment to a 505(b)(2) application or ANDA, we 
are proposing to add Sec. Sec.  314.60(f) and 314.96(d). If an 
applicant submits an amendment to a 505(b)(2) application or ANDA for 
any of the categories of changes described in these provisions and does 
not submit a new patent certification, the applicant will be required 
to verify that the proposed change described in the amendment is not 
the type of change for which a new patent certification is required 
(e.g., the proposed formulation change meets the criteria for a 
``minor'' formulation change). We seek comment on this proposal.
    We also are proposing to add Sec. Sec.  314.70(i) and 314.97(c), 
and make conforming revisions to Sec. Sec.  314.50(i)(6)(iii)(B) and 
314.94(a)(12)(viii)(C)(2), to clarify our requirements for submission 
of new patent certifications with a supplement to a 505(b)(2) 
application or ANDA. Proposed Sec. Sec.  314.70(i) and 314.97(c) would 
require an applicant to also submit a patent certification described in 
Sec.  314.50(i) or 314.94(a)(12), as appropriate, if approval is sought 
for either of the following types of supplements to a 505(b)(2) 
application or ANDA: (1) To add a new indication or other condition of 
use or (2) to add a new strength.
    FDA is not proposing to require a patent certification with a 
supplement to change the formulation or to change the physical form or 
crystalline structure of the active ingredient of a product approved in 
a 505(b)(2) application or ANDA. It is not necessary for FDA to use its 
limited resources to require patent certifications under these 
circumstances because the NDA holder for a listed drug and any patent 
owner can monitor postapproval changes in the formulation or active 
ingredient of a marketed drug product and address any patent-related 
concerns without the involvement of FDA. With respect to NDA 
supplements, it should be noted that these patent certification 
requirements apply to 505(b)(2) supplements, irrespective of whether 
the original application to which the supplement was submitted was 
approved as a stand-alone 505(b)(1) application or a 505(b)(2) 
application. A supplement to a 505(b)(2) application of the type 
described in proposed Sec.  314.70(i) is generally a 505(b)(2) 
supplement.
    Table 10 summarizes the proposed changes related to patent 
certification requirements for amendments and supplements to 505(b)(2) 
applications and ANDAs:

 Table 10--Highlights of Proposed Changes Regarding Patent Certification
  Requirements for Amendments and Supplements to 505(b)(2) Applications
                              and ANDAs \1\
------------------------------------------------------------------------
                                                Proposed revisions to
            Current regulations                      regulations
------------------------------------------------------------------------
Amended certifications--Other amendments    Amended certifications--
 (Sec.  Sec.   314.50(i)(6)(iii),            Other amendments (Sec.
 314.94(a)(12)(viii)(C))                     Sec.   314.50(i)(6)(iii),
                                             314.94(a)(12)(viii)(C))
     Except as otherwise provided,   Except as otherwise
     an applicant must amend a submitted     provided, an applicant must
     certification if, at any time before    amend a submitted
     approval of the 505(b)(2) application   certification if, at any
     or ANDA, the applicant learns that      time before approval of the
     the submitted certification is no       505(b)(2) application or
     longer accurate.                        ANDA, the applicant learns
                                             that the submitted
                                             certification is no longer
                                             accurate.
                                            Patent certification
                                             requirements (Sec.  Sec.
                                             314.60(f) and 314.96(d)).
                                             Except as provided
                                             below, an amendment to a
                                             505(b)(2) application or
                                             ANDA is required to contain
                                             patent certifications
                                             described in Sec.  Sec.
                                             314.50(i) or 314.94(a)(12),
                                             respectively, if approval
                                             is sought for any of the
                                             following types of
                                             amendments or supplements:
                                               --(1) To add a new
                                                indication or other
                                                condition of use;
                                               --(2) to add a new
                                                strength;
                                               --(3) to make other than
                                                minor changes in product
                                                formulation; or
                                               --(4) to change the
                                                physical form or
                                                crystalline structure of
                                                the active ingredient.
                                            Patent certification
                                             requirements (Sec.  Sec.
                                             314.70(i) and 314.97(c)).
                                             Except as provided
                                             below, a supplement to a
                                             505(b)(2) application or
                                             ANDA is required to contain
                                             patent certifications
                                             described in Sec.  Sec.
                                             314.50(i) or 314.94(a)(12),
                                             respectively, if approval
                                             is sought for either of the
                                             following types of
                                             supplements:
                                               --(1) To add a new
                                                indication or other
                                                condition of use; or
                                               --(2) to add a new
                                                strength.
                                             A supplement to a
                                             505(b)(2) application that
                                             seeks approval to add a new
                                             indication or other
                                             condition of use is
                                             required to contain patent
                                             certifications described in
                                             Sec.   314.50(i) only for
                                             patents that are identified
                                             as claiming an approved
                                             use. If the method-of-use
                                             patent is identified as
                                             also claiming the drug
                                             substance or drug product,
                                             the patent certification
                                             also must address the drug
                                             substance and/or drug
                                             product claims.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
  regulations, but should not be relied upon in place of the proposed
  regulation.


[[Page 6849]]

    We invite comment on this proposal and whether a new patent 
certification should be required with the submission of other types of 
amendments or supplements to a 505(b)(2) application or ANDA that may 
change the drug product in a manner that could be protected by patent.
II.F.1. Types of Amendments or Supplements for Which Patent 
Certification is Required
    II.F.1.a. Amendments or supplements to add a new indication or 
other condition of use. Proposed Sec. Sec.  314.60(f)(1), 
314.70(i)(1)(i), 314.96(d)(1), and 314.97(c)(1) require a 505(b)(2) or 
ANDA applicant to submit a new patent certification with an amendment 
or supplement to add a new indication or other condition of use for the 
drug product that is the subject of the 505(b)(2) application or ANDA. 
Although most requests for approval of a different indication or 
condition of use by a 505(b)(2) applicant could not be made as an 
amendment to the 505(b)(2) application (see Separate Marketing 
Application Guidance at 4 to 5), there are certain scenarios in which 
an applicant may submit an amendment to a 505(b)(2) application (or 
ANDA) for a new indication or other condition of use. For example, a 
505(b)(2) or ANDA applicant seeking approval for a drug product for 
which the indication has changed from prescription status to OTC use 
for the listed drug relied upon or RLD, as applicable, would be 
required to submit a new patent certification with an amendment or 
supplement to the application. These patent certification requirements 
are currently encompassed by Sec. Sec.  314.50(i)(6)(iii) and 
314.94(a)(12)(viii)(C). Proposed Sec. Sec.  314.60(f)(1), 
314.70(i)(1)(i), 314.96(d)(1), and 314.97(c)(1) would parallel the 
requirements for submission of patent information by an NDA applicant 
seeking approval of a supplement to add a new indication or other 
condition of use (see proposed Sec.  314.53(d)(2)(ii)).
    Currently, an applicant is required to submit a patent 
certification or statement with a 505(b)(2) supplement that seeks 
approval for a new indication or other condition of use (``efficacy 
supplement''). We are proposing to reduce the current patent 
certification requirements with respect to a supplement to a 505(b)(2) 
application that seeks approval for a new indication or other condition 
of use. Proposed Sec.  314.70(i)(2) states that a supplement to a 
505(b)(2) application that only seeks approval to add a new indication 
or other condition of use is required to contain patent certifications 
described in Sec.  314.50(i) only for patents that are identified as 
claiming an approved use. This proposed change preserves the NDA 
holder's intellectual property rights without requiring the 505(b)(2) 
applicant to submit a duplicative certification to patents listed in 
the Orange Book for the listed drug relied upon that have not been 
identified by the NDA holder as claiming a method of use and would not 
be implicated by the efficacy supplement. We note, however, that if a 
method-of-use patent is identified as also claiming the drug substance 
or drug product, a statement under section 505(b)(2)(B) of the FD&C Act 
would not be sufficient. The 505(b)(2) applicant's patent certification 
also must address the drug substance and/or drug product claims in the 
patent.
    II.F.1.b. Amendments or supplements to add a new strength or change 
an existing strength. Proposed Sec. Sec.  314.60(f)(2), 
314.70(i)(1)(ii), 314.96(d)(2), and 314.97(c)(2) would codify our 
current requirements with respect to an applicant's submission of a new 
patent certification with an amendment or supplement to add a new 
strength for the drug product that is the subject of the 505(b)(2) 
application or ANDA. As noted in section II.A.2.q, it is our 
longstanding practice to regard different strengths of a drug product 
as different drug products (see Apotex, Inc. v. Shalala, 53 F. Supp. 2d 
454 (D.D.C.), aff'd, 1999 U.S. App. LEXIS 29571 (D.C. Cir. 1999)).
    II.F.1.c. Amendments to make other than minor changes in product 
formulation. Proposed Sec. Sec.  314.60(f)(3) and 314.96(d)(3) would 
require a 505(b)(2) or ANDA applicant to submit a new patent 
certification with an amendment to make other than minor changes in the 
formulation of the drug product that is the subject of the original 
505(b)(2) application or ANDA. This enhanced patent certification 
requirement is intended to facilitate ongoing compliance with section 
505(b)(2)(A) and (j)(2)(A)(vii) of the FD&C Act. An applicant that 
submits a 505(b)(2) application or ANDA containing a paragraph IV 
certification to a listed patent must reevaluate whether the patent 
certification continues to be accurate after a change to the 
formulation of the proposed product submitted in an amendment to the 
505(b)(2) application or ANDA. By requiring a new patent certification 
and, with respect to a paragraph IV certification, a new notice of 
paragraph IV certification to be sent at the same time the amendment 
for the change in formulation is submitted to FDA, we aim to uphold the 
legislative balance of the Hatch-Waxman Amendments that facilitates the 
availability of generic drug products while protecting innovator 
intellectual property rights. We seek comment on this proposal.
    This requirement would apply to all amendments to change the 
formulation of a proposed product in an original 505(b)(2) application 
or ANDA, except for minor changes in product formulation that FDA would 
regard as resulting in essentially the same product. A new patent 
certification would not be required if the new formulation in the 
amendment is qualitatively (Q1) the same as the previous formulation 
(i.e., contains all of the same inactive ingredients) and 
quantitatively (Q2) essentially the same (i.e., each inactive 
ingredient differs by no more than plus or minus 5 percent from the 
previous formulation). These limits correspond to the Agency's policy 
on products that generally can be regarded as essentially the same 
(see, e.g., draft guidance for industry entitled ``Bioavailability and 
Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local 
Action'' (April 2003) at 8, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070111.pdf; 
compare Sec.  314.70(b)(2)(i)), and thus a change within these limits 
would not be likely to affect an applicant's patent certification. 
These limits also are similar to ``Level 1'' changes (those that are 
unlikely to have any detectable impact on formulation quality and 
performance) in components and composition of a drug product under the 
Agency's Scale-Up and Postapproval Changes guidance (see guidance for 
industry entitled ``Immediate Release Solid Oral Dosage Forms; Scale-Up 
and Postapproval Changes: Chemistry, Manufacturing, and Controls, In 
Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation'' 
(November 1995) at 6 to 8, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070636.pdf).
    It should be noted that an applicant seeking approval for an ANDA 
for a product intended for parenteral, ophthalmic, otic, or topical use 
must submit information to show that the proposed product contains the 
same inactive ingredients in the same concentration as the RLD, subject 
to exceptions specified in Sec.  314.94(a)(9)(iii) through (a)(9)(v). 
Additional regulatory considerations related to changes to the 
formulation of a drug product proposed in an

[[Page 6850]]

amendment to an ANDA are discussed in section II.G.1 to II.G.2 and 
II.L.
    II.F.1.d. Amendments to change the physical form or crystalline 
structure of the active ingredient. Proposed Sec. Sec.  314.60(f)(4) 
and 314.96(d)(4) would require a 505(b)(2) or ANDA applicant to submit 
a new patent certification with an amendment to change the physical 
form (e.g., different waters of hydration, solvates, and amorphous 
forms) or crystalline structure of the active ingredient of the drug 
product that is the subject of the 505(b)(2) application or ANDA. For 
example, a new patent certification would be required for an amendment 
to an ANDA that includes a change to the physical form of the active 
ingredient to conform with the physical form(s) of the active 
ingredient described in a final USP monograph.
    These patent certification requirements apply to changes to the 
active ingredient that may be submitted as an amendment to a 505(b)(2) 
application or ANDA and do not alter the Agency's policy regarding the 
types of different active ingredients (e.g., different salts, esters, 
and complexes of the same active moiety) that should be submitted in a 
separate application (see Separate Marketing Application Guidance; see 
also section II.G.3 to II.G.4). We note that the Agency has long 
considered different polymorphs to be the ``same active ingredient'' 
and pharmaceutical equivalents (see section 1.7 of the preface to the 
Orange Book (33rd Edition, 2013, at xv).
II.F.2. Requirements for Notice of Paragraph IV Certifications and 
Implications for 180-Day Exclusivity
    There are additional regulatory considerations related to the 
submission of a paragraph IV certification by an applicant required to 
submit a new patent certification with its amendment or supplement to a 
505(b)(2) application or ANDA. As a preliminary matter, we note that 
notice is required for all paragraph IV certifications, irrespective of 
whether the applicant previously provided notice of paragraph IV 
certification to the same patent or to another patent claiming the 
listed drug relied upon or RLD (see section 505(b)(3)(B) and 
(j)(2)(B)(ii) of the FD&C Act). If patent infringement litigation has 
been initiated in response to a previous notice of paragraph IV 
certification, a new paragraph IV certification submitted with an 
amendment or supplement to the 505(b)(2) application or ANDA still 
requires formal notice in accordance with Sec. Sec.  314.52 and 314.95.
    The new notice of paragraph IV certification must contain the 
information required by section 505(b)(3)(D) and (j)(2)(B)(iv) of the 
FD&C Act and Sec. Sec.  314.52(c) and 314.95(c), updated to correspond 
to the proposed product as changed by the amendment or supplement. For 
example, the detailed statement of the factual and legal basis of the 
applicant's opinion that the patent is invalid, unenforceable, or will 
not be infringed by its proposed product must be updated, as necessary, 
by the 505(b)(2) or ANDA applicant to reflect the changes proposed in 
the amendment or supplement. The notice of paragraph IV certification 
also must clarify whether the amendment or supplement contains any 
required bioavailability or bioequivalence data that was necessary to 
support the proposed change to the 505(b)(2) application or ANDA.
    With respect to any listed patent challenged by the applicant in an 
amendment or supplement to the 505(b)(2) application or ANDA for which 
the NDA holder or patent owner initiated patent infringement litigation 
within the statutory timeframe in response to notice of paragraph IV 
certification, the availability of a 30-month stay will depend upon 
whether the NDA holder filed information on the patent at issue with 
FDA prior to the date of submission of the 505(b)(2) application or the 
date of submission of the ANDA (which FDA later determined to be 
substantially complete) that refers to the listed drug claimed by the 
patent (see section 505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act). 
Accordingly, a 30-month stay may result from initiation of a patent 
infringement action in response to a second notice of paragraph IV 
certification provided at the time of submission of an amendment or 
supplement to a 505(b)(2) application or ANDA if the patent was listed 
prior to the date of submission of the original 505(b)(2) application 
or ANDA and, for example, the infringement action was warranted by the 
change proposed in the amendment or supplement.
    A first applicant that submits an amendment to its pending ANDA or 
a supplement would be considered to have lawfully maintained a 
paragraph IV certification to the patent upon which eligibility for 
180-day exclusivity was based if the amendment or supplement is 
accompanied by another paragraph IV certification to the patent and 
notice of paragraph IV certification is sent in accordance with Sec.  
314.95(d).

II.G. Amendments or Supplements to a 505(b)(2) Application for a 
Different Drug and Amendments or Supplements to an ANDA That Reference 
a Different Listed Drug (Proposed Sec. Sec.  314.60, 314.70, 314.96, 
314.97)

    The MMA added section 505(b)(4)(A), (b)(4)(B), (j)(2)(D)(i), and 
(j)(2)(D)(ii) to the FD&C Act, which generally prohibit the submission 
of certain types of changes in an amendment or a supplement to a 
505(b)(2) application or an ANDA, respectively. We interpret these 
provisions in the context of the MMA's amendment of section 
505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act to restrict the 
availability of a 30-month stay of approval in certain circumstances 
involving amendments and supplements to a 505(b)(2) application or ANDA 
and seek comment on this approach.
    Section 1101(a)(1)(A) of the MMA amended section 505(j) of the FD&C 
Act to generally prohibit an ANDA applicant from amending or 
supplementing an ANDA ``to seek approval of a drug referring to a 
different listed drug from the listed drug identified in the 
application as submitted [to FDA]'' (section 505(j)(2)(D)(i) of the 
FD&C Act). The textual reference in the statute to ``seek approval of a 
drug referring to a different listed drug'' is clearly understood in 
the context of section 505(j) of the FD&C Act and FDA's regulatory 
scheme for the approval of ANDAs. An applicant that submits an ANDA for 
a duplicate of a listed drug is required to identify and rely upon the 
listed drug designated by FDA as the RLD (see Sec.  314.94(a)(3)). An 
applicant also may petition FDA to request permission to submit an ANDA 
that differs from a selected listed drug in route of administration, 
dosage form, or strength, or that has one different active ingredient 
in a combination drug product (see section 505(j)(2)(C) of the FD&C 
Act). Accordingly, we are proposing to add Sec. Sec.  314.96(c) and 
314.97(b) to state that an ANDA applicant may not amend or supplement 
an ANDA to seek approval of a drug referring to listed drug that is 
different from the RLD identified in the ANDA. An ANDA applicant that 
seeks to refer to a listed drug different from the RLD identified in 
the initial ANDA must submit a new ANDA (see section 505(j)(2)(D)(i) of 
the FD&C Act; see also section II.G.1 to II.G.2 of this document).
    Section 1101(b)(1)(A) of the MMA amended section 505(b) of the FD&C 
Act to generally prohibit an applicant from amending or supplementing 
``an application referred to in [section

[[Page 6851]]

505(b)(2)] to seek approval of a drug that is a different drug than the 
drug identified in the application as submitted to the Secretary.'' 
Although section 1101(a) and (b) of the MMA are parallel in structure, 
the statutory text restricting an applicant from amending or 
supplementing a 505(b)(2) application in certain circumstances differs 
from the corresponding restrictions for ANDAs. Section 505(b)(4)(A) 
prohibits an amendment or a supplement ``to seek approval of a drug 
that is a different drug'' (emphasis added) while section 
505(j)(2)(D)(i) prohibits an amendment or supplement to an ANDA ``to 
seek approval of a drug referring to a different listed drug'' 
(emphasis added).
    The MMA also amended section 505(c)(3)(C) and (j)(5)(B)(iii) of the 
FD&C Act to permit a 30-month stay of approval of a 505(b)(2) 
application or ANDA only with respect to patents for which the NDA 
holder submitted information to FDA prior to the date of submission of 
the 505(b)(2) application or the date of submission of the ANDA (which 
FDA later determines to be substantially complete) that refers to the 
listed drug claimed by the patent. The ``date on which the application 
. . . was submitted'' specifically excludes the date of submission of 
an amendment or supplement to a 505(b)(2) application or ANDA. Given 
this limitation on the patents that may give rise to a 30-month stay, 
the MMA may have created an incentive for a 505(b)(2) or ANDA applicant 
to seek approval for a change to a drug, or to reference a different 
listed drug, through an amendment or a supplement, rather than by 
submitting a new application. To address this concern, section 
505(b)(4)(A) and (j)(2)(D)(i) of the FD&C Act ensure that 505(b)(2) and 
ANDA applicants do not use the amendment or supplement process to evade 
the possibility of a 30-month stay of approval that otherwise would 
have applied if the 505(b)(2) applicant sought approval for a drug that 
is a different drug or if the ANDA applicant sought to refer to a 
different RLD in the original 505(b)(2) application or ANDA, 
respectively. Accordingly, we interpret section 505(b)(4)(A) of the 
FD&C Act in a manner that is consistent with the statutory text, 
accomplishes the statutory goal of preserving a meaningful opportunity 
for a single 30-month stay, and reflects, to the extent feasible, 
Congress' expressed intent to preserve rather than disrupt FDA 
processes regarding submission of amendments and supplements to 
505(b)(2) applications and ANDAs.
    We propose that a drug will be considered a ``different drug'' for 
purposes of section 505(b)(4)(A) of the FD&C Act if it has been 
modified to have a different active ingredient, different route of 
administration, or different dosage form. Similarly, a drug will be 
considered to be a different drug if it has been modified to have 
different excipients that require either a separate clinical study to 
establish safety or effectiveness or, for topical products, that 
requires a separate in vivo demonstration of bioequivalence (see 
proposed Sec. Sec.  314.60(e) and 314.70(h)). Consistent with FDA's 
``bundling'' policy in effect at the time of enactment of the MMA, an 
applicant may not seek approval for these types of changes to a drug 
through an amendment or supplement to the 505(b)(2) application; the 
applicant is required to submit a new 505(b)(2) application (see draft 
guidance for industry entitled ``Submitting Separate Marketing 
Applications and Clinical Data for Purposes of Assessing User Fees'' 
(describing FDA's bundling policy at the time of enactment of the MMA 
in 2003); see also Separate Marketing Applications Guidance). These 
changes to a drug product are significant enough that it is reasonable 
to assume that one or more patents for the listed drug might be 
implicated by the change and, if an action for patent infringement is 
brought in response to a paragraph IV certification to a listed patent, 
an opportunity for 30-month stay would be appropriate. Thus, FDA has 
concluded that these modifications to a drug would make the drug a 
``different drug'' for purposes of section 505(b)(4)(A) of the FD&C 
Act. An applicant seeking marketing approval for a drug that has been 
modified in these ways must submit a separate marketing application for 
the different drug product, and not an amendment or supplement.
    We considered possible alternative interpretations of the phrase 
``to seek approval of a drug that is a different drug'' in section 
505(b)(4)(A) of the FD&C Act. The narrowest reading of this text would 
preclude the submission of an amendment or a supplement to a 505(b)(2) 
application for any change (including labeling changes and 
manufacturing changes) that would arguably render the proposed product 
a ``different drug'' than the drug identified in the original 
submission of the application. If labeling changes, for example, could 
not be made through an amendment or a supplement to a 505(b)(2) 
application, each such change would require the submission of a 
separate 505(b)(2) application, with related regulatory and 
administrative burdens, and user fee and review cycle implications. We 
did not adopt this reading because it would have resulted in an 
unwarranted departure from FDA's previous practice for handling such 
changes.
    In applying section 505(b)(4)(A) of the FD&C Act, we initially 
interpreted the phrase ``drug that is a different drug'' in section 
505(b)(4)(A) in a manner that was influenced by and intended to be 
consistent with the phrase ``drug referring to a different listed 
drug'' in section 505(j)(2)(D)(i) of the FD&C Act. Under this 
interpretation, an applicant was not permitted to amend or supplement a 
505(b)(2) application to seek approval of a drug that relied on the 
Agency's finding of safety and/or effectiveness for a listed drug that 
was different from the listed drug(s) identified in the original 
submission of the application. This approach assumed that the 
difference in phrasing between section 505(b)(4)(A) and (j)(2)(D)(i) of 
the FD&C Act was simply intended to reflect the different statutory 
frameworks for 505(b)(2) applications and ANDAs. This interpretation 
also was intended to ensure that a 505(b)(2) applicant did not 
circumvent the 30-month stay provisions of the FD&C Act by amending or 
supplementing a 505(b)(2) application to identify a new or additional 
listed drug upon which it relied for approval.
    We found our initial approach to be overly restrictive in practice, 
however, as this interpretation required withdrawal and resubmission of 
a 505(b)(2) application to identify a new or additional listed drug 
even where there were no patents listed in the Orange Book for the new 
or additional listed drug, and thus there was no possibility of a 30-
month stay.
    Accordingly, we are proposing a narrower interpretation that is 
guided by Congress' expressed view that these provisions are intended 
to ``reflect the FDA's current practice regarding those changes and 
variations to both innovator and generic drugs that may be approved 
under amendments and supplements to previously filed NDAs and ANDAs . . 
.'' (see Conference Report on H.R. 1, November 20, 2003, at H12099).
    Our interpretation of section 505(b)(4)(A), (b)(4)(B), 
(j)(2)(D)(i), and (j)(2)(D)(ii) of the FD&C Act seeks to preserve the 
legislative balance of the Hatch-Waxman Amendments with respect to 
facilitating the availability of drug products that meet the statutory 
requirements for approval while protecting innovator intellectual 
property rights (and allowing for an early resolution of any patent 
infringement litigation). We seek

[[Page 6852]]

comment on this proposal and potential alternatives to maintain the 
intended balance.
    In the Federal Register of November 4, 2004 (69 FR 64314), FDA 
announced the availability of a draft guidance for industry, issued as 
required by section 505(j)(2)(D)(iii) of the FD&C Act, that defined the 
term ``listed drug'' for purposes of section 505(j)(2)(D) with respect 
to amendments and supplements to an ANDA (see draft guidance for 
industry entitled ``Listed Drugs, 30-Month Stays, and Approval of ANDAs 
and 505(b)(2) Applications Under Hatch-Waxman, as Amended by the 
Medicare Prescription Drug, Improvement, and Modernization Act of 
2003'' (October 2004), available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072887.pdf) (Draft 
Guidance on Listed Drugs). In the Draft Guidance on Listed Drugs, we 
advised that our definition of the term ``listed drug'' is set forth in 
Sec.  314.3, and that we did not intend to amend that definition to 
implement section 505(j)(2)(D) of the FD&C Act. Although minor 
revisions to the definition of listed drug are proposed in this 
rulemaking (see section II.A.2.s), these proposed revisions do not 
substantively alter the definition for purposes of section 505(j)(2)(D) 
of the FD&C Act. We note that different strengths of an approved drug 
product continue to be regarded as different listed drugs. However, the 
FD&C Act expressly permits an applicant to amend or supplement a 
505(b)(2) application or ANDA to seek approval of a different strength 
(see section 505(b)(4)(B) and (j)(2)(D)(ii) of the FD&C Act).
    Table 11 summarizes the proposed changes related to amendments or 
supplements to a 505(b)(2) application or ANDA:

    Table 11--Highlights of Proposed Changes Regarding Amendments or
           Supplements to a 505(b)(2) Application or ANDA \1\
------------------------------------------------------------------------
        Current regulations           Proposed revisions to regulations
------------------------------------------------------------------------
[No corresponding regulation].....  Amendments and Supplements--
                                     Different drug (Sec.  Sec.
                                     314.60(e) and 314.70(h))
                                     Applicant may not amend a
                                     505(b)(2) application to seek
                                     approval of a drug that is a
                                     different drug from the drug in the
                                     original submission of the
                                     505(b)(2) application.
                                     Applicant may not
                                     supplement a 505(b)(2) application
                                     to seek approval of a drug that is
                                     a different drug from the drug in
                                     the approved 505(b)(2) application.
                                     For purposes of this
                                     section, a drug is a different drug
                                     if it has been modified to have a
                                     different active ingredient,
                                     different route of administration,
                                     different dosage form, or
                                     difference in excipients that
                                     requires either a separate clinical
                                     study to establish safety or
                                     effectiveness or, for topical
                                     products, that requires a separate
                                     in vivo demonstration of
                                     bioequivalence.
                                     Approval of a different
                                     drug must be requested in a new
                                     505(b)(2) application.
                                     Notwithstanding the
                                     limitations described above, an
                                     applicant may amend or supplement
                                     the 505(b)(2) application to seek
                                     approval of a different strength.
[No corresponding regulation].....  Amendments and Supplements--
                                     Different listed drug (Sec.  Sec.
                                     314.96(c) and 314.97(b))
                                     Applicant may not amend an
                                     ANDA to seek approval of a drug
                                     referring to a listed drug that is
                                     different from the RLD identified
                                     in the ANDA.
                                    --Applies if, at any time before
                                     ANDA approval, a different listed
                                     drug approved in an NDA is
                                     pharmaceutically equivalent to the
                                     product in the ANDA and is
                                     designated as an RLD.
                                    --Applies if changes are proposed in
                                     an amendment to the ANDA such that
                                     the proposed product is a
                                     pharmaceutical equivalent to a
                                     different listed drug than the RLD
                                     identified in the ANDA.
                                     Applicant may not
                                     supplement an ANDA to seek approval
                                     of a drug referring to a listed
                                     drug that is different from the
                                     current RLD identified in the ANDA.
                                    --Applies if changes are proposed in
                                     a supplement to the ANDA such that
                                     the proposed product is a
                                     pharmaceutical equivalent to a
                                     different listed drug than the RLD
                                     identified in the ANDA.
                                     A change of the RLD must be
                                     submitted in a new ANDA.
                                     Notwithstanding the
                                     limitations described above, an
                                     applicant may amend or supplement
                                     the ANDA to seek approval of a
                                     different strength.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
  regulations, but should not be relied upon in place of the proposed
  regulation.

II.G.1. Amendments to an Unapproved ANDA (Proposed Sec.  314.96(c))
    We are proposing to revise Sec.  314.96 regarding amendments to an 
unapproved ANDA by adding paragraph (c) to implement section 
505(j)(2)(D)(i) and (ii) of the FD&C Act. Proposed Sec.  314.96(c) 
states that an applicant may not amend an ANDA to seek approval of a 
drug referring to a listed drug that is different from the RLD 
identified in the ANDA. Two examples in proposed Sec.  314.96(c) 
illustrate the application of this provision.
    II.G.1.a. Approval of a pharmaceutically equivalent drug product. 
Proposed Sec.  314.96(c) states that if at any time before approval of 
the ANDA, an NDA is approved for a drug product that is 
pharmaceutically equivalent to the product in the pending ANDA and that 
NDA is designated as an RLD, the applicant is not permitted to amend 
its pending ANDA to reference the new RLD. This change must be 
submitted in a new ANDA. As a preliminary matter, we note that the drug 
product designated as an RLD may not necessarily be the drug product 
identified in the Orange Book as the reference standard for 
bioequivalence studies, for example, for drug product lines with 
multiple strengths. An ANDA would not be ineligible for approval 
because it relied upon an RLD that was not the reference standard or 
because it relied upon one of two or more potential RLDs for a 
pharmaceutically equivalent product. FDA's policy on designating an 
additional RLD for multiple source products is set forth in the 
preamble to the 1992 final rule and also described in the preface to 
the Orange Book. In the 1992 final rule, we stated in relevant part: 
``FDA recognizes that, for multiple source products, a product not 
designated as the listed drug and not shown bioequivalent to the listed 
drug may be shielded from direct generic competition. If an applicant 
believes that there are sound reasons for designating another drug as a 
reference listed drug, it should consult FDA'' (57 FR 17950 at 17958; 
see also Letter to Robert W. Pollock, Lachman Consultant Services, 
Inc., dated April 18, 2005, regarding Docket No. FDA-2004-P-0466 
(requesting designation of DiaBeta as a second RLD for glyburide 
tablets, 5

[[Page 6853]]

mg), available at http://www.regulations.gov).
    The scenario described in proposed Sec.  314.96(c) arises, for 
example, when an ANDA is submitted after the grant of a suitability 
petition pursuant to section 505(j)(2)(C) of the FD&C Act for a new 
dosage form, route of administration, or new active ingredient (in a 
drug product containing more than one active ingredient) and another 
applicant obtains approval of an NDA (including a 505(b)(2) 
application) for the change described in the suitability petition 
before the ANDA is approved. Under these circumstances, it is FDA's 
longstanding position that an ANDA (including a tentatively approved 
ANDA) can no longer reference the approved suitability petition and the 
listed drug described therein as the basis for ANDA submission (see 
Sec. Sec.  314.94(a)(3) and 314.127(a)(5), (a)(6), and (a)(12) and 
section II.I). Prior to enactment of the MMA, an applicant with a 
pending ANDA based upon an approved ``suitability petition'' (a 
petitioned ANDA) could have amended its ANDA to change the basis for 
submission (see Sec.  314.94(a)(3)) to a pharmaceutically equivalent 
product that subsequently had been approved in an NDA and was 
designated by FDA as the RLD. However, the plain language of section 
505(j)(2)(D)(i) of the FD&C Act (added by the MMA) prohibits an ANDA 
applicant from amending its ANDA to change the basis for submission to 
a pharmaceutically equivalent product subsequently approved in an NDA. 
Accordingly, for an ANDA applicant to obtain approval for a 
pharmaceutically equivalent product, the applicant would be required to 
submit a new ANDA that identifies the pharmaceutically equivalent 
product as its basis for ANDA submission under Sec.  314.94 and meet 
applicable statutory and regulatory requirements (see, generally, 
discussion in the Letter from Janet Woodcock, M.D., Director, CDER, to 
Mark S. Aikman, Pharm.D., Osmotica Pharmaceutical Corp., dated November 
25, 2008, regarding Docket No. FDA-2008-P-0329, available at http://www.regulations.gov) (Venlafaxine ER Citizen Petition Response).
    FDA's policy is scientifically justified because an NDA (either a 
``stand-alone'' NDA or 505(b)(2) application) approved for the change 
described in a suitability petition need not be bioequivalent to the 
listed drug identified in the suitability petition. For example, a 
505(b)(2) applicant may develop a different dosage form of a drug 
product that is intentionally more bioavailable than a previously 
approved product (see Sec.  314.54(b)). A 505(b)(2) applicant also may 
have relied upon a different listed drug in support of its 505(b)(2) 
application than the listed drug identified in the suitability 
petition. By ensuring that an ANDA has clearly demonstrated 
bioequivalence to a pharmaceutically equivalent drug product identified 
as the RLD, we enhance the utility and accuracy of FDA's therapeutic 
equivalence determinations. We previously have explained that ``this 
approach reduces the potentially confusing proliferation of 
pharmaceutically equivalent drug products that have not demonstrated 
therapeutic equivalence, and ensures that ANDAs . . . will be 
therapeutically equivalent and thus substitutable for the RLD'' 
(Venlafaxine ER Citizen Petition Response at 13).
    FDA's requirement that an applicant with a pending ANDA must change 
its basis for ANDA submission upon approval of an NDA for the same drug 
product described in the suitability petition also is intended to 
ensure that ANDA applicants do not circumvent the patent certification 
requirements of section 505(j)(2)(A)(vii) and (j)(2)(A)(viii) of the 
FD&C Act through the suitability petition process. Otherwise, if a 
patent were listed for a drug product approved in an NDA and designated 
as the RLD and a pending ANDA submitted pursuant to an approved 
suitability petition were permitted to amend its application to refer 
to the new RLD, even a single 30-month stay would not be available 
should the NDA holder or patent owner initiate patent infringement 
litigation within the statutory timeframe in response to a paragraph IV 
certification for a patent listed after submission of the original ANDA 
that FDA later determined to be substantially complete. In addition, 
our policy appropriately protects any marketing exclusivity that has 
been granted to the newly approved RLD.
    The Agency has rejected the argument that a pending ANDA submitted 
pursuant to an approved suitability petition may continue to reference 
the listed drug identified in the suitability petition after a 
pharmaceutically equivalent product has been approved in an NDA 
(including a 505(b)(2) application) and is designated as the RLD (see 
generally Venlafaxine ER Citizen Petition Response). This ``reflects 
the Agency's judgment that considerations regarding an ANDA's limited 
reliance on an approved suitability petition are outweighed by the need 
for a clear determination of therapeutic equivalence for a generic drug 
product and protection of intellectual property rights accorded an NDA 
holder'' (Venlafaxine ER Citizen Petition Response at 9). In section 
II.I, we describe our proposed revisions to Sec.  314.93(e) and (f) to 
codify FDA's policy that the listed drug identified in an approved 
suitability petition can no longer be the basis for submission for an 
unapproved ANDA after a drug product is approved in an NDA for the 
change described in the petition.
    In the case of a first applicant that had been eligible for 180-day 
exclusivity based on a paragraph IV certification to a patent listed in 
the Orange Book for the listed drug described in the suitability 
petition, we note that a new assessment of first applicant status would 
begin upon submission of a new ANDA. This reflects the fact that any 
ANDA that referenced the listed drug identified in the suitability 
petition after approval of a pharmaceutically equivalent product could 
not be approved. Further, an applicant that withdrew its ANDA would not 
have lawfully maintained its paragraph IV certification and would no 
longer be eligible for first applicant status.
    II.G.1.b. Changes to the drug product proposed in the ANDA. The 
second example in proposed Sec.  314.96(c) that illustrates the 
application of this provision involves one or more changes proposed in 
an amendment to an ANDA that would result in the proposed product being 
a pharmaceutical equivalent to a different listed drug than the RLD 
identified in the ANDA. This type of change must be submitted in a new 
ANDA that identifies the pharmaceutically equivalent product as the new 
RLD. In the Draft Guidance on Listed Drugs, we explained that ``[a]ll 
changes that would have the effect of seeking approval for a drug 
product different from the listed drug cited in the initial submission 
(e.g., different active ingredient, dosage form, route of 
administration) should be made in a new application. When the Orange 
Book identifies as a separate listed drug a product with the 
characteristics (e.g., active ingredient, dosage form, route of 
administration) for which the applicant is seeking approval, the 
applicant should submit a separate ANDA referencing the corresponding 
listed drug'' (Draft Guidance on Listed Drugs, at 3). This generally 
conforms with Agency practice before passage of the MMA with respect to 
certain types of changes (e.g., a change in the dosage form or a change 
in the formulation that may significantly affect absorption of the 
active drug ingredient or active moiety) that should be submitted as a 
separate ANDA (see guidance for industry entitled ``Variations in Drug

[[Page 6854]]

Products that May Be Included in a Single ANDA'' (December 1998), 
available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072892.pdf) 
(Guidance on Drug Product Variations). For example, we noted 
``[g]enerally, when there is a separate NDA as a RLD for a specific 
drug product there should be a separate abbreviated application for 
that NDA'' (Guidance on Drug Product Variations, at 2).
    Proposed Sec.  314.96(c) clarifies that, notwithstanding these 
restrictions on amendments to an ANDA, an applicant is permitted to 
amend an ANDA to seek approval for a different strength of the drug 
product (see section 505(j)(2)(D)(ii) of the FD&C Act). As discussed in 
section II.A.2.bb, we interpret this exception for different strengths 
of the drug product to include changes to the concentration or to the 
total drug content of a parenteral drug product. We note that, unlike 
original ANDAs, not all amendments are subject to a filing review by 
the Office of Generic Drugs to determine whether the submission may be 
formally received for substantive review. Accordingly, it is possible 
that an ANDA applicant that submits an amendment not permitted by 
statute may be informed late in the review process that the proposed 
change to its ANDA must be submitted as a new ANDA. We encourage ANDA 
applicants with questions about whether a proposed amendment to an ANDA 
would be precluded by section 505(j)(2)(D)(i) of the FD&C Act to 
contact the Office of Generic Drugs for further guidance.
II.G.2. Supplements to an ANDA (Proposed Sec.  314.97(b))
    We are proposing to revise Sec.  314.97 regarding supplements by 
designating the current text as paragraph (a) and by adding proposed 
paragraph (b) to implement section 505(j)(2)(D)(i) and (ii) of the FD&C 
Act. Proposed Sec.  314.97(b) explains that an applicant may not 
supplement an ANDA to seek approval of a drug referring to a listed 
drug that is different from the current RLD identified in the ANDA. 
This restriction applies if changes are proposed in a supplement to the 
ANDA that would result in the proposed product being pharmaceutically 
equivalent to a different listed drug than the RLD identified in the 
underlying ANDA. This type of change must be submitted in a new ANDA 
that identifies the pharmaceutically equivalent product as the new RLD.
    There are several types of changes that may be proposed in a 
supplement to an ANDA that would result in the proposed product being 
pharmaceutically equivalent to a different listed drug than the RLD 
identified in the underlying ANDA. For example, the scenario described 
in proposed Sec.  314.97(b) may arise if the RLD for the drug product 
approved in an ANDA is subsequently changed from prescription use to 
OTC status for some or all conditions of use of the drug product. An 
ANDA holder for the drug product with the ``switched'' conditions of 
use would be required to seek approval of the drug product for OTC use 
because the FD&C Act does not permit a drug product to be marketed as 
prescription and OTC for the same conditions of use at the same time 
(see section 503(b) of the FD&C Act (21 U.S.C. 353(b)). However, if the 
NDA holder for the RLD obtained approval of the switch from 
prescription use to OTC status in a separate NDA (for example, if fewer 
than all conditions of use were switched to OTC status), then the NDA 
for OTC use would be considered a different RLD. Section 
505(j)(2)(D)(i) of the FD&C Act does not permit an ANDA holder to refer 
to a different RLD in a supplement (or, with respect to a pending ANDA, 
an amendment) to its ANDA. This type of change must be submitted in a 
new ANDA that identifies the different NDA for OTC use as the RLD.
    We note, however, that an ANDA holder may submit a supplement that 
seeks to demonstrate bioequivalence to a different listed drug when 
there are multiple RLDs (see, e.g., Orange Book, 33rd Edition (2013) at 
xx to xxi (Description of Special Situations--levothyroxine sodium)). 
In this case, the submission of additional bioequivalence data in an 
ANDA supplement is not for the purpose of seeking approval of a drug 
referring to a different RLD, but rather to obtain an additional 
therapeutic equivalence rating. This type of change may continue to be 
submitted as a supplement to an ANDA.
    Proposed Sec.  314.97(b) clarifies that, notwithstanding these 
restrictions on supplements to an ANDA, an applicant is permitted to 
supplement an ANDA to seek approval for a different strength of the 
drug product (see section 505(j)(2)(D)(ii) of the FD&C Act). As 
discussed in section II.G.1.b, we interpret this exception for 
different strengths of the drug product to include changes to the 
concentration or to the total drug content of a parenteral drug product 
(see also section II.A.2.bb).
II.G.3. Amendments to an Unapproved 505(b)(2) Application (Proposed 
Sec.  314.60(e))
    We are proposing to revise Sec.  314.60 regarding amendments to an 
unapproved 505(b)(2) application by adding proposed paragraph (e) to 
implement section 505(b)(4)(A) and (b)(4)(B) of the FD&C Act. Proposed 
Sec.  314.60(e) states that an applicant may not amend a 505(b)(2) 
application to seek approval of a drug that is a different drug from 
the drug in the original submission of the 505(b)(2) application. For 
purposes of this section, a drug is a different drug if it has been 
modified to have a different active ingredient, different route of 
administration, different dosage form, or difference in excipients that 
requires either a separate clinical study to establish safety or 
effectiveness or, for topical products, that requires a separate in 
vivo demonstration of bioequivalence.
    II.G.3.a. Applications within the scope of section 505(b)(4)(A) of 
the FD&C Act. Section 505(b)(4)(A) of the FD&C Act restricts certain 
types of amendments and supplements to a 505(b)(2) application. We 
interpret this statutory provision to apply to an NDA that was 
submitted as a 505(b)(2) application and to an NDA that was submitted 
as a stand-alone 505(b)(1) application but was misclassified by the 
applicant. A stand-alone 505(b)(1) application would be misclassified 
if, for example, the application relied, at least in part, on the 
Agency's finding of safety and/or effectiveness for one or more listed 
drugs or published literature. Such an NDA is considered to be a 
505(b)(2) application even if the applicant failed to identify the 
listed drug(s) in accordance with Sec.  314.54(a)(1)(iii) and comply 
with applicable regulatory requirements. It would be inconsistent with 
the statutory scheme, as amended by the MMA, to permit an applicant to 
circumvent the restrictions on amendments to a 505(b)(2) application 
and the potential implications for the availability of a 30-month stay 
of approval pursuant to section 505(c)(3)(C) of the FD&C Act merely by 
incorrectly characterizing the original submission as a stand-alone 
505(b)(1) application.
    We note, however, that reliance on a listed drug pursuant to 
section 505(b)(2) of the FD&C Act generally assumes that the drug the 
applicant is referencing is one for which it is not the application 
holder and for which it would not have a right of reference or use. 
Accordingly, an applicant that cross-references relevant studies in its 
own previous

[[Page 6855]]

505(b)(2) application (i.e., studies that were conducted by or for the 
applicant or to which the applicant has obtained a right of reference 
or use) would not be a 505(b)(2) applicant as to those portions of its 
previous 505(b)(2) application. However, an applicant may be relying, 
in part, for approval of its current NDA upon the Agency's finding of 
safety and/or effectiveness for a listed drug identified in its 
previous 505(b)(2) application, to which it does not have a right of 
reference or use. In this scenario, if an applicant continues to rely 
upon the original listed drug for approval of its current NDA, then it 
is a 505(b)(2) application and the applicant must identify the original 
listed drug in accordance with Sec.  314.54 and comply with other 
applicable regulatory requirements.
    An applicant also may not amend a literature-based 505(b)(2) 
application to seek approval of a drug that has been modified to have a 
different active ingredient, different route of administration, 
different dosage form, or difference in excipients that requires either 
a separate clinical study to establish safety or effectiveness or, for 
topical products, that requires a separate in vivo demonstration of 
bioequivalence.
    II.G.3.b. Proposed amendments subject to section 505(b)(4)(A) of 
the FD&C Act. Proposed Sec.  314.60(e) provides that the statutory 
restriction on amending a 505(b)(2) application to seek approval of a 
drug that is a different drug from the drug in the original submission 
of the 505(b)(2) application applies to any proposed amendment, even if 
the amendment is submitted prior to the Agency's decision regarding 
whether the 505(b)(2) application can be filed in accordance with Sec.  
314.101(a). This standard is consistent with the MMA's amendments to 
section 505(c)(3)(C) of the FD&C Act to limit the availability of a 30-
month stay of approval to patents for which the NDA holder submitted 
information to FDA ``before the date on which the application 
(excluding an amendment or supplement to the application) was 
submitted.''
    Under proposed Sec.  314.60, an applicant cannot amend a 505(b)(2) 
application to seek approval for a drug that has been modified to have 
a different active ingredient. This includes, but is not limited to, a 
different salt, ester, or complex of the same active moiety (compare 
section II.F.1.d). A change in the route of administration or dosage 
form also cannot be made in an amendment to a 505(b)(2) application 
unless the product is qualitatively (Q1) the same and quantitatively 
(Q2) essentially the same as the proposed drug product in the original 
505(b)(2) application for all routes of administration or dosage forms, 
as applicable.
    An applicant also cannot amend a 505(b)(2) application to seek 
approval for a drug that has been modified to have a difference in 
excipients that requires either a separate clinical study to establish 
safety or effectiveness or, for topical products, that requires a 
separate in vivo demonstration of bioequivalence (see Sec.  
320.24(b)(4)). These proposed modifications would result in a different 
drug for which approval must be requested in a new 505(b)(2) 
application.
    However, notwithstanding these restrictions on amendments to a 
505(b)(2) application, an applicant is permitted to amend a 505(b)(2) 
application to identify a new or additional listed drug upon which the 
application relies for approval.
    In addition, proposed Sec.  314.60(e) clarifies that an applicant 
is permitted to amend a 505(b)(2) application to seek approval for a 
different strength of the drug product (see section 505(b)(4)(B) of the 
FD&C Act; see also sections II.A.2.bb and II.G.1.b of this document).
II.G.4. Supplements to a 505(b)(2) Application (Proposed Sec.  
314.70(h))
    We are proposing to revise Sec.  314.70 regarding supplements to an 
approved 505(b)(2) application by adding proposed paragraph (h) to 
implement section 505(b)(4)(A) and (b)(4)(B) of the FD&C Act. Proposed 
Sec.  314.70(h) states that an applicant may not supplement a 505(b)(2) 
application to seek approval of a drug that is a different drug from 
the drug in the original submission of the 505(b)(2) application. For 
purposes of this section, a drug is a different drug if it has been 
modified to have a different active ingredient, different route of 
administration, different dosage form, or difference in excipients that 
requires either a separate clinical study to establish safety or 
effectiveness or, for topical products, that requires a separate in 
vivo demonstration of bioequivalence (see discussion in section 
II.G.3.b). These proposed modifications would result in a different 
drug for which approval must be requested in a new 505(b)(2) 
application.
    In addition, proposed Sec.  314.70(h) clarifies that, 
notwithstanding these restrictions on supplements to a 505(b)(2) 
application, an applicant is permitted to supplement a 505(b)(2) 
application to seek approval for a different strength of the drug 
product (see section 505(b)(4)(B) of the FD&C Act; see also sections 
II.A.2.bb and II.G.1.b of this document).
    We interpret section 505(b)(4)(A) of the FD&C Act to apply to the 
submission of a 505(b)(2) supplement to an NDA approved through the 
505(b)(2) pathway, irrespective of whether the original 505(b)(2) 
application relied upon published literature or the Agency's finding of 
safety and/or effectiveness for one or more listed drugs. However, 
because the statutory text expressly applies to a supplement to a 
505(b)(2) application, we do not interpret the restriction in section 
505(b)(4)(A) to apply to a 505(b)(2) supplement to an NDA that received 
approval as a stand-alone 505(b)(1) application unless an intervening 
505(b)(2) supplement has been approved for that NDA (see Sec.  314.3(b) 
(defining the term ``application'' to include all supplements to the 
application)).

II.H. Procedure for Submission of an Application Requiring 
Investigations for Approval of a New Indication for, or Other Change 
From, a Listed Drug (Proposed Sec.  314.54)

    We are proposing to revise Sec. Sec.  314.50(i), 314.54(a), and 
314.125(b) to establish the requirement that an applicant identify a 
pharmaceutically equivalent product, if already approved, as a listed 
drug relied upon to support approval of a 505(b)(2) application.
    FDA's longstanding policy has been that a 505(b)(2) applicant may 
rely on FDA's finding of safety and/or effectiveness for a listed drug 
only to the extent that the proposed product in the 505(b)(2) 
application shares characteristics (e.g., active ingredient, dosage 
form, route of administration, strength, indication, conditions of use) 
in common with the listed drug. To the extent that the listed drug and 
the drug proposed in the 505(b)(2) application differ, the 505(b)(2) 
application must include sufficient data to demonstrate that the 
proposed drug meets the statutory approval standard for safety and 
effectiveness. The 505(b)(2) approval pathway is not intended for a 
``duplicate'' of a listed drug that is eligible for approval in an 
ANDA, and FDA would refuse to file such a 505(b)(2) application (see 
Sec.  314.101(d)(9)). The Hatch-Waxman Amendments established a 
specific abbreviated approval pathway for duplicates of a listed drug 
in section 505(j) of the FD&C Act.
    However, there are circumstances in which a proposed drug product 
that is pharmaceutically equivalent to a listed drug (i.e., drug 
products in the same dosage form and route(s) of

[[Page 6856]]

administration that contain the same amount of the same active drug 
ingredient and that meet other applicable standards) is not eligible 
for approval as an ANDA and must be submitted as an NDA. For example, a 
proposed extended-release drug product may intentionally differ in its 
pharmacokinetic profile from a listed drug that is also an extended-
release drug product such that the proposed product cannot meet the 
bioequivalence requirement for ANDAs (see section 505(j)(2)(A)(iv) of 
the FD&C Act; compare Sec.  314.54(b)). Certain drug products intended 
for parenteral, ophthalmic, otic, or topical use may contain 
differences in excipients that render the drug product ineligible for 
submission in an ANDA (see Sec.  314.94(a)(9)(iii) to (a)(9)(v)). For 
certain complex drug products, an applicant may be unable to 
demonstrate ``sameness'' of the active ingredient as required for 
submission of an ANDA (see section 505(j)(2)(A)(ii) of the FD&C Act). A 
request for approval of a new indication for a pharmaceutically 
equivalent drug product also is ineligible for submission as an ANDA. 
These changes to a listed drug must be submitted in an NDA.
    We have explained that a 505(b)(2) applicant may rely on FDA's 
finding of safety and effectiveness for a listed drug ``only to the 
extent that such reliance would be allowed under section 505(j) of the 
act'' (1989 proposed rule, 54 FR 28872 at 28892). If a pharmaceutically 
equivalent drug product has been approved before a 505(b)(2) 
application is submitted, then we consider the 505(b)(2) applicant to 
be implicitly relying on the approval of such drug product. We are 
proposing to revise Sec.  314.54(a)(1)(iii) to require that the listed 
drug or drugs identified as relied upon by a 505(b)(2) applicant must 
include any approved drug product that: (1) Is pharmaceutically 
equivalent to the drug product for which the 505(b)(2) application is 
submitted and (2) was approved before the 505(b)(2) application was 
submitted. This requirement is intended to help ensure that the 
505(b)(2) pathway is not used to circumvent the statutory obligation 
that would have applied if the proposed product was submitted as an 
ANDA--namely, submission of a patent certification for a listed patent 
that corresponds to the protected aspects of the pharmaceutically 
equivalent listed drug (see draft guidance for industry entitled 
``Applications Covered by Section 505(b)(2)'' (October 1999), available 
at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079345.pdf) (``If 
there is a listed drug that is the pharmaceutical equivalent of the 
drug proposed in the 505(b)(2) application, the 505(b)(2) applicant 
should provide patent certifications for the patents listed for the 
pharmaceutically equivalent drug''). Clarifying revisions in proposed 
Sec.  314.54(a)(1)(iii) and (a)(1)(vi) replace the reference to ``other 
drugs'' with ``listed drug'' to conform with our longstanding policy 
that an applicant may rely upon more than one listed drug to support 
approval of a 505(b)(2) application. In addition, we are proposing to 
replace the term ``reference listed drug'' in Sec.  314.54(b) with 
``listed drug'' because the descriptor ``reference listed drug'' is a 
term of art that applies to an ANDA. A 505(b)(2) application may rely 
on FDA's finding of safety and/or effectiveness for one or more listed 
drugs.
    We also are proposing to add Sec.  314.50(i)(1)(i)(C) to require 
that if, before the date of submission of the 505(b)(2) application, 
there is an approved drug product that is pharmaceutically equivalent 
to the drug product for which the 505(b)(2) application is submitted, 
the applicant must submit an appropriate patent certification under 
Sec.  314.50(i) with respect to each patent listed for the 
pharmaceutically equivalent product that claims the drug substance or 
drug product or that claims an approved use for such drug.
    We are proposing a conforming revision to Sec.  314.125(b) to state 
that we may refuse to approve a 505(b)(2) application based on the 
applicant's failure to submit an appropriate patent certification or 
statement with respect to each listed patent for a drug product that: 
(1) Is pharmaceutically equivalent to the drug product for which the 
505(b)(2) application is submitted and (2) was approved before the 
505(b)(2) application was submitted. If FDA approves a pharmaceutically 
equivalent product within the 60-day filing review period after a 
505(b)(2) application is submitted, the 505(b)(2) applicant is not 
required to identify the product as a listed drug relied upon or submit 
a patent certification under Sec.  314.50(i) and FDA would not refuse 
to file the application under Sec.  314.101(d)(9) based on the new 
approval.
    It also should be noted that the requirement to identify a 
pharmaceutically equivalent product as a listed drug relied upon (and 
to submit an appropriate patent certification or statement with respect 
to each listed patent) does not apply if a pharmaceutically equivalent 
product is approved while the 505(b)(2) application is pending.
    We intend to promptly publish on FDA's Web site information 
regarding the approval of new drug products to facilitate, among other 
things, a 505(b)(2) applicant's compliance with proposed Sec.  
314.54(a)(1)(iii) and (a)(1)(vi) and Sec.  314.50(i)(1)(i)(C).

II.I. Petition To Request a Change From a Listed Drug (Proposed Sec.  
314.93)

    We are proposing to amend Sec.  314.93 regarding petitioned ANDAs 
to codify FDA's policy that the listed drug identified in an approved 
suitability petition can no longer be the basis for submission for an 
unapproved ANDA after a drug product is approved in an NDA for the 
change described in the petition (see generally Venlafaxine ER Citizen 
Petition Response). This proposed revision is intended to facilitate 
implementation of section 505(j)(2)(D)(i) and (ii) of the FD&C Act and 
complement proposed revisions to Sec.  314.96(c) regarding amendments 
to an unapproved ANDA (see section II.F.1.a).
    We are proposing to revise Sec.  314.93(f) regarding withdrawal of 
approval of a suitability petition by redesignating the current text as 
paragraph (f)(1) and by adding paragraph (f)(2). Proposed Sec.  
314.93(f)(2) clarifies that if, after approval of a petition and before 
approval of an ANDA submitted pursuant to the approved petition, a drug 
product is approved in an NDA for the change described in the petition, 
the petition and the listed drug identified in the petition can no 
longer be the basis for ANDA submission, irrespective of whether FDA 
has withdrawn approval of the petition. Because an ANDA applicant may 
not amend its ANDA to change the basis for submission to the new RLD 
(see section 505(j)(2)(D)(i) of the FD&C Act), a person seeking 
approval for such drug product would be required to submit a new ANDA 
that identifies the pharmaceutically equivalent RLD as the basis for 
ANDA submission and comply with applicable statutory and regulatory 
requirements.
    We also are proposing to add Sec.  314.93(e)(1)(vi) to codify our 
longstanding policy that FDA will not approve a suitability petition if 
a drug product is approved in an NDA for the change described in the 
petition. The suitability petition process is intended for a proposed 
``drug product which is not identical to a listed drug in route of 
administration, dosage form, and strength, or in which one active 
ingredient is substituted for one of the active ingredients in a listed 
combination drug'' (Sec.  314.93(b)). If a pharmaceutically equivalent 
drug

[[Page 6857]]

product has been approved in an NDA, the ANDA applicant should refer to 
the approved pharmaceutical equivalent designated by the Agency as the 
RLD as its basis for ANDA submission. Throughout the pendency of review 
of the ANDA, applicants should confirm that an NDA has not been 
approved for the drug product described in the suitability petition.
    Although FDA currently has the authority to withdraw approval of a 
suitability petition after a drug product is approved in an NDA for the 
change described in the petition, we note that it has been the Agency's 
practice not to rescind approval of the petition under these 
circumstances due to the administrative burden. We previously have 
explained: ``we need not withdraw approval of the suitability petition 
to implement our long-standing practice that the intervening approval 
of an NDA for the product described by the suitability petition 
precludes an ANDA applicant from referring to the suitability petition 
and listed drug described therein as its basis for ANDA submission. Any 
pending ANDA that referred to the suitability petition and the listed 
drug described therein would not be eligible for approval, and any 
newly submitted ANDA that sought to reference the suitability petition 
instead of the RLD identified in the Orange Book would not be received 
by the Agency'' (Venlafaxine ER Citizen Petition Response at 25). To 
ensure that our regulations consistently reflect this policy, we are 
proposing to add Sec.  314.127(a)(14) to state that FDA will refuse to 
approve a petitioned ANDA if an NDA subsequently has been approved for 
the change described in the suitability petition.

II.J. Filing an NDA and Receiving an ANDA (Proposed Sec.  314.101)

II.J.1. Notification of Filing of a 505(b)(2) Application or Receipt of 
an ANDA
    We are proposing to amend Sec.  314.101, with respect to 505(b)(2) 
applications and ANDAs that contain a paragraph IV certification, to 
facilitate implementation of the MMA's timing requirements for sending 
notice of a paragraph IV certification and for efficient enforcement of 
the FD&C Act.
    Section 505(b)(3)(B)(i) and (j)(2)(B)(ii)(I) of the FD&C Act 
require a 505(b)(2) or ANDA applicant, respectively, to send notice of 
a paragraph IV certification within 20 days after the date of the 
postmark on the notice with which FDA informs the applicant that the 
505(b)(2) application has been filed or the ANDA has been received (see 
section II.D.1). Our proposed revisions to Sec.  314.101(a)(2) and 
(b)(2) clarify that FDA will notify the applicant that the 505(b)(2) 
application is regarded as filed or the ANDA is regarded as received, 
respectively, by means of an acknowledgment letter or a paragraph IV 
acknowledgment letter (see also section II.A.2.c and II.A.2.u).
    We are proposing to revise Sec.  314.101(b)(1) and (b)(2) regarding 
ANDAs to incorporate the statutory definition of a ``substantially 
complete application,'' which was added by the MMA for purposes of 
section 505(j)(5) of the FD&C Act (see section 505(j)(5)(B)(iv)(II)(cc) 
of the FD&C Act and section II.A.2.cc of this document). Proposed Sec.  
314.101(b)(1) states that receipt of an ANDA means that FDA has made a 
threshold determination that the ANDA is substantially complete. We 
also are proposing to revise proposed Sec.  314.101(b)(2) to clarify 
that if an ANDA is determined to have been substantially complete as of 
the date on which it was submitted, the date of submission is 
considered to be the date of receipt. As noted in section II.A.2.cc, 
our proposed replacement of the current standard ``sufficiently 
complete to permit a substantive review'' with the phrase 
``substantially complete application'' is not intended to alter the 
meaning. Rather, we are seeking to consistently use defined terms 
throughout our regulations.
    We are proposing to amend Sec.  314.101(b)(3) to remove the method 
of notification by which FDA will advise an ANDA applicant that FDA has 
refused to receive the ANDA under Sec.  314.101(d) or (e). The 
regulations currently state that FDA will ordinarily notify an ANDA 
applicant by telephone; however, this does not accurately describe 
FDA's current practice to inform the ANDA applicant in writing by 
issuing a ``refuse to receive'' letter.
    In proposed Sec.  314.101(b)(4), we establish an administrative 
consequence for an ANDA applicant that fails to timely provide notice 
of a paragraph IV certification as required by section 505(j)(2)(B)(ii) 
of the FD&C Act and Sec.  314.95(b) and (d). If FDA determines that an 
ANDA applicant did not send notice of a paragraph IV certification 
within the timeframe described in Sec.  314.95(b) or (d), as 
applicable, FDA will deem the date that the ANDA was submitted to be 
delayed by the number of days by which the timeframe for sending notice 
of a paragraph IV certification was exceeded. As discussed in section 
II.D.5, an ANDA applicant that fails to provide timely notice of a 
paragraph IV certification may, based upon the revised date on which 
the ANDA was determined to have been received, lose its first applicant 
status and thus its eligibility for 180-day exclusivity. In addition, 
such an ANDA may be repositioned in the review queue consistent with 
the revised date of ANDA submission.
II.J.2. Other Proposed Revisions
    We are proposing several clarifying revisions to Sec.  314.101. 
First, we are proposing to delete the reference to section 507 of the 
FD&C Act in Sec.  314.101(d)(3). As discussed in section II.A.2.b, 
FDAMA repealed section 507 of the FD&C Act under which marketing 
applications, including abbreviated applications, for antibiotics had 
been approved (see section 125 of FDAMA). Section 125(d) of FDAMA 
provided that abbreviated applications for antibiotics previously 
approved under section 507 of the FD&C Act would be deemed approved 
under section 505(j) of the FD&C Act.
    Second, we are proposing to replace the term ``application'' in 
Sec.  314.101(d)(6) and (d)(7) with ``NDA and ANDA'' to clarify that 
these provisions apply to ANDAs as well as NDAs. As discussed in 
section II.A.2.b and II.A.2.i, we have proposed to incorporate the 
commonly used acronyms NDA and ANDA in place of the terms application 
and abbreviated application, as appropriate, throughout the sections of 
part 314 and part 320 in this rulemaking. Proposed Sec.  314.101(d)(6) 
states that FDA may refuse to file an NDA or may not consider an ANDA 
to be received if the NDA or ANDA does not contain a statement for each 
nonclinical laboratory study regarding compliance with the requirements 
of part 58 of this chapter. This criterion is applicable to ANDAs as 
well as NDAs. Nonclinical studies submitted in an ANDA may include, but 
are not limited to, dissolution studies and ``dose-dumping'' studies. 
Proposed Sec.  314.101(d)(7) provides that FDA may refuse to file an 
NDA or may not consider an ANDA to be received if the NDA or ANDA does 
not contain a statement for each clinical study regarding whether it 
was conducted in compliance with the regulations in part 50 and part 56 
of this chapter. Clinical studies submitted in an ANDA which may be 
subject to the regulations in part 50 and part 56 of this chapter 
include, for example, comparative clinical trials conducted for the 
purpose of demonstrating bioequivalence (see Sec.  320.24(b)(4); see 
also Sec.  314.94(a)(7)(iii)).
    Third, we are proposing to replace the current text of Sec.  
314.101(e)(2) with a

[[Page 6858]]

statement that FDA will refuse to file a 505(b)(2) application or will 
consider an ANDA not to have been received if submission of a 505(b)(2) 
application or an ANDA for the active moiety is not permitted under 
Sec.  314.108(b)(2). This is not a substantive revision, as Sec.  
314.108(b)(2) describes the conditions set forth in current Sec.  
314.101(e)(2)(i) and (e)(2)(ii).
    We also propose to add headings to certain paragraphs for 
administrative convenience.

II.K. Approval of an NDA and ANDA (Proposed Sec.  314.105)

    We are proposing to revise Sec.  314.105(a) and (d) regarding 
approval of an NDA (including a 505(b)(2) application) and an ANDA to 
remove the references to a ``delayed effective date'' and clarify that 
an application is approved on the date of issuance of an approval 
letter. These proposed revisions reflect current FDA practice and 
policy with respect to approval letters. The Agency does not issue 
approval letters with delayed effective dates. Rather, the Agency will 
issue a tentative approval letter when an NDA or ANDA that is otherwise 
eligible for approval cannot be approved due to unexpired patents, 
certain circumstances related to patent litigation (see Sec.  
314.107(b)(3) and (e)(1)(vi)), or various types of exclusivity (see 
proposed Sec.  314.107(b)(1)(iii), (c) and (d)). ``Tentative approval'' 
is defined in proposed Sec.  314.3. We also have made conforming 
revisions throughout this proposed rulemaking to replace references to 
the ``effective date'' of an application with language reflecting our 
current practice.
    A drug product granted tentative approval is not an approved drug. 
Prior to obtaining approval of a 505(b)(2) application or ANDA, the 
applicant may be requested to submit updated labeling; chemistry, 
manufacturing, and controls (CMC) data; a safety update; and any other 
information necessary to ensure that the 505(b)(2) application or ANDA 
meets the statutory and regulatory requirements for approval. For a 
505(b)(2) application or ANDA to be approved, the applicant must 
receive an approval letter from FDA (see proposed Sec.  314.107(b)(4)).
    We note that an applicant with a tentatively approved 505(b)(2) 
application or ANDA has a continuing obligation to amend its patent 
certification or statement if, at any time before approval of the 
505(b)(2) application or ANDA, the submitted certification is no longer 
accurate (see proposed Sec. Sec.  314.50(i)(6) and 
314.94(a)(12)(viii)). In the context of a tentatively approved 
application, this obligation may apply, for example, if the NDA holder 
for the listed drug relied upon or RLD timely submits new patent 
information for a patent that claims the drug substance, drug product, 
or a method of use after the 505(b)(2) application or ANDA has been 
tentatively approved. In this scenario, the 505(b)(2) or ANDA applicant 
would be required to submit an amendment to its tentatively approved 
application with an appropriate patent certification or statement 
regarding the newly listed patent.
    The applicant with a tentatively approved application also may need 
to update the draft product labeling to incorporate relevant revisions 
to the labeling of the listed drug relied upon or RLD made after the 
tentative approval of the 505(b)(2) application or ANDA, respectively. 
This caveat is particularly relevant for an ANDA, which is required by 
statute to have, among other things, the same labeling and conditions 
of use as the RLD (see section 505(j)(2)(A)(i) and (j)(2)(A)(v) of the 
FD&C Act; compare section 505(j)(10) of the FD&C Act), unless the ANDA 
applicant is not seeking approval for an indication or other aspect of 
labeling protected by patent or accorded exclusivity under section 
505(j)(4)(D) of the FD&C Act (see Sec.  314.94(a)(8)(iv); see also 
section 505(j)(2)(A)(viii) of the FD&C Act). In addition, a tentatively 
approved ANDA for a drug product intended for parenteral, ophthalmic, 
otic, or topical use that is required to contain the same inactive 
ingredients in the same concentration as the RLD, subject to exceptions 
specified in Sec.  314.94(a)(9)(iii) through (a)(9)(v), may be required 
to modify its drug product and amend its ANDA to address certain 
changes in the formulation of the RLD subsequent to tentative approval 
unless FDA has made a determination that the RLD was not withdrawn from 
sale for reasons of safety or effectiveness (see Sec. Sec.  314.122 and 
314.161; see also discussion in section II.L).
    In addition, we are proposing to revise Sec.  314.105(a) and (d) to 
expressly state that FDA's tentative approval of a drug product is 
based on information available to FDA at the time of the tentative 
approval letter (i.e., information in the 505(b)(2) application or ANDA 
and the status of current good manufacturing practices of the 
facilities used in the manufacturing and testing of the drug product) 
and is therefore subject to change on the basis of new information that 
may come to FDA's attention.
    Finally, it should be noted that a tentatively approved application 
is subject to any applicable period of marketing exclusivity granted to 
the listed drug relied upon (for a 505(b)(2) application) or RLD (for 
an ANDA) after tentative approval. For example, approval of a 
tentatively approved application may be delayed by the intervening 
grant, pursuant to section 505A of the FD&C Act, of a period of 
pediatric exclusivity to the NDA holder for the listed drug relied upon 
or RLD after tentative approval of the 505(b)(2) application or ANDA, 
respectively (see, e.g., Barr Labs., Inc. v. Thompson, 238 F. Supp. 2d 
236 (D.D.C. 2002) (upholding FDA's determination that a 6-month period 
of pediatric exclusivity that had attached to a listed patent for which 
a paragraph III certification had been submitted applied to a 
tentatively approved application)).

II.L. Refusal to Approve an NDA or ANDA (Proposed Sec. Sec.  314.125 
and 314.127 and Related Provisions in Proposed Sec. Sec.  314.90 and 
314.99)

    We are proposing to revise Sec. Sec.  314.90 and 314.99 to clarify 
the effect of FDA's grant of an applicant's request for waiver of a 
requirement under Sec. Sec.  314.50 through 314.81 or Sec. Sec.  314.92 
through 314.99, respectively. If FDA grants such a request, the 
applicant's failure to comply with the requirement that is the subject 
of the waiver request will not constitute a basis for refusal to 
approve the NDA under Sec.  314.125 or the ANDA under Sec.  314.127, as 
applicable. We also are proposing corresponding revisions to Sec. Sec.  
314.125(b) and 314.127(a), which address permissive refusal to approve 
an NDA and mandatory refusal to approve an ANDA, respectively. Proposed 
Sec.  314.125(b) states that FDA may refuse to approve an NDA for any 
of the following reasons listed, unless the requirement has been waived 
pursuant to Sec.  314.90. Proposed Sec.  314.127(a) states that FDA 
will refuse to approve an ANDA for a new drug under section 505(j) of 
the FD&C Act for any of the following reasons listed, unless the 
requirement has been waived pursuant to Sec.  314.99.
    Sections 314.90 and 314.99 currently provide that an NDA or ANDA 
applicant may ask FDA to waive any requirement that applies to the 
applicant under Sec. Sec.  314.50 through 314.81 or Sec. Sec.  314.92 
through 314.99, respectively. FDA has interpreted its waiver of a 
submission requirement under these provisions to carry with it the 
implicit waiver of any corresponding approval requirement under 
Sec. Sec.  314.125 or 314.127. Otherwise, the waiver of a submission 
requirement for an NDA or ANDA would be meaningless if there was a 
parallel

[[Page 6859]]

requirement under Sec. Sec.  314.125 or 314.127, respectively, for 
approval of the application.
    The proposed revisions to Sec. Sec.  314.90 and 314.99, and 
corresponding proposed revisions to proposed Sec. Sec.  314.125 and 
314.127, codify FDA's approach to this issue. For example, FDA has 
relied on Sec.  314.99(b) to grant a waiver of the requirement that the 
formulation of a drug product intended for parenteral use contain the 
same inactive ingredients in the same concentration as the RLD, with 
limited exceptions for preservatives, buffers, and antioxidants, where 
the formulation proposed by the ANDA applicant had previously been 
approved by FDA as safe and effective. We note that FDA may not waive a 
statutory requirement (see 1989 Proposed Rule, 54 FR 28872 at 28889).

II.M. Date of Approval of a 505(b)(2) Application or ANDA (Proposed 
Sec.  314.107)

    Section 314.107 establishes the earliest date on which a 505(b)(2) 
application or ANDA may be approved in light of the statutory 
provisions that can delay the approval of an application that is 
otherwise eligible for approval. Approval of a 505(b)(2) application or 
ANDA can be delayed by the marketing exclusivity granted to another 
drug product under section 505(c)(3)(E) and (j)(5)(F) of the FD&C Act 
(and, with respect to ANDAs, section 505(j)(5)(B)(iv) of the FD&C Act 
for 180-day exclusivity) or pediatric exclusivity under section 505A of 
the FD&C Act that may attach to a patent listed for a drug product. 
Approval of a 505(b)(2) application or ANDA also can be delayed by a 
30-month stay of approval should the NDA holder or patent owner 
initiate patent infringement litigation within the statutory timeframe 
in response to notice of a paragraph IV certification (see section 
505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act). The MMA amended the 
FD&C Act to alter the circumstances under which a 30-month stay of 
approval can arise. The MMA also amended the FD&C Act to specify the 
types of court actions that will terminate a 30-month stay of approval. 
In addition, approval of a 505(b)(2) application or ANDA can be delayed 
by a court order pursuant to 35 U.S.C. 271(e)(4)(A) ordering that the 
application may be approved no earlier than the date specified 
(irrespective of whether the injunction relates to a patent described 
in Sec.  314.107(b)(3) (see proposed Sec.  314.107(b)(4) and 
(e)(1)(vi)).
    Table 12 summarizes the proposed changes related to the effect of 
patent(s) on the listed drug with respect to the date of approval of a 
505(b)(2) application or ANDA.

    Table 12--Highlights of Proposed Changes Regarding the Effect of
                    Patent(s) on the Listed Drug \1\
------------------------------------------------------------------------
                                                Proposed revisions to
            Current regulations                      regulations
------------------------------------------------------------------------
Effect of patent on the listed drug (Sec.   Effect of patent(s) on the
  314.107(b))                                listed drug (Sec.
                                             314.107(b))
 Introduction to criteria for        Introduction to
 determining date on which approval of a     criteria that must be used
 505(b)(2) application or ANDA will become   to determine, for each
 effective.                                  relevant patent, the date
                                             that patent will no longer
                                             prevent approval.
                                             The first possible
                                             date of approval will be
                                             calculated for each patent,
                                             and the 505(b)(2)
                                             application or ANDA may be
                                             approved on the last
                                             applicable date.
Multiple certifications (Sec.
 314.107(b)(4))
 If the applicant has submitted
 certifications for more than one patent,
 the date of approval will be calculated
 for each certification, and the approval
 will become effective on the last
 applicable date.
Date of approval letter (Sec.               Timing of approval based on
 314.107(b)(1))                              patent certification or
                                             statement (Sec.
                                             314.107(b)(1))
 Except as provided in Sec.          If none of the
 314.107(b)(3), (b)(4), and (c), approval    reasons in Sec.   314.125
 will become effective on the date FDA       or Sec.   314.127 for
 issues an approval letter if the            refusing to approve the
 applicant certifies that:                   application apply, and none
(i) there are no relevant patents; or        of the reasons in Sec.
(ii) the patent information has not been     314.107(d) for delaying
 submitted to FDA; or                        approval apply, the
(iii) the relevant patent has expired; or    505(b)(2) application or
(iv) the relevant patent is invalid,         ANDA may be approved--
 unenforceable, or will not be infringed.   (i) Immediately, if the
                                             applicant certifies that:
                                            (A) the patent information
                                             has not been submitted to
                                             FDA; or
                                            (B) the relevant patent has
                                             expired; or
                                            (C) the relevant patent is
                                             invalid, unenforceable, or
                                             will not be infringed,
                                             except as provided in Sec.
                                              314.107(b)(3) and (c), and
                                             the 45-day period provided
                                             for in section 505(c)(3)(C)
                                             and 505(j)(5)(B)(iii) of
                                             the FD&C Act has expired;
                                             or
                                            (D) there are no relevant
                                             patents.
                                               (ii) Immediately, if the
                                                applicant submits an
                                                appropriate statement
                                                explaining that a method-
                                                of-use patent does not
                                                claim an indication or
                                                other condition of use
                                                for which it is seeking
                                                approval.
Patent expiration (Sec.   314.107(b)(2))    Timing of approval based on
                                             patent certification or
                                             statement (Sec.
                                             314.107(b)(1)(iii))
 If the applicant certifies that     If the applicant
 the relevant patent will expire on a        certifies that the relevant
 specified date (paragraph III               patent will expire on a
 certification), approval will become        specified date (paragraph
 effective on the specified date.            III certification), a
                                             505(b)(2) application or
                                             ANDA otherwise eligible for
                                             approval may be approved on
                                             the specified date.
[No corresponding regulation]               Patent information filed
                                             after submission of
                                             505(b)(2) application or
                                             ANDA (Sec.   314.107(b)(2))
                                             If an NDA holder
                                             submits patent information
                                             for a listed drug after the
                                             date on which a 505(b)(2)
                                             application or ANDA relying
                                             on such drug was submitted
                                             to FDA, the 505(b)(2) or
                                             ANDA applicant must submit
                                             an amended patent
                                             certification or statement
                                             in accordance with Sec.
                                             Sec.   314.50(i)(4) and
                                             (i)(6) and
                                             314.94(a)(12)(vi) and
                                             (a)(12)(viii).

[[Page 6860]]

 
                                             If the applicant
                                             submits a paragraph IV
                                             certification to the newly-
                                             listed patent information
                                             and complies with the
                                             notice requirements of Sec.
                                               314.52 or Sec.   314.95,
                                             the 505(b)(2) application
                                             or ANDA may be approved
                                             immediately upon submission
                                             of documentation of receipt
                                             of notice of paragraph IV
                                             certification.
                                             The 45-day period
                                             provided for in section
                                             505(c)(3)(C) and
                                             (j)(5)(B)(iii) of the FD&C
                                             Act does not apply.
Disposition of patent litigation (Sec.      Disposition of patent
 314.107(b)(3)(i))                           litigation (Sec.
                                             314.107(b)(3)(i))
 (A) Except as provided in Sec.      (A) Except as
 314.107(b)(3)(ii) through (b)(3)(iv), if    provided in Sec.
--applicant submits a paragraph IV           314.107(b)(3)(ii) through
 certification; and                          (b)(3)(viii), if, with
--patent owner or its representative or      respect to patents for
 the exclusive patent licensee brings suit   which required information
 for patent infringement within 45 days of   was submitted before the
 receipt by the patent owner of the notice   date on which the 505(b)(2)
 of paragraph IV certification,              application or ANDA was
                                             submitted to FDA (excluding
                                             an amendment or
                                             supplement),
                                            --applicant submits a
                                             paragraph IV certification;
                                             and
Approval may be made effective 30 months    --patent owner or the
 after the date of the receipt of the        exclusive patent licensee
 notice of paragraph IV certification by     brings suit for patent
 the patent owner or by the exclusive        infringement within 45 days
 licensee (or their representatives)         of receipt of the notice of
 unless the court has extended or reduced    paragraph IV certification,
 the period; or                              505(b)(2) application, or
 (B) If the patented drug product    ANDA may be approved 30
 qualifies for 5-year exclusivity, and       months after the later of
                                             the date of the receipt of
                                             the notice of certification
                                             by any owner of the listed
                                             patent or by the NDA holder
                                             who is an exclusive patent
                                             licensee (or their
                                             representatives) unless the
                                             court has extended or
                                             reduced the period; or
                                             (B) If the patented
                                             drug product qualifies for
                                             5-year exclusivity, and--
                                             patent owner or its
                                             representative or the
                                             exclusive patent licensee
                                             brings suit for patent
                                             infringement during the 1-
                                             year period beginning 4
                                             years after the date the
                                             patented drug was approved
                                             and within 45 days of
                                             receipt by the patent owner
                                             of the notice of paragraph
                                             IV certification,
                                            Approval may be made
                                             effective at the expiration
                                             of 7\1/2\ years from the
                                             date of NDA approval for
                                             the patented drug product.
                                            --patent owner or its
                                             representative or the
                                             exclusive patent licensee
                                             brings suit for patent
                                             infringement during the 1-
                                             year period beginning 4
                                             years after the date the
                                             patented drug was approved
                                             and within 45 days of
                                             receipt of the notice of
                                             paragraph IV certification,
                                            the 505(b)(2) application or
                                             ANDA may be approved at the
                                             expiration of 7\1/2\ years
                                             from the date of NDA
                                             approval for the patented
                                             drug product.
Disposition of patent litigation (Sec.      Disposition of patent
 314.107(b)(3)(ii)-(b)(3)(iv))               litigation (Sec.
                                             314.107(b)(3)(ii)-(b)(3)(vi
                                             ii)
If before the expiration of the 30-month    If before the expiration of
 period, or 7\1/2\ years where applicable:   the 30-month period, or 7\1/
                                             2\ years where applicable:
     (ii) the court issues a final   (ii) the district
     order that the patent is invalid,       court decides that the
     unenforceable, or not infringed,        patent is invalid,
     approval may be made effective on:      unenforceable, or not
    --the date the court enters judgment;    infringed (including any
     (iii) the court issues a        substantive determination
     final order or judgment that the        that there is no cause of
     patent has been infringed, approval     action for patent
     may be made effective on:               infringement or
    --the date the court determines that     invalidity), the 505(b)(2)
     the patent will expire or otherwise     application or ANDA may be
     orders                                  approved on:
     (iv) the court grants a        --(A) the date on which the
     preliminary injunction prohibiting      court enters judgment
     the applicant from engaging in the      reflecting the decision; or
     commercial manufacture or sale of the  --(B) the date of a
     drug product until the court decides    settlement order or consent
     the issues of patent validity and       decree signed and entered
     infringement, and if the court later    by the court stating that
     decides that the patent is invalid,     the patent that is the
     unenforceable, or not infringed,        subject of the
     approval may be made effective on:      certification is invalid or
    --the date the court enters a final      not infringed.
     order or judgment that the patent is    (iii) the district
     invalid, unenforceable, or not          court decides that the
     infringed.                              patent has been infringed
                                             and the judgment is
                                             appealed, the 505(b)(2)
                                             application or ANDA may be
                                             approved on:
                                            --(A) the date on which the
                                             mandate is issued by the
                                             court of appeals entering
                                             judgment that the patent is
                                             invalid or not infringed;
                                             or
                                            --(B) the date of a
                                             settlement order or consent
                                             decree signed and entered
                                             by the court of appeals
                                             stating that the patent is
                                             invalid or not infringed.
                                                (iv) the
                                                district court decides
                                                that the patent has been
                                                infringed and the
                                                judgment is not appealed
                                                or is affirmed, the
                                                505(b)(2) application or
                                                ANDA may be approved no
                                                earlier than the date
                                                specified by the
                                                district court in an
                                                order under 35 U.S.C.
                                                271(e)(4)(A).
                                                (v) the district
                                                court grants a
                                                preliminary injunction
                                                prohibiting the
                                                applicant from engaging
                                                in the commercial
                                                manufacture or sale of
                                                the drug product until
                                                the court decides the
                                                issues of patent
                                                validity and
                                                infringement:
                                                 -- if the court later
                                                  decides the patent is
                                                  invalid,
                                                  unenforceable, or not
                                                  infringed, the
                                                  505(b)(2) application
                                                  or ANDA may be
                                                  approved per Sec.
                                                  314.107(b)(3)(ii).

[[Page 6861]]

 
                                                 --if the court decides
                                                  that the patent has
                                                  been infringed, the
                                                  505(b)(2) application
                                                  or ANDA may be
                                                  approved per Sec.
                                                  314.107(b)(3)(iii) or
                                                  (b)(3)(iv), as
                                                  applicable.
                                                (vi) the patent
                                                owner or the exclusive
                                                patent licensee (or
                                                their representatives)
                                                agrees in writing that
                                                the 505(b)(2)
                                                application or ANDA may
                                                be approved any time on
                                                or after the date of the
                                                consent, approval may be
                                                granted on or after that
                                                date.
                                                (vii) the court
                                                enters an order
                                                requiring the 30-month
                                                or 7\1/2\-year period to
                                                be terminated, the
                                                505(b)(2) application or
                                                ANDA may be approved in
                                                accordance with the
                                                court's order.
                                                (viii) the court
                                                enters an order of
                                                dismissal, with or
                                                without prejudice,
                                                without a finding of
                                                infringement, the
                                                505(b)(2) application or
                                                ANDA may be approved on
                                                or after the date of the
                                                order.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
  regulations, but should not be relied upon in place of the proposed
  regulation.

II.M.1. General (Proposed Sec.  314.107(a))
    We are not proposing any substantive revisions to Sec.  314.107(a). 
As noted in section II.A.2.dd and II.I, we are proposing to amend 
references to the ``effective date of approval'' and the date the 
approval of a 505(b)(2) application or ANDA ``becomes effective'' to 
simply refer to the date the 505(b)(2) application or ANDA ``is 
approved.'' The current text incorrectly suggests that FDA might issue 
an approval letter that would become effective at some date in the 
future. The proposed revision clarifies that a 505(b)(2) application or 
ANDA is not approved until the date the Agency issues its approval 
letter.
II.M.2. Effect of Patent(s) on the Listed Drug (Proposed Sec.  
314.107(b))
    We are proposing to revise the introduction to proposed Sec.  
314.107(b) to clarify that an analysis is required for each relevant 
patent to determine the effect of one or more patents listed for the 
listed drug(s) relied upon or the RLD on the date of approval of a 
505(b)(2) application or ANDA, respectively. For each relevant patent, 
the patent certification or statement submitted by the 505(b)(2) or 
ANDA applicant is reviewed to determine the first possible date of 
approval based upon each patent. The 505(b)(2) application or ANDA may 
be approved on the last applicable date for all relevant patents. This 
approach to the evaluation of multiple patent certifications is 
described in current Sec.  314.107(b)(4), which is proposed for 
deletion because the substance of that paragraph is in proposed Sec.  
314.107(b).
    II.M.2.a. Timing of approval based on patent certification or 
statement (proposed Sec.  314.107(b)(1)). We are proposing to amend 
Sec.  314.107(b)(1) to describe, in a more comprehensive manner, the 
timing of approval of a 505(b)(2) application or ANDA based on the 
patent certification(s) or statement(s) submitted by the 505(b)(2) or 
ANDA applicant. As explained in proposed Sec.  314.107(b)(1), the 
timing of approval based on an analysis of an applicant's patent 
certification(s) or statement(s) is directed to a 505(b)(2) application 
or ANDA that is otherwise eligible for approval. A 505(b)(2) 
application or ANDA is otherwise eligible for approval if none of the 
reasons in Sec.  314.125 or Sec.  314.127 for refusing to approve the 
505(b)(2) application or ANDA applies, and if no delay is required by 
the exclusivity provisions of Sec.  314.108, Sec.  316.31, or section 
505A of the FD&C Act (see section II.I).
    In proposed Sec.  314.107(b)(1)(i) and (b)(1)(ii), we describe the 
types of patent certifications or statements that would result in an 
immediate first possible date of approval of a 505(b)(2) application or 
ANDA that is otherwise eligible for approval. Proposed Sec.  
314.107(b)(1)(i) reflects a reorganization of the current regulation 
and not a substantive revision. Current Sec.  314.107(b)(i) through 
(b)(iv) are redesignated as proposed Sec.  314.107(b)(1)(i)(A) through 
(b)(1)(i)(D). We have proposed to move the phrase ``except as provided 
in paragraphs (b)(3) and (c)'' from the introduction to current Sec.  
314.107(b)(1) to Sec.  314.107(b)(1)(i)(C) to more closely associate 
this very important and common exception to an immediate date of 
approval with the paragraph that describes a paragraph IV 
certification. In addition, we are proposing to clarify that a 
505(b)(2) application or ANDA containing a paragraph IV certification 
may be approved immediately only if the 45-day period provided for in 
section 505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act has expired.
    We are proposing to revise Sec.  314.107(b)(1)(ii) (the current 
text of which is proposed for incorporation into Sec.  
314.107(b)(1)(i)) to clarify that an appropriate statement under Sec.  
314.50(i)(1)(iii) or Sec.  314.94(a)(12)(iii) also could result in an 
``immediate'' first possible date of approval. This proposed revision 
addresses an omission in the current regulations. A 505(b)(2) or ANDA 
applicant may submit a statement under Sec.  314.50(i)(1)(iii) or Sec.  
314.94(a)(12)(iii), respectively, explaining that a method-of-use 
patent does not claim an indication or other condition of use for which 
the applicant is seeking approval (see section 505(b)(2)(B) and 
(j)(2)(A)(viii) of the FD&C Act). If the patent only claims the method 
of use for which the 505(b)(2) or ANDA applicant submitted a statement 
under Sec.  314.50(i)(1)(iii) or Sec.  314.94(a)(12)(iii), 
respectively, then a 505(b)(2) application or ANDA otherwise eligible 
for approval may be approved immediately.
    As described in section II.B.1.a, a listed patent may claim the 
drug substance and/or drug product in addition to one or more methods 
of use, and a 505(b)(2) or ANDA applicant could submit a statement 
under Sec.  314.50(i)(1)(iii) or Sec.  314.94(a)(12)(iii) with respect 
to one or more methods of use and a paragraph IV certification with 
respect to the remaining drug substance and/or drug product claims and/
or any additional methods of use. In this scenario, the applicant's 
paragraph IV certification and statement under Sec.  314.50(i)(1)(iii) 
or Sec.  314.94(a)(12)(iii) to the patent would be analyzed in 
accordance with proposed Sec.  314.107(b)(1)(i)(C) and (b)(1)(ii) to 
determine whether the first possible date of approval for the 505(b)(2) 
application or ANDA based on this patent is ``immediately'' or whether

[[Page 6862]]

the exceptions described in Sec.  314.107(b)(3) and (c) apply with 
respect to the paragraph IV certification. Approval of a 505(b)(2) 
application or ANDA that contains a statement under Sec.  
314.50(i)(1)(iii) or Sec.  314.94(a)(12)(iii) with respect to one or 
more methods of use and a paragraph IV certification with respect to 
the remaining patent claims may be subject to a 30-month stay (or 7\1/
2\ years where applicable) if patent infringement litigation is 
initiated within the statutory timeframe with respect to the patent 
claims that were the subject of the paragraph IV certification (see 
Sec.  314.107(b)(3)). It should be noted that if the paragraph IV 
certification that gave rise to the 30-month stay (or 7\1/2\ years 
where applicable) is subsequently amended to a statement under Sec.  
314.50(i)(1)(iii) or Sec.  314.94(a)(12)(iii) with respect to one or 
more methods of use, the 30-month stay (or 7\1/2\ years where 
applicable) will not be terminated in the absence of a qualifying event 
under Sec.  314.107(b)(3).
    We are proposing to move Sec.  314.107(b)(2) regarding paragraph 
III certifications, which delay approval until the date on which the 
patent will expire, to proposed Sec.  314.107(b)(1)(iii) for 
organizational convenience. An analysis of the effect of patents on the 
timing of approval of a 505(b)(2) application or ANDA is made when the 
505(b)(2) application or ANDA is otherwise eligible for approval.
    II.M.2.b. Patent information filed after submission of 505(b)(2) 
application or ANDA (proposed Sec.  314.107(b)(2)). We are proposing to 
revise Sec.  314.107(b)(2) (redesignated as proposed Sec.  
314.107(b)(1)(iii)) to clarify the effect of patent information filed 
after submission of a 505(b)(2) application or ANDA on the date of 
approval of a 505(b)(2) application or ANDA. If an NDA holder submits 
patent information for a listed drug after the date on which a 
505(b)(2) application or ANDA relying upon such drug was submitted to 
FDA, the 505(b)(2) or ANDA applicant must comply with the requirements 
of Sec. Sec.  314.50(i)(4) and (i)(6) and 314.94(a)(12)(vi) and 
(a)(12)(viii) regarding amendment of its patent certification or 
statement (see section II.E.4). Thus, if the patent information was 
timely filed by the NDA holder under Sec.  314.53(d)(3), the 505(b)(2) 
or ANDA applicant would be required to amend its patent certification 
or statement for the listed drug relied upon or RLD, respectively, to 
address the newly listed patent. (A 505(b)(2) or ANDA applicant whose 
pending application did not contain an appropriate patent certification 
at the time of submission would be required to submit a patent 
certification or statement to the newly listed patent even if such 
patent information was filed by the NDA holder more than 30 days after 
patent issuance (i.e., untimely filed).)
    If the 505(b)(2) or ANDA applicant submits an amendment containing 
a paragraph IV certification to the newly listed patent, proposed Sec.  
314.107(b)(2) clarifies that the 505(b)(2) application or ANDA may be 
approved immediately upon the submission of an amendment containing 
documentation that the NDA holder and each patent owner have received 
notice of paragraph IV certification under Sec.  314.52(e) or Sec.  
314.95(e). There is no need to delay approval until the expiration of 
the 45-day period provided for in section 505(c)(3)(C) and 
(j)(5)(B)(iii) of the FD&C Act. Even if the NDA holder or patent owner 
initiated patent infringement litigation within the 45-day period after 
receipt of notice of paragraph IV certification, a 30-month stay of 
approval would not be available in connection with a paragraph IV 
certification to a patent submitted after a 505(b)(2) application or 
ANDA had been submitted to FDA (see section 505(c)(3)(C) and 
(j)(5)(B)(iii) of the FD&C Act).
    Although a 30-month stay of approval is not available in these 
circumstances, a 505(b)(2) or ANDA applicant still must comply with the 
requirements for provision of notice of paragraph IV certification 
described in section 505(b)(3) and (j)(2)(B) of the FD&C Act and 
Sec. Sec.  314.52 and 314.95. An NDA holder or patent owner may assert 
a claim of patent infringement against the 505(b)(2) or ANDA applicant 
in response to the notice of paragraph IV certification and may seek 
injunctive relief during the pendency of the litigation despite the 
absence of a 30-month stay. Notice of paragraph IV certification in 
accordance with applicable regulations also is necessary for an ANDA 
applicant to be eligible for 180-day exclusivity based upon a paragraph 
IV certification to a newly listed patent (see section II.D.1).
    II.M.2.c. Disposition of patent litigation (proposed Sec.  
314.107(b)(3)).
    II.M.2.c.i. Approval upon expiration of 30-month stay or 7\1/2\ 
years from date of reference product approval (proposed Sec.  
314.107(b)(3)(i)). We are proposing to revise Sec.  314.107(b)(3)(i)(A) 
to reflect one of the central elements of the MMA's amendments to the 
FD&C Act: The limitation on multiple 30-month stays of approval of a 
505(b)(2) application or an ANDA containing a paragraph IV 
certification to certain patents submitted to FDA on or after August 
18, 2003. Proposed Sec.  314.107(b)(3)(i)(A) states that a 30-month 
stay of approval is available only when the patent owner or exclusive 
patent licensee initiates a patent infringement action within the 
statutory timeframe in response to a paragraph IV certification to a 
patent submitted to FDA before the date on which the original 505(b)(2) 
application or ANDA was submitted. As discussed in section II.E, the 
MMA expressly provides that, for purposes of determining the 
availability of a 30-month stay, the date of submission of a 505(b)(2) 
application or ANDA does not include the date of submission of an 
amendment or supplement to the 505(b)(2) application or ANDA (see 
section 505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act). In other 
words, there will be no possibility of a 30-month stay with respect to 
an action for infringement of a patent listed after the reference 
product is approved if the patent was submitted to FDA on or after the 
date the 505(b)(2) application or ANDA was first submitted. Due to this 
limitation, most 505(b)(2) applications and ANDAs will be subject to no 
more than one 30-month stay of approval.
    Multiple 30-month stays, however, still may be possible in certain 
cases. For example, an original 505(b)(2) application or ANDA may 
contain a paragraph IV certification to a patent that results in a 30-
month stay of approval. If the same application also contains a 
paragraph III certification to a different patent that was submitted to 
FDA on or after August 18, 2003, and before the 505(b)(2) application 
or ANDA was submitted, and the applicant subsequently amends the 
paragraph III certification to a paragraph IV certification, a second 
30-month stay would be possible. Two 30-month stays are possible in 
this example because the challenged patents that gave rise to 
sequential actions for patent infringement were both submitted to FDA 
before submission of the original 505(b)(2) application or ANDA. It 
should be noted that the relevant benchmark for determining whether a 
patent was submitted by the NDA holder prior to submission of an 
original 505(b)(2) application or prior to submission of an ANDA later 
determined to be substantially complete is the date of submission of 
the patent to FDA and not the date on which the patent information is 
published in the Orange Book (see Sec.  314.53(d)(5)). We note, 
however, that if the original submission of an ANDA is not determined 
to be substantially complete (i.e., FDA refuses to receive the ANDA 
under Sec.  314.101), then the relevant

[[Page 6863]]

benchmark is the date of the ANDA amendment that results in a 
subsequent determination that the ANDA is substantially complete.
    We also are proposing to revise Sec.  314.107(b)(3)(i) to clarify 
that a 30-month stay of approval begins on the later of the date of 
receipt of the notice of paragraph IV certification by any owner of the 
listed patent or by the NDA holder who is an exclusive patent licensee 
(or their representatives). This proposed revision codifies our current 
practice and provides an administratively efficient means of ensuring 
that each patent owner or NDA holder that is entitled to receive notice 
of paragraph IV certification receives the full statutory 30-month stay 
of approval should one of these parties initiate patent infringement 
litigation within 45 days of its receipt of notice. Even if a patent 
infringement action was initiated within 45 days of receipt of notice 
of paragraph IV certification by the first of two intended recipients, 
the 30-month stay of approval would begin on the later of the dates of 
receipt of notice of paragraph IV certification by any owner of the 
listed patent or by the NDA holder.
    Finally, we are proposing to revise Sec.  314.107(b)(3) to 
supplement the list that describes different scenarios related to the 
timing of approval of a 505(b)(2) application or ANDA containing a 
paragraph IV certification that was the subject of patent litigation. 
Many of our proposed additions to the Sec.  314.107(b) list reflect 
corresponding MMA amendments to section 505(c)(3)(C) and (j)(5)(B)(iii) 
of the FD&C Act (see sections II.M.3.e to II.M.3.h). It should be noted 
that we are not proposing revisions to Sec.  314.107(b)(3) to describe 
the date on which a 505(b)(2) application or ANDA may be approved when 
a 30-month stay relates to a patent to which pediatric exclusivity has 
attached (see section 505A of the FD&C Act). However, a period of 
pediatric exclusivity under section 505A of the FD&C Act may affect the 
approval date of a 505(b)(2) application or ANDA in the circumstances 
described in Sec.  314.107(b)(3).
    II.M.2.c.ii. Federal district court decision of invalidity, 
unenforceability, or non infringement (proposed Sec.  
314.107(b)(3)(ii)). The MMA amended section 505(c)(3)(C) and 
(j)(5)(B)(iii) of the FD&C Act for 505(b)(2) applications and ANDAs, 
respectively, to clarify the type of court decision in patent 
litigation that will terminate a 30-month stay (or 7\1/2\ years where 
applicable) and lead to approval of a 505(b)(2) application or ANDA 
that is otherwise eligible for approval. Prior to the MMA, FDA 
interpreted the reference to a court decision in section 
505(c)(3)(C)(i) and (j)(5)(B)(iii)(I) of the FD&C Act to mean ``the 
court that enters final judgment from which no appeal can be or has 
been taken'' (see guidance for industry entitled ``Court Decisions, 
ANDA Approvals, and 180-Day Exclusivity Under the Hatch-Waxman 
Amendments to the Federal Food, Drug, and Cosmetic Act'' (March 2000), 
available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072868.pdf) 
(superseded Guidance on Court Decisions). The MMA amended the FD&C Act 
to codify the types of Federal district court decisions and, as 
discussed in section II.M.2.c.iii to II.M.2.c.iv, the types of Federal 
appellate court decisions that will terminate a 30-month stay (or 7\1/
2\ years where applicable). Accordingly, FDA is not required to delay 
approval of an otherwise approvable ANDA until there has been a court 
decision from which no appeal can be or has been taken.
    The MMA amended section 505(c)(3)(C)(i) and (j)(5)(B)(iii)(I) of 
the FD&C Act to describe the Federal district court decisions in patent 
litigation that will terminate a 30-month stay (or 7\1/2\ years where 
applicable) and lead to approval of a 505(b)(2) application or ANDA 
that is otherwise eligible for approval (see Sanofi-Aventis v. FDA, 643 
F.Supp.2d 82, 86 (D.D.C.), inj. denied, 2009 U.S. Dist. LEXIS 74578 
(D.D.C. 2009) (``The plain language of the entry of judgment provision 
of the Hatch-Waxman Act is clear that the FDA's approval of a generic 
application `shall be made effective on the . . . date on which the 
court enters judgment' '' irrespective of whether the enforceability of 
that judgment is stayed) (emphasis in original)). We are proposing to 
revise Sec.  314.107(b)(3)(ii) to reflect these statutory revisions 
that change the decisive event from court issuance of a final order 
that the patent is invalid, unenforceable, or not infringed to a 
district court's entry of judgment pursuant to Federal Rule of Civil 
Procedure (Fed. R. Civ. P.) Rule 58 that the patent is invalid, 
unenforceable, or not infringed. As with current Sec.  
314.107(b)(3)(ii), we are proposing to implement section 
505(c)(3)(C)(i) and (j)(5)(B)(iii)(I) of the FD&C Act to include a 
court decision that the applicable patent is unenforceable. Thus, a 
Federal district court's entry of judgment that a patent has been 
infringed by the 505(b)(2) or ANDA applicant but is unenforceable (for 
example, due to inequitable conduct in patent prosecution) would 
terminate a 30-month stay (or 7\1/2\ years where applicable). 
Consistent with section 505(c)(3)(C)(i) and (j)(5)(B)(iii)(I) of the 
FD&C Act, proposed Sec.  314.107(b)(3)(ii) also includes cases in which 
a Federal district court has made a substantive determination that 
there is no cause of action for patent infringement or invalidity.
    We are proposing to further revise Sec.  314.107(b)(3)(ii) to 
incorporate the text of section 505(c)(3)(C)(i) and (j)(5)(B)(iii)(I) 
of the FD&C Act, as amended by the MMA, regarding the timing of 
approval of a 505(b)(2) application or ANDA in relation to the district 
court decision. Proposed Sec.  314.107(b)(3)(ii) provides that in cases 
in which a district court decides that the patent is invalid, 
unenforceable, or not infringed, the 505(b)(2) application or ANDA may 
be approved on the date on which the court enters judgment reflecting 
the decision (paragraph (A)); or the date of a settlement order or 
consent decree signed and entered by the court stating that the patent 
that is the subject of the certification is invalid or not infringed 
(paragraph (B)).
    II.M.2.c.iii. Appeal of Federal district court judgment of 
infringement (proposed Sec.  314.107(b)(3)(iii)). The MMA amended 
section 505(c)(3)(C)(ii) and (j)(5)(B)(iii)(II) of the FD&C Act for 
505(b)(2) applications and ANDAs, respectively, to describe the 
earliest date on which a 30-month stay (or 7\1/2\ years where 
applicable) can be terminated after a Federal district court has 
decided that the patent has been infringed based on whether the 
judgment is appealed. We are proposing to revise Sec.  
314.107(b)(3)(iii) and, as discussed in section II.M.2.c.iv, Sec.  
314.107(b)(3)(iv) to reflect these statutory revisions.
    Proposed Sec.  314.107(b)(3)(iii) states that if the Federal 
district court decides that the patent has been infringed and the 
district court judgment is appealed, the 505(b)(2) application or ANDA 
may be approved on the date on which the mandate is issued by the court 
of appeals entering judgment that the patent is invalid or not 
infringed (including any substantive determination that there is no 
cause of action for patent infringement or invalidity) (paragraph (A)); 
or the date of a settlement order or consent decree signed and entered 
by the court of appeals stating that the patent that is the subject of 
the certification is invalid or not infringed (paragraph (B)). Proposed 
Sec.  314.107(b)(3)(iii) restates the text of section 505(c)(3)(C)(ii) 
and (j)(5)(B)(iii)(II) of the FD&C Act except that we are proposing to 
further specify that the date of the court of appeals decision is the 
date on which the

[[Page 6864]]

mandate is issued by the court of appeals (see Federal Rule of 
Appellate Procedure Rule 41). This proposal reflects the Agency's 
current practice in implementing section 505(c)(3)(C)(ii) and 
(j)(5)(B)(iii)(II) of the FD&C Act, which recognizes that a party may 
request rehearing by the appellate panel or rehearing en banc. In such 
circumstances, it would be premature to terminate the 30-month stay and 
possibly approve the 505(b)(2) application or ANDA while a decision 
regarding patent noninfringement, invalidity, or unenforceability was 
being reheard by the court of appeals. By interpreting the ``date on 
which the court of appeals decides that the patent is invalid or not 
infringed'' (see section 505(c)(3)(C)(ii) and (j)(5)(B)(iii)(II) of the 
FD&C Act) to mean the date on which the mandate issues, we are ensuring 
that the Agency's action reflects the judgment of the court of appeals. 
We seek comment on this interpretation.
    II.M.2.c.iv. Affirmation or non-appeal of Federal district court 
judgment of infringement (proposed Sec.  314.107(b)(3)(iv)). The MMA 
amended section 505(c)(3)(C)(ii)(II) and (j)(5)(B)(iii)(II)(bb) of the 
FD&C Act to describe the timing of approval of a 505(b)(2) application 
or ANDA, respectively, that a Federal district court has decided 
infringes a patent that was the subject of a paragraph IV certification 
if the district court decision was not appealed or was affirmed on 
appeal. In such a case, section 505(c)(3)(C)(ii)(II) and 
(j)(5)(B)(iii)(II)(bb) of the FD&C Act provide that the 505(b)(2) 
application or ANDA will be approved on the date specified by the 
district court in an order under 35 U.S.C. 271(e)(4)(A). We are 
proposing to revise Sec.  314.107(b)(3)(iv) to reflect these statutory 
revisions with certain clarifications.
    Proposed Sec.  314.107(b)(3)(iv) provides that if the district 
court decides that the patent at issue is infringed and this judgment 
is not appealed or is affirmed on appeal, the 505(b)(2) application or 
ANDA may be approved no earlier than the date specified by the district 
court in an order under 35 U.S.C. 271(e)(4)(A). Although the date 
specified by the district court order would not be earlier than the 
date of expiration of the infringed patent (see 35 U.S.C. 
271(e)(4)(A)), the date specified by the order may not take into 
account any other unexpired patents or unexpired exclusivity (or 
deficiencies in the application) that would delay approval of the 
505(b)(2) application or ANDA beyond the date of expiration of the 
infringed patent. Therefore, proposed Sec.  314.107(b)(3)(iv) states 
that the 505(b)(2) application or ANDA may be approved no earlier than 
the date specified in a district court's order under 35 U.S.C. 
271(e)(4)(A), rather than using the statutory phrasing that the 
``approval shall be made effective on the date'' specified by such 
order (see section 505(c)(3)(C)(ii)(II) and (j)(5)(B)(iii)(II)(bb) of 
the FD&C Act and section II.I regarding removal of references to the 
effective date of approval).
    II.M.2.c.v. Grant of preliminary injunction by Federal district 
court (proposed Sec.  314.107(b)(3)(v)). The MMA amended section 
505(c)(3)(C)(iii), (c)(3)(C)(iv), (j)(5)(B)(iii)(III), and 
(j)(5)(B)(iii)(IV) of the FD&C Act to clarify that the timing of 
approval of a 505(b)(2) application or ANDA, respectively, is subject 
to provisions of section 505(c)(3)(C)(i), (c)(3)(C)(ii), 
(j)(5)(B)(iii)(I), and (j)(5)(B)(iii)(II) even if preceded by a 
preliminary injunction prohibiting the applicant from engaging in the 
commercial manufacture or sale of the drug until the court decides the 
issues of patent validity and infringement. We are proposing to revise 
current Sec.  314.107(b)(3)(iv) (redesignated as proposed Sec.  
314.107(b)(3)(v)) to reflect these statutory revisions. Proposed Sec.  
314.107(b)(3)(v) cross-references the applicable paragraph of Sec.  
314.107(b)(3) that would address the timing of approval of the 
505(b)(2) application or ANDA based on the court's decision with 
respect to patent validity and infringement. If a preliminary 
injunction is entered before the expiration of the 30-month stay, FDA 
interprets section 505(j)(5)(B)(iii) of the FD&C Act to require that 
the stay of approval is extended until the court decides the issues of 
patent infringement and validity. Once such a decision is made, the 
references to section 505(j)(5)(B)(iii)(I) and (j)(5)(B)(iii)(II) of 
the FD&C Act provide for the timing of approval (see section 
505(j)(5)(B)(iii)(III) and (j)(5)(B)(iii)(IV) of the FD&C Act). We seek 
comment on this approach.
    In addition, proposed Sec.  314.107(b)(3)(v) makes clear that the 
court that grants a preliminary injunction pending a decision on the 
issues of patent validity and infringement refers to the Federal 
district court hearing the patent infringement action.
    II.M.2.c.vi. Written consent to approval by patent owner or 
exclusive patent licensee (proposed Sec.  314.107(b)(3)(vi)). We are 
proposing to add Sec.  314.107(b)(3)(vi) to clarify that if the patent 
owner or exclusive patent licensee (or their representatives) agrees in 
writing that the 505(b)(2) application or ANDA application may be 
approved, the 30-month stay (or 7\1/2\ years where applicable) will be 
terminated and the approval may be granted on or after the date of the 
consent. Thus, proposed Sec.  314.107(b)(3)(vi) would permit 
termination of the 30-month stay (or 7\1/2\ years where applicable) 
without a court order. This scenario may arise, for example, if 
settlement of the patent litigation results in a license to the 
505(b)(2) or ANDA applicant.
    II.M.2.c.vii. Court order terminating 30-month or 7\1/2\-year 
period (proposed Sec.  314.107(b)(3)(vii)). We are proposing to add 
Sec.  314.107(b)(3)(vii) to clarify that if a court enters an order 
requiring the termination of the 30-month stay (or 7\1/2\ years where 
applicable), the 505(b)(2) application or ANDA, if otherwise ready for 
approval, may be approved in accordance with the court order.
    II.M.2.c.viii. Court order of dismissal without a finding of 
infringement (proposed Sec.  314.107(b)(3)(viii)). The MMA's amendments 
to section 505(c)(3)(C)(i), (c)(3)(C)(ii), (j)(5)(B)(iii)(I), and 
(j)(5)(B)(iii)(II) of the FD&C Act clarify the timing of approval of a 
505(b)(2) application or ANDA, respectively, in relation to a 
settlement order or consent decree stating that the patent that is the 
subject of the paragraph IV certification is invalid or not infringed. 
However, the statute does not address whether a 30-month stay may be 
terminated and a 505(b)(2) application or ANDA approved if the court 
enters an order of dismissal without a finding of patent infringement--
a scenario that FDA encounters frequently. We are proposing to add 
Sec.  314.107(b)(3)(viii) to codify FDA's policy that court entry of an 
order of dismissal, with or without prejudice, of patent infringement 
litigation that was timely initiated in response to notice of a 
paragraph IV certification will terminate the 30-month period (or 7\1/
2\ years where applicable) if such order does not state a finding of 
patent infringement. It is appropriate that a 30-month stay terminates 
under these circumstances because the statutory purpose of the stay is 
to allow time for claims of patent infringement to be litigated prior 
to approval of the potentially infringing drug product. If the patent 
owner or exclusive patent licensee dismisses the patent infringement 
action on terms that the court considers proper (see Fed. R. Civ. P. 
Rule 41(a)(2)), then there should be no further delay of approval of a 
505(b)(2) application or ANDA otherwise eligible for approval.
    II.M.2.d. Tentative approval (proposed Sec.  314.107(b)(4)). We are

[[Page 6865]]

proposing to redesignate current Sec.  314.107(b)(3)(v) as proposed 
Sec.  314.107(b)(4) for organizational convenience. Proposed Sec.  
314.107(b)(4) describes tentative approval of a 505(b)(2) application 
or ANDA as appropriate in accordance with Sec.  314.107(b)(3). In 
addition, we are proposing to revise Sec.  314.107(b)(4) to state that 
FDA will issue a tentative approval letter when tentative approval is 
appropriate in accordance with a court order pursuant to 35 U.S.C. 
271(e)(4)(A) that a 505(b)(2) application or ANDA may be approved no 
earlier than the date specified, irrespective of whether the injunction 
relates to a patent described in Sec.  314.107(b)(3) (see proposed 
Sec.  314.107(e)(1)(vi)). This proposed revision is intended to 
complement proposed Sec.  314.107(g), which clarifies that if a court 
enters an order requiring that the date of approval be delayed for an 
already approved 505(b)(2) application or ANDA, FDA will convert the 
approval to a tentative approval, if appropriate. This scenario may 
occur, for example, if a patent infringement action is initiated after 
the 45-day period described in section 505(c)(3)(C) and (j)(5)(B)(iii) 
of the FD&C Act and results in a judgment of patent infringement. 
Proposed Sec.  314.107(b)(4) would expressly describe FDA's practice of 
giving effect to the court order under 35 U.S.C. 271(e)(4)(A), 
irrespective of whether the order relates to a patent associated with a 
30-month stay of approval (see, e.g., Mylan Labs., Inc. v. Thompson, 
389 F.3d 1272 (D.C. Cir. 2004)).
    We also are proposing to amend references to ``receiv[ing] final 
approval'' and making an approval ``effective'' to refer instead to 
receipt of an approval letter (see sections II.A.2.dd and II.I).
II.M.3. Subsequent ANDA Submission (Proposed Sec.  314.107(c))
    Section 1102 of the MMA amended section 505(j)(5) of the FD&C Act 
to modify the conditions under which a 180-day period of exclusivity is 
granted and to establish conditions under which a first applicant would 
forfeit the 180-day exclusivity period. As noted in section I.D, we are 
currently implementing the 180-day exclusivity provisions of the MMA 
directly from the statute and will determine if additional rulemaking 
is necessary in the future. At this time, we are proposing to revise 
Sec.  314.107(c) to remove provisions that have been superseded by the 
statute, as revised by the MMA, and to generally conform with the 
statute.
    Table 13 summarizes the proposed changes related to submission of 
an ANDA containing a paragraph IV certification by a subsequent ANDA 
applicant.

   Table 13--Highlights of Proposed Changes Regarding Subsequent ANDA
                             Submission \1\
------------------------------------------------------------------------
                                                Proposed revisions to
            Current regulations                      regulations
------------------------------------------------------------------------
Subsequent ANDA submission (Sec.            Subsequent ANDA submission
 314.107(c)(1),(3))                          (Sec.   314.107(c)(1))
 If an ANDA contains a paragraph     If an ANDA contains
 IV certification and the ANDA is for a      a paragraph IV
 generic copy of the same listed drug for    certification for a
 which one or more substantially complete    relevant patent and the
 ANDAs were previously submitted             ANDA is not that of a first
 containing a paragraph IV certification     applicant, the ANDA is
 to the same patent, approval of the         regarded as that of a
 subsequent ANDA will be made effective no   subsequent applicant.
 sooner than 180 days from whichever of      The ANDA of a
 the following dates is earlier:             subsequent applicant will
--(i) The date the applicant submitting      not be approved during the
 the first application first commences       period when any first
 commercial marketing of its drug product;   applicant for the drug
 or                                          product is eligible for 180-
--(ii) The date of a decision of the court   day exclusivity or during
 holding the relevant patent invalid,        the 180-day exclusivity
 unenforceable, or not infringed.            period of a first
                                             applicant.
                                             Any applicable 180-
                                             day exclusivity period can
                                             not extend beyond the
                                             expiration of the patent
                                             upon which the 180-day
                                             exclusivity period was
                                             based.
 For purposes of Sec.
 314.107(c)(1), if FDA concludes that the
 applicant submitting the first ANDA is
 not actively pursuing approval, FDA will
 make the approval of subsequent ANDAs
 immediately effective if they are
 otherwise eligible for an immediately
 effective approval.
Subsequent ANDA submission (Sec.            Definitions (Sec.
 314.107(c)(2))                              314.3(b))
 For purposes of Sec.                First applicant is
 314.107(c)(1), the `applicant submitting    an applicant that, on the
 the first application' is the applicant     first day on which a
 that submits an ANDA that is both           substantially complete ANDA
 substantially complete and contains a       containing a paragraph IV
 certification that the patent was           certification is submitted
 invalid, unenforceable, or not infringed    for approval of a drug,
 prior to the submission of any other        submits a substantially
 application for the same listed drug that   complete ANDA that
 is both substantially complete and          contains, and for which the
 contains the same certification.            applicant lawfully
 A `substantially complete'          maintains, a paragraph IV
 application must contain the results of     certification for the drug.
 any required bioequivalence studies, or,    Substantially
 if applicable, a request for a waiver of    complete application is an
 such studies.                               ANDA that on its face is
                                             sufficiently complete to
                                             permit a substantive review
                                             and contains all the
                                             information required under
                                             section 505(j)(2)(A) of the
                                             FD&C Act and Sec.   314.94.
Subsequent ANDA submission (Sec.            Subsequent ANDA submission
 314.107(c)(4))                              (Sec.   314.107(c)(2))
     For purposes of Sec.            For purposes of
     314.107(c)(1)(i), the applicant         Sec.   314.107(c)(1), a
     submitting the first ANDA shall         first applicant must submit
     notify FDA of the date that it          a supplement to its ANDA
     commences commercial marketing of its   notifying FDA within 30
     drug product.                           days of the date of first
                                             commercial marketing of its
                                             drug product.
     If an applicant does not        If an applicant
     promptly notify FDA of such date, the   does not notify FDA, as
     effective date of approval shall be     required above, of this
     deemed to be the date of the            date, the date of first
     commencement of first commercial        commercial marketing will
     marketing.                              be deemed to be the date of
                                             the drug product's
                                             approval.
     Commercial marketing           Definitions (Sec.
     commences with the first date of        314.3(b))
     introduction or delivery for            Commercial
     introduction into interstate commerce   marketing is the
     outside the control of the              introduction or delivery
     manufacturer of a drug product,         for introduction into
     except for investigational use under    interstate commerce of a
     part 312 of this chapter, but does      drug product described in
     not include transfer of the drug        an approved ANDA, outside
     product for reasons other than sale     the control of the ANDA
     within the control of the               holder, except for
     manufacturer or application holder.     investigational use under
                                             part 312 of this chapter,
                                             but does not include
                                             transfer of the drug
                                             product for reasons other
                                             than sale to parties
                                             identified in the approved
                                             ANDA.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
  regulations, but should not be relied upon in place of the proposed
  regulation.


[[Page 6866]]

    We are proposing to revise Sec.  314.107(c)(1) to incorporate the 
term ``first applicant,'' as defined by section 
505(j)(5)(B)(iv)(II)(bb) of the FD&C Act and in proposed Sec.  314.3(b) 
(see section II.A.2.q), and to distinguish a ``first applicant'' from a 
``subsequent applicant.'' An ANDA has been submitted by a subsequent 
applicant if the ANDA has not been submitted by a first applicant and 
contains a paragraph IV certification to a relevant patent that has 
been listed for the drug product for which a first applicant has 
submitted an ANDA. A subsequent applicant's ANDA will not be approved 
during the period when any first applicant for the drug product is 
eligible for 180-day exclusivity or during the 180-day exclusivity 
period of a first applicant (see section 505(j)(5)(B)(iv)(I) of the 
FD&C Act). By including the period during which any first applicant is 
eligible for 180-day exclusivity, proposed Sec.  314.107(c)(1) 
clarifies that a subsequent ANDA for the drug product may not be 
approved while a first applicant is eligible for 180-day exclusivity as 
long as a forfeiture event has not occurred with respect to that first 
applicant (see section 505(j)(2)(D)(ii) of the FD&C Act). These 
proposed revisions replace the current text of Sec.  314.107(c)(1), 
superseded by statute, which describe a patent-by-patent analysis to 
determine eligibility for 180-day exclusivity and events that would 
trigger the start of the 180-day period under the pre-MMA statutory 
scheme.
    We are proposing to delete the definition of the ``applicant 
submitting the first application'' in current Sec.  314.107(c)(2) 
because it has been superseded by the statutory definition added by the 
MMA. We are proposing to incorporate the MMA's definition of the term 
``first applicant,'' with minor editorial changes and additional 
clarifying text, into Sec.  314.3(b) (see section 
505(j)(5)(B)(iv)(II)(bb) of the FD&C Act and section II.A.2.q). We also 
are proposing to delete Sec.  314.107(c)(3), which described the 
potential consequences of a first applicant's failure to actively 
pursue approval of its ANDA because this regulation has been superseded 
by the statutory provisions that specify events that will result in 
forfeiture of the 180-day exclusivity period by a first applicant (see 
section 505(j)(5)(D) of the FD&C Act).
    The MMA amended the FD&C Act to modify the types of events that can 
trigger the start of the 180-day exclusivity period for a first 
applicant (see section 505(j)(5)(B)(iv)(I) of the FD&C Act; see also 
section 1102(b)(3) of the MMA). Section 505(j)(5)(B)(iv)(I) of the FD&C 
Act provides that the period of 180-day exclusivity will begin on the 
``date of the first commercial marketing of the drug (including the 
commercial marketing of the listed drug) by any first applicant.'' This 
commercial marketing trigger differs from the version of section 
505(j)(5)(B)(iv)(I) in effect prior to enactment of the MMA, which 
provided that the 180-day exclusivity period will begin on the earlier 
of two events, one of which was the date the Secretary receives notice 
from the applicant of the first commercial marketing of the drug 
eligible for 180-day exclusivity. We are proposing to revise Sec.  
314.107(c)(4) to conform with these changes to the FD&C Act and 
redesignate this provision as Sec.  314.107(c)(2) (``redesignated Sec.  
314.107(c)(2)'').
    In light of the change in the commercial marketing trigger from the 
date on which FDA receives notice from the applicant of the first 
commercial marketing to the date of the first commercial marketing of 
the drug, we are proposing to revise redesignated Sec.  314.107(c)(2) 
to require a first applicant to submit correspondence to its ANDA 
notifying FDA within 30 days of the date of first commercial marketing 
of the drug product (see current Sec.  314.107(c)(4)). This proposal to 
require notification within 30 days of the date of first commercial 
marketing is intended to facilitate the efficient enforcement of the 
FD&C Act and provide adequate notice to subsequent applicants that have 
received tentative approval and are awaiting expiration of the period 
of 180-day exclusivity. If the first applicant does not notify FDA 
within this timeframe, we are proposing to deem the date of first 
commercial marketing to be the date of the drug product's approval. 
This may have the effect of shortening the 180-day period of 
exclusivity in a manner similar to current Sec.  314.107(c)(4).
    We also are proposing to revise redesignated Sec.  314.107(c)(2) to 
remove the description of ``commercial marketing.'' As explained in 
section II.A.2.l, we are proposing to define ``commercial marketing'' 
in Sec.  314.3(b) with certain modifications, as compared to current 
Sec.  314.107(c)(4), to the scope of the exclusion for transfer of the 
drug product for reasons other than sale.
II.M.4. Delay of Approval Due to Exclusivity (Proposed Sec.  
314.107(d))
    We are proposing to revise Sec.  314.107(d) to clarify that 
approval of a 505(b)(2) application or ANDA may be delayed by orphan 
drug exclusivity and pediatric exclusivity in addition to the 
exclusivities described in Sec.  314.108. Proposed Sec.  314.107(d) 
explains that when approval of a 505(b)(2) application or ANDA is 
delayed under Sec.  314.107 and Sec.  314.108, 21 CFR 316.31 (orphan 
drug exclusivity), or section 505A of the FD&C Act (pediatric 
exclusivity), the 505(b)(2) application or ANDA will be approved on the 
latest of the dates specified under these provisions. We also have made 
conforming revisions to proposed Sec.  314.107(d) that are described 
elsewhere in section II.M.
II.M.5. Notification of Court Actions or Documented Agreement (Proposed 
Sec.  314.107(e))
    We are proposing to revise Sec.  314.107(e) to expand the scope of 
documentation that an applicant must submit to FDA regarding court 
actions and settlements related to patents. These changes are intended 
to ensure that FDA is promptly advised of court actions and documented 
agreements that may affect the timing of approval of a 505(b)(2) 
application or ANDA for the efficient administration of the FD&C Act. 
FDA does not have the resources to monitor the numerous court actions 
that are pending at any given time which may affect the date of 
approval of a 505(b)(2) application or ANDA that is otherwise eligible 
for approval.
    Table 14 summarizes the proposed changes related to notification of 
court actions or documented agreements.

Table 14--Highlights of Proposed Changes Regarding Notification of Court
                   Actions or Documented Agreements\1\
------------------------------------------------------------------------
                                              Proposed revisions to
          Current regulations                      regulations
------------------------------------------------------------------------
Notification of court actions (Sec.      Notification of court actions
 314.107(e))                              or documented agreements (Sec.
                                            314.107(e)(1) and (e)(2))

[[Page 6867]]

 
 Applicant must submit a copy     Applicant must submit
 of the entry of the order or judgment    the following information to
 to the Office of Generic Drugs or to     FDA, as applicable:
 the appropriate division in the Office  --a copy of any judgment by the
 of New Drugs, as applicable, within 10   court (district court or
 working days of a final judgment.        mandate of the court of
                                          appeals) or settlement order
                                          or consent decree signed and
                                          entered by the court (district
                                          court or court of appeals)
                                          finding a patent described in
                                          Sec.   314.107(b)(3) invalid,
                                          unenforceable, or not
                                          infringed, or finding the
                                          patent valid and infringed,
                                          and written notification of
                                          whether any such court action
                                          has been appealed;
                                            --A copy of any order
                                             entered by the court
                                             terminating the 30-month or
                                             7\1/2\-year period
                                             described in Sec.
                                             314.107(b)(3)(i) and
                                             (b)(3)(ii);
                                            --A copy of any documented
                                             agreement described in Sec.
                                               314.107(b)(3)(vi);
                                            --A copy of any preliminary
                                             injunction described in
                                             Sec.   314.107(b)(3)(v),
                                             and a copy of any
                                             subsequent court order
                                             lifting the injunction; and
                                            --A copy of any court order
                                             pursuant to 35 U.S.C.
                                             271(e)(4)(A) ordering that
                                             a 505(b)(2) application or
                                             ANDA may be approved no
                                             earlier than the date
                                             specified (irrespective of
                                             whether the injunction
                                             relates to a patent
                                             described in Sec.
                                             314.107(b)(3)).
                                          All required
                                          information must be sent to
                                          the Office of Generic Drugs or
                                          to the appropriate division in
                                          the Office of New Drugs, as
                                          applicable, within 14 days of:
                                            --the date of entry by the
                                             court,
                                            --the date of appeal or
                                             expiration of the time for
                                             appeal, or
                                            --the date of documented
                                             agreement, as applicable.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
  regulations, but should not be relied upon in place of the proposed
  regulation.

    Proposed Sec.  314.107(e)(1)(i) would require a 505(b)(2) or ANDA 
applicant to submit a copy of any judgment by the court (district court 
or mandate of the court of appeals) finding a patent described in Sec.  
314.107(b)(3) invalid, unenforceable, or not infringed, or finding the 
patent valid and infringed. This proposed requirement imposes a duty on 
505(b)(2) and ANDA applicants to notify FDA regarding any court 
judgment regardless of whether or not the action for patent 
infringement has resulted in a substantive determination by the court 
regarding validity, enforceability, and/or infringement of the patent.
    In addition, we are proposing to require 505(b)(2) and ANDA 
applicants to submit to FDA a copy of certain documented agreements and 
court actions other than judgments to facilitate FDA's administration 
of the FD&C Act. Proposed Sec.  314.107(e)(1)(i) would require a 
505(b)(2) or ANDA applicant to submit a copy of a settlement order or 
consent decree signed and entered by the court (district court or court 
of appeals) finding a patent described in proposed Sec.  314.107(b)(3) 
invalid, unenforceable, or not infringed, or finding the patent valid 
and infringed. It should be noted that this proposal would require 
submission of written documentation that the parties have entered into 
a settlement that has terminated the patent infringement litigation, 
but does not require applicants to send copies of the actual settlement 
agreement to FDA (compare section 1112 of the MMA (requiring that 
generic drug applicants file certain agreements with the FTC)). 
Proposed Sec.  314.107(e)(1)(ii) would require a 505(b)(2) or ANDA 
applicant to submit written notification of whether or not any action 
by the court described in Sec.  314.107(e)(1)(i) has been appealed 
within the time permitted for an appeal. Proposed Sec.  
314.107(e)(1)(iii) and (e)(1)(iv) would require a 505(b)(2) or ANDA 
applicant to submit a copy of any order entered by the court 
terminating the 30-month or 7\1/2\-year period described in proposed 
Sec.  314.107(b)(3)(i) and (b)(3)(ii), and any documented agreement 
described in proposed Sec.  314.107(b)(3)(vi). Proposed Sec.  
314.107(e)(1)(v) would require a 505(b)(2) or ANDA applicant to submit 
a copy of any preliminary injunction described in Sec.  
314.107(b)(3)(v), and a copy of any subsequent court order lifting the 
injunction. Proposed Sec.  314.107(e)(1)(vi) would require a 505(b)(2) 
or ANDA applicant to submit a copy of any court order pursuant to 35 
U.S.C. 271(e)(4)(A) ordering that a 505(b)(2) application or ANDA may 
be approved no earlier than the date specified (irrespective of whether 
the injunction relates to a patent described in Sec.  314.107(b)(3)). 
This revision is intended to conform with proposed Sec.  314.107(b)(4) 
(see section II.M.2.d). These court actions and documented agreements 
also may affect the timing of approval of a 505(b)(2) application or 
ANDA and frequently are unpublished. If an applicant is unsure whether 
a particular court action or documented agreement requires notification 
to FDA under proposed Sec.  314.107(e), we recommend submission.
    We also are proposing to modify the timeframe for a 505(b)(2) or 
ANDA applicant to submit the required information to the appropriate 
division in OND or to OGD, as applicable, to ensure timely notification 
to FDA. Proposed Sec.  314.107(e)(2) would require submission of all 
required information within 14 calendar days of entry by the court, the 
date of appeal or expiration of the time for appeal, or the date of 
written agreement, as applicable. We are proposing to change the 
timeframe for submission of required information from 10 working days 
to 14 calendar days for clarity and consistency with other counting 
conventions used in part 314.
II.M.6. Computation of the 45-Day Time Clock (Proposed Sec.  
314.107(f))
    We are proposing to revise Sec.  314.107(f) to clarify the 
computation of the 45-day period after receipt of notice of paragraph 
IV certification and to enhance the requirements for notifying FDA of 
any legal action filed

[[Page 6868]]

within this timeframe. Table 15 summarizes the proposed changes related 
to the 45-day period after receipt of notice of paragraph IV 
certification. We seek comment on the proposed notification requirement 
and alternative ways for FDA to monitor compliance with the FD&C Act.

  Table 15--Highlights of Proposed Changes Regarding the 45-Day Period
        After Receipt of Notice of Paragraph IV Certification \1\
------------------------------------------------------------------------
                                                Proposed revisions to
            Current regulations                      regulations
------------------------------------------------------------------------
Computation of 45-day time clock (Sec.      Computation of 45-day time
 314.107(f)(1))                              clock (Sec.
                                             314.107(f)(1))
 The 45-day clock described in       The 45-day clock
 Sec.   314.107(b)(3) begins on the day      described in Sec.
 after the date of receipt of the            314.107(b)(3) as to each
 applicant's notice of certification by      recipient required to
 the patent owner or its representative,     receive notice of paragraph
 and by the approved application holder.     IV certification under Sec.
                                              Sec.   314.52 or 314.95
                                             begins on the day after the
                                             date of receipt of the
                                             applicant's notice of
                                             certification by each
                                             recipient.
Computation of 45-day time clock (Sec.      Notification of filing of
 314.107(f)(2))                              legal action (Sec.
                                             314.107(f)(2)(i) to
                                             (f)(2)(ii))
 The 505(b)(2) or ANDA applicant     The 505(b)(2) or
 must notify FDA immediately of the filing   ANDA applicant must notify
 of any legal action filed within 45 days    FDA in writing within 14
 of receipt of the notice of                 days of the filing of any
 certification.                              legal action filed within
                                             45 days of receipt of the
                                             notice of certification by
                                             any recipient.
 The notification to FDA of the      The notification to
 legal action must include, among other      FDA of the legal action
 things: (iv) A certification that an        must include, among other
 action for patent infringement identified   things: (iv) A statement
 by number, has been filed in an             that an action for patent
 appropriate court on a specified date.      infringement, identified by
 A patent owner or its               the court, case number and
 representative may also notify FDA of the   the patent number(s) of the
 filing of any legal action for patent       patent(s) at issue in the
 infringement.                               action, has been filed in
                                             an appropriate court on a
                                             specified date.
                                             A patent owner or
                                             NDA holder (or their
                                             representatives) may also
                                             notify FDA of the filing of
                                             any legal action for patent
                                             infringement.
Computation of 45-day time clock (Sec.      Notification of filing of
 314.107(f)(2))                              legal action (Sec.
                                             314.107(f)(2)(iii))
 If the 505(b)(2) or ANDA            If the 505(b)(2) or
 applicant or the patent owner or its        ANDA applicant, the patent
 representative does not notify FDA in       owner(s), the NDA holder,
 writing before the expiration of the 45-    or their representatives do
 day time period or the completion of the    not notify FDA in writing
 Agency's review of the application,         before the expiration of
 whichever occurs later, that a legal        the 45-day time period or
 action for patent infringement was filed    the completion of the
 within 45 days of receipt of the notice     Agency's review of the
 of certification, approval of the           505(b)(2) application or
 505(b)(2) application or ANDA will be       ANDA, whichever occurs
 made effective immediately upon             later, that a legal action
 expiration of the 45 days or upon           for patent infringement was
 completion of FDA's review and approval     filed within 45 days of
 of the application, whichever is later.     receipt of the notice of
                                             paragraph IV certification,
                                             the 505(b)(2) application
                                             or ANDA may be approved
                                             upon expiration of the 45-
                                             day period (if the
                                             505(b)(2) or ANDA applicant
                                             confirms that a legal
                                             action for patent
                                             infringement has not been
                                             filed) or upon completion
                                             of FDA's review of the
                                             505(b)(2) application or
                                             ANDA, whichever is later.
Computation of 45-day time clock (Sec.      Waiver (Sec.
 314.107(f)(3))                              314.107(f)(3))
 If the patent owner or approved     If the patent owner
 application holder who is an exclusive      or NDA holder who is an
 patent licensee waives its opportunity to   exclusive patent licensee
 file a legal action for patent              (or their representatives)
 infringement within 45 days of a receipt    waives its opportunity to
 of the notice of certification and the      file a legal action for
 patent owner or approved application        patent infringement within
 holder who is an exclusive patent           45 days of a receipt of the
 licensee submits to FDA a valid waiver      notice of certification and
 before the 45 days elapse, approval of      the patent owner or NDA
 the ANDA or the 505(b)(2) application       holder who is an exclusive
 will be made effective upon completion of   patent licensee (or their
 FDA's review and approval of the            representatives) submits to
 application. FDA will only accept a         FDA a valid waiver before
 waiver in the form specified in Sec.        the 45 days elapse, the
 314.107(f)(3)).                             505(b)(2) application or
                                             ANDA may be approved upon
                                             completion of the Agency's
                                             review of the application.
                                             FDA will only accept a
                                             waiver in the form
                                             specified in Sec.
                                             314.107(f)(3), as proposed
                                             for revision.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
  regulations, but should not be relied upon in place of the proposed
  regulation.

    We are proposing to revise Sec.  314.107(f)(1) to clarify that the 
45-day period after receipt of notice of paragraph IV certification is 
calculated for each recipient required to be notified under Sec. Sec.  
314.52(a) and 314.95(a). This proposed revision would codify FDA's 
longstanding interpretation of section 505(b)(3) and (j)(2)(B) of the 
FD&C Act, as amended by the MMA. This interpretation ensures that each 
person required to receive notice under Sec.  314.52 or Sec.  314.95, 
as applicable, also receives the full 45-day period in order to 
evaluate whether to initiate an action for patent infringement and 
obtain a 30-month (or 7\1/2\-year) stay of approval while litigation is 
pending. Accordingly, a 505(b)(2) or ANDA applicant's notice of 
paragraph IV certification may result in more than one ``45-day clock'' 
if the NDA holder and patent owners(s) are different entities and 
receive notice of paragraph IV certification on different days.
    Proposed Sec.  314.107(f)(2) would require that a 505(b)(2) or ANDA 
applicant notify FDA in writing within 14 calendar days of the filing 
of any legal action filed within 45 days of receipt of the notice of 
certification. We are proposing to replace the current requirement for 
``immediate'' notification to establish a date certain by which the 
applicant must send written notification to FDA. This revision is 
intended to enhance compliance and conform with proposed Sec.  
314.107(e), which would require a 505(b)(2) or ANDA applicant to submit 
notification of court actions and documented agreements (and a copy of 
certain court actions) to FDA within 14 calendar days of entry by the 
court, the date of appeal or expiration of the time for appeal, or the 
date of documented agreement, as applicable (see section II.M.5).
    We also are proposing to revise Sec.  314.107(f)(2)(iv) 
(redesignated as Sec.  314.107(f)(2)(i)(D)) to eliminate the 
requirement that the notification to the Agency include a 
``certification'' that an action has been filed. This requirement has 
resulted in confusion, and the Agency has concluded that a written 
``statement'' containing the necessary information is adequate. We are 
proposing to require that this statement contain the patent number(s) 
of the listed patent(s) at issue in the patent infringement action, in 
addition to the court and case number. The patent number(s) of the 
listed patent(s) at issue in the litigation will assist FDA in its 
administration of the approval

[[Page 6869]]

requirements for 505(b)(2) applications and ANDAs.
    We are proposing to expressly state that an NDA holder or its 
representative also may notify FDA of the filing of any legal action 
for patent infringement, irrespective of whether the NDA holder is an 
exclusive patent licensee and initiated the patent infringement action. 
The notification must be sent to the appropriate office or division and 
contain the information described in proposed Sec.  314.107(f)(2)(i).
    Proposed Sec.  314.107(f)(2)(iii) clarifies that a 505(b)(2) 
application or ANDA may be approved upon expiration of the 45-day 
period (if the 505(b)(2) or ANDA applicant confirms that a legal action 
for patent infringement has not been filed within the 45-day period) or 
upon completion of FDA's review of the 505(b)(2) application or ANDA, 
whichever is later. This provision would apply, for example, if an 
applicant changed a paragraph III certification or a statement pursuant 
to section 505(b)(2)(B) or 505(j)(2)(A)(viii), as applicable, to a 
paragraph IV certification during review of the 505(b)(2) application 
or ANDA and the 45-day period had not elapsed by the time the office or 
division was ready to take an action on the application. It is unlikely 
that this provision would be implicated in most cases, however, because 
a 505(b)(2) or ANDA applicant is required by statute to provide notice 
of paragraph IV certification not later than 20 days after the date of 
the postmark on the acknowledgment letter or paragraph IV 
acknowledgment letter, and review of an application would not be 
expected to be completed before the 45-day period for each recipient 
had ended. The proposed revisions to Sec.  314.107(f)(2)(iii) and 
(f)(3) would replace the current references to the approval of a 
505(b)(2) application or ANDA being made effective because this text 
incorrectly suggests that FDA might issue an approval letter that would 
become effective at some date in the future (see section II.A.2.dd and 
II.I). In addition, proposed Sec.  314.107(f)(2)(iii) clarifies that 
FDA would not approve a 505(b)(2) application or ANDA upon expiration 
of the 45-day period unless the 505(b)(2) or ANDA applicant had 
confirmed that a legal action for patent infringement had not been 
filed.
    Proposed Sec.  314.107(f)(3) would permit a representative of the 
patent owner or NDA holder who is an exclusive patent licensee to waive 
the opportunity to file a patent infringement action within the 45-day 
period. This revision is intended to conform with other sections of 
part 314, including Sec. Sec.  314.52 and 314.95 which permit notice of 
paragraph IV certification to be sent to a representative designated by 
the patent owner to receive notice and the NDA holder's attorney, 
agent, or other authorized official.
    Finally, we are proposing to revise the title to Sec.  314.107(f) 
and add titles to paragraphs (f)(1), (f)(2), and (f)(3) of that section 
for administrative convenience.
II.M.7. Conversion of Approval to Tentative Approval (Proposed Sec.  
314.107(g))
    We are proposing to add Sec.  314.107(g) to clarify that if FDA 
issues an approval letter in error or a court enters an order requiring 
that the date of approval be delayed for an already approved 505(b)(2) 
application or ANDA, FDA will convert the approval to a tentative 
approval if appropriate.
    An approved application may be converted to tentatively approved 
status if a court determines that a listed patent has been infringed by 
a 505(b)(2) or ANDA applicant and issues an order pursuant to 35 U.S.C. 
271(e)(4) requiring that the effective date of approval shall not be 
earlier than the date on which the infringed patent will expire, 
including any pediatric exclusivity that may attach to that patent 
(see, e.g., Mylan Labs., Inc. v. Thompson, 389 F.3d 1272 (D.C. Cir. 
2004)). In addition, FDA will convert an approval to tentatively 
approved status if the approval letter was issued in error (for 
example, if an ANDA applicant failed to notify FDA of an adverse 
decision in patent infringement litigation).

II.N. Assessing Bioavailability and Bioequivalence for Drugs Not 
Intended To Be Absorbed Into the Bloodstream (Proposed Sec.  320.23)

    The MMA amends section 505(j)(8) of the FD&C Act to explicitly 
authorize FDA to establish methods for assessing bioavailability and 
bioequivalence for drugs that are not absorbed into the bloodstream 
(see section 505(j)(8)(A)(ii) and (j)(8)(C) of the FD&C Act). These 
amendments essentially codify our existing practice of establishing 
such methods, as reflected in current Sec. Sec.  320.23(a)(1) and 
320.24 and in our implementation of these regulations.
    Our proposal would revise the text of Sec.  320.23 to more 
precisely reflect the text of section 505(j)(8) of the FD&C Act. 
However, these proposed revisions are not intended to change our 
current interpretation of Sec.  320.23, as the amendments to section 
505(j)(8) of the FD&C Act are intended to codify our existing 
interpretation (see section 1103(b) of the MMA, which specifically 
states that the amendments made to section 505(j)(8) of the FD&C Act 
``do[] not alter the standards for approval of [ANDAs].'').

II.O. Miscellaneous

II.O.1. Clarifying Revisions and Editorial Changes
    We are proposing several clarifying revisions and editorial changes 
throughout the sections of parts 314 and 320 that are the subject of 
this rulemaking. These changes are intended to promote consistency 
throughout our regulations, incorporate ``plain language,'' employ 
grammatically correct phrasing, and otherwise clarify the text of these 
regulations. Examples of proposed revisions that are not otherwise 
described in this document are provided below.
     Change ``means'' to ``is'' after each term described in 
the definitions section (see proposed Sec.  314.3(b));
     change ``shall'' to ``must'' as appropriate (see generally 
part 314);
     change ``are required'' to ``must'' because an applicant 
is always required to comply with applicable regulations (see proposed 
Sec.  314.50(d)(5));
     change ``prior to the submission of'' to ``before 
submitting'' for clarity (see proposed Sec.  314.50(d)(5));
     change ``claims no uses'' to ``does not claim a use'' to 
correct grammar (see proposed Sec. Sec.  314.52(a) and 314.95(a)); and
     change ``each amendment to Sec.  314.50(d)(1)'' to ``each 
amendment to a section of the NDA described in Sec.  314.50(d)(1)'' for 
clarity (see proposed Sec.  314.60(d)).
    In the codified section of this proposed rule, we have indicated 
proposed editorial changes as amendatory instructions to remove and add 
text. In some instances, however, it was necessary to print an entire 
paragraph to indicate proposed changes that are only editorial changes 
and would not affect substantive portions of the proposed rule.
    We also are proposing to correct statutory citations in part 314 
that have changed due to a series of amendments to the FD&C Act (see, 
e.g., proposed Sec. Sec.  314.52(c), 314.60(c), and 314.95(c) and (f)).
II.O.2. Effect of Other Rulemaking
    In anticipation of the Agency's business process efforts to move 
all submissions to FDA to electronic submission, we are proposing 
certain revisions to provisions that clearly contemplate submission of 
paper to facilitate the transition to electronic submissions and reduce 
the volume of conforming revisions that may be needed in the future. 
Examples of these proposed revisions are provided below:

[[Page 6870]]

     Change ``in a form other than hard copy, for example, on 
microfiche or computer tapes'' to ``in an alternate form'' to reflect 
advances in technology and facilitate the transition to electronic 
submissions (see proposed Sec.  314.50(f)(4));
     delete references to ``mailing cover'' (see proposed 
Sec. Sec.  314.53(d)(6) and 314.70(b)(4)); and
     change ``cover letter'' to ``submission'' (see proposed 
Sec.  314.70(a)(6)).
    FDA is committed to adapting its business practices to evolving 
technology, including using the significant advancements in Web-based, 
electronic systems. We anticipate that Web-based filing of most 
submissions eventually will be required. We anticipate that when such a 
change to an electronic submission system is implemented, future 
guidance will address any technical questions related to such 
submissions. Until such time, the sponsor or applicant must submit them 
in the manner described in the regulations and to the appropriate FDA 
location identified in the regulations.

III. Legal Authority

    The MMA and sections 505, 505A, 527, and 701 (21 U.S.C. 360cc and 
371) of the FD&C Act provide the principal legal authority for this 
proposed rule. Section 505(b) of the FD&C Act describes the contents of 
an NDA and 505(b)(2) application, including patent listing and patent 
certification requirements. Section 505(j) of the FD&C Act describes 
the contents of an ANDA, including bioequivalence information, patent 
certification requirements, and criteria for a petitioned ANDA. Section 
505(b) and (j) of the FD&C Act restrict certain amendments and 
supplements to a 505(b)(2) application or an ANDA. Section 505(b), (c), 
and (j) of the FD&C Act describe the timing of approval for 505(b)(2) 
applications and ANDAs that are subject to the patent and marketing 
exclusivity protections accorded the listed drug(s) relied upon and the 
RLD, respectively. Section 505(j) also describes the availability of 
180-day exclusivity for a first ANDA applicant.
    Section 505A of the FD&C Act describes the availability of 
pediatric exclusivity and describes the effect of such exclusivity on 
approval of 505(b)(2) applications and ANDAs. Section 527 of the FD&C 
Act describes the effect of orphan exclusivity on approval of 505(b)(2) 
applications and ANDAs.
    Thus, sections 505, 505A, and 527 of the FD&C Act, in conjunction 
with our general rulemaking authority in section 701(a) of the FD&C 
Act, serve as our principal legal authority for this proposal.

IV. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct Agencies to assess all 
costs and benefits of available regulatory alternatives and, when 
regulation is necessary, to select regulatory approaches that maximize 
net benefits (including potential economic, environmental, public 
health and safety, and other advantages; distributive impacts; and 
equity).
    The Regulatory Flexibility Act requires Agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. We do not believe this proposed rule would result in 
a significant impact on a substantial number of small entities, but the 
impacts are uncertain. Because we are uncertain whether the proposed 
rule would have a significant economic impact on a substantial number 
of small entities, this and other sections of the preamble and the full 
preliminary regulatory impact analysis constitute the Agency's 
regulatory flexibility analysis.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that Agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $141 million, using the most current (20132) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
proposed rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    This proposed rule would implement portions of the MMA in a manner 
that preserves the balance struck in the 1984 Hatch-Waxman Amendments 
between encouraging the availability of less expensive generic drugs 
and bringing innovative new drugs to market. This rule would also 
revise and clarify procedures related to the approval of 505(b)(2) 
applications and ANDAs to reduce uncertainty among drug firms, reduce 
costs to industry, and reduce demands on FDA resources responding to 
industry inquiries.
    FDA has been implementing the MMA directly from the statute for 
several years and based on this experience has identified opportunities 
to clarify MMA provisions through the adoption of codified language. To 
the extent that clarified regulatory language improves certainty among 
regulated entities, this proposal, if promulgated, would reduce 
industry compliance costs and Agency enforcement costs. The full 
discussion of economic impacts is available in docket FDA-2011-N-0830 
and at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm (Ref. 1).

IV.A. Summary of the Benefits and Costs of the Proposed Rule

    Although many provisions of this proposed rule would codify current 
practice, elements of this proposal would lead to changes that generate 
additional benefits and costs. This proposed rule would affect 
applicants and application holders for NDAs (including 505(b)(2) 
applications) and ANDAs. Provisions of this rule would affect the 
submission of patent information by NDA holders for listing in the 
Orange Book and the submission by 505(b)(2) and ANDA applicants of a 
patent certification or statement addressing the listed patent(s) for 
the listed drug(s) relied upon or RLD, respectively. This proposed rule 
would also affect, for those certifying that a listed patent is 
invalid, unenforceable, or not infringed (paragraph IV certification), 
the requirements for the provision of notice of the paragraph IV 
certification to each patent owner and the NDA holder for the listed 
drug. The proposed rule would also affect other requirements associated 
with 505(b)(2) applications and ANDAs.
    This proposed rule would revise certain aspects of the regulations 
on listing of patent information, patent certification requirements, 
and a 30-month stay of approval. It would also update regulations 
pertaining to the type of bioavailability and bioequivalence data that 
can be used to support 505(b)(2) applications and ANDAs. These proposed 
revisions to the Agency's regulations in parts 314 and 320 would 
implement portions of Title XI of the MMA and facilitate compliance 
with and enforcement of the FD&C Act.
    We present a summary of benefits and costs in Table 16. The 
estimated annual monetized benefits of this proposed rule are $194,314, 
and estimated annual monetized costs are $91,371. We have also 
identified, but are unable to

[[Page 6871]]

quantify, impacts from proposed changes to submitted patent information 
and the implementation of an administrative consequence for failing to 
provide notice within the timeframe specified by the MMA.

                                                  Table 16--Economic Data: Costs and Benefits Statement
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                      Units
                                                                      Primary      Low        High   ---------------------------------------
                              Category                                estimate   estimate   estimate      Year       Discount      Period       Notes
                                                                                                        dollars        rate       covered
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits
    Annualized Monetized $millions/year............................      $0.19      $0.19      $0.19  ...........           7%       Annual  ...........
                                                                         $0.19      $0.19      $0.19  ...........           3%       Annual  ...........
    Annualized Quantified..........................................  .........  .........  .........  ...........           7%       Annual  ...........
                                                                                                                                             ...........
    Qualitative....................................................  .........  .........  .........  ...........           3%       Annual  ...........
Costs
    Annualized Monetized $millions/year............................      $0.09      $0.09      $0.09         2012           7%       Annual  ...........
                                                                         $0.09      $0.09      $0.09         2012           3%       Annual  ...........
    Annualized Quantified..........................................  .........  .........  .........  ...........           7%  ...........  ...........
 
    Qualitative....................................................  .........  .........  .........  ...........           3%               ...........
Transfers
    Federal Annualized Monetized $millions/year....................  .........  .........  .........  ...........           7%  ...........        None.
                                                                     .........  .........  .........  ...........           3%               ...........
    From/To........................................................      From:        To:
    Other Annualized Monetized $millions/year......................  .........  .........  .........  ...........           7%  ...........        None.
 
    From/To........................................................      From:        To:                                   3%
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects
State, Local, or Tribal Government: Not applicable
Small Business: For firms with 25 to 49 employees, which is a more likely lower bound for firms submitting 505(b)(2) applications, the unit cost of this
 provision would be less than 0.05 percent of average shipments.
Wages: No estimated effect
Growth: No estimated effect
--------------------------------------------------------------------------------------------------------------------------------------------------------

IV.B. Summary of Regulatory Flexibility Analysis

    FDA conducted a regulatory flexibility analysis of the impact of 
the proposed rule on small entities. Statistics on the classification 
of firms by employment size from the U.S. Bureau of the Census show 
that in 2005, at least 85 percent of pharmaceutical manufacturing 
entities had fewer than 500 employees and would have been considered 
small by the U.S. Small Business Administration (Ref. 2).
    We have provided monetized estimates for $194,314 in benefits and 
$91,371 in costs. These costs of this proposed rule are generally small 
unit costs incurred across many entities. Our estimated unit costs for 
all but one item are less than $190 per unit. In table 17, we express 
the unit cost of an amendment to a patent certification in terms of 
hundredths of a percent of average establishment shipments. Excluding 
one item (505(b)(2) applicants providing a patent certification to a 
pharmaceutically equivalent drug product), there are costs of $83,146 
attributable to about 1,200 units. Some affected entities would face 
multiple unit costs of some type in a year, but even this circumstance 
would not approach a significant impact on a substantial number of 
small entities. For a unit cost of $190 to amount to 1 percent of 
average shipments among establishment with fewer than 5 employees, the 
entity would have to incur that cost more than 40 times.

   Table 17--Small Entity Characteristics and the Impact of Unit Costs
                   Attributable to This Proposed Rule
------------------------------------------------------------------------
 
------------------------------------------------------------------------
                                          Pharmaceutical Preparation
                                                 Manufacturing
                                                (NAICS 325412)
------------------------------------------------------------------------
No. of Employees....................                <5             20-49
Total Value of Shipments ($1,000)...           187,933           978,494
No. of Establishments...............               228               109
Average Value of Shipments ($)......           824,268         8,977,009
Unit Costs of Identifying a                      0.50%            0.046%
 Pharmaceutically Equivalent Drug
 Product as a Listed Drug Relied
 Upon per Sec.   314.50(i)(1)(i)(C)
 as a Percentage of the Average
 Value of Shipments.................
------------------------------------------------------------------------

V. Paperwork Reduction Act of 1995

    This proposed rule contains information collection requirements 
that are subject to public comment and review by the Office of 
Management and Budget (OMB) under the Paperwork Reduction Act of 1995 
(44 U.S.C. 3501-3520). We describe these provisions below in this 
section of the document with an estimate of the annual reporting 
burden. Our estimate includes the time for reviewing instructions, 
searching existing data sources, gathering and maintaining the data 
needed, and completing and reviewing each collection of information.

[[Page 6872]]

    We invite comments on these topics: (1) Whether the proposed 
collection of information is necessary for the proper performance of 
FDA's functions, including whether the information will have practical 
utility; (2) the accuracy of FDA's estimate of the burden of the 
proposed collection of information, including the validity of the 
methodology and assumptions used; (3) ways to enhance the quality, 
utility, and clarity of the information to be collected; and (4) ways 
to minimize the burden of the collection of information on respondents, 
including through the use of automated collection techniques, when 
appropriate, and other forms of information technology.
    Title: Abbreviated New Drug Applications and 505(b)(2) 
Applications; Proposed Revisions to Implement Portions of the Medicare 
Prescription Drug, Improvement, and Modernization Act of 2003 and Other 
Changes.
    Description of Respondents: Respondents to this collection of 
information are NDA applicants (including 505(b)(2) applicants) and 
ANDA applicants, patent owners, and their representatives.
    Burden Estimate: This proposed rule would implement portions of 
Title XI of the MMA that pertain to a 505(b)(2) or ANDA applicant's 
provision of notice of paragraph IV certification to each patent owner 
and the NDA holder; the availability of 30-month stays of approval on 
505(b)(2) applications and ANDAs that are otherwise ready to be 
approved; submission of amendments and supplements to 505(b)(2) 
applications and ANDAs; and the types of bioavailability and 
bioequivalence data that can be used to support these applications. 
This proposed rule also would amend certain regulations regarding 
505(b)(2) applications and ANDAs to facilitate compliance with and 
efficient enforcement of the FD&C Act.
    FDA currently has OMB approval for the collection of information 
entitled ``Application for Food and Drug Administration Approval to 
Market a New Drug'' (OMB control number 0910-0001). This collection of 
information includes, among other things:
     The requirements in Sec. Sec.  314.50(i) and 314.94(a)(12) 
for submission of an appropriate patent certification or statement in a 
505(b)(2) application or ANDA;
     the requirements in Sec. Sec.  314.52 and 314.95 for a 
505(b)(2) or ANDA applicant to send notice of any paragraph IV 
certification to each patent owner and the NDA holder and amend its 
505(b)(2) application or ANDA to certify that notice has been provided 
and to document receipt of the notice;
     the content requirements in Sec.  314.54 for a 505(b)(2) 
application;
     the requirements in Sec. Sec.  314.60 and 314.96 for 
applicants that amend an unapproved 505(b)(2) application or ANDA, 
respectively;
     the requirements in Sec. Sec.  314.70 and 314.97 for 
supplements submitted to FDA for certain changes to an approved 
505(b)(2) application or ANDA;
     the requirements in Sec. Sec.  314.90 and 314.99 for 
applicants that request waivers from FDA for compliance with Sec. Sec.  
314.50 through 314.81 or Sec. Sec.  314.92 through 314.99, 
respectively;
     the procedures in Sec.  314.107(c) by which a first 
applicant notifies FDA of the date of first commercial marketing;
     the requirement in Sec.  314.107(e) for an applicant to 
submit to FDA a copy of certain court decisions related to a patent 
that is the subject of a paragraph IV certification;
     the requirement in Sec.  314.107(f) for a 505(b)(2) or 
ANDA applicant to notify FDA immediately of the filing of any legal 
action within 45 days of receipt of the notice of paragraph IV 
certification by each patent owner or the NDA holder; and
     the requirement in Sec.  314.107(f) for a patent owner or 
NDA holder who is an exclusive patent licensee that waives its 
opportunity to file a legal action for patent infringement within the 
45-day period to submit to FDA a waiver in the specified format.
    FDA has OMB approval for the collection of information entitled 
``General Administrative Procedures: Citizen Petitions; Petition for 
Reconsideration or Stay of Action; Advisory Opinions'' (OMB control 
number 0910-0183). This collection of information includes, among other 
things, the requirements in Sec.  314.93 for submitting a suitability 
petition in accordance with 21 CFR 10.20 and 10.30.
    FDA also has received OMB approval for the collection of 
information entitled ``Applications for Food and Drug Administration 
Approval to Market a New Drug: Patent Submission and Listing 
Requirements and Application of 30-Month Stays on Approval of 
Abbreviated New Drug Applications Certifying That a Patent Claiming a 
Drug is Invalid or Will Not Be Infringed'' (OMB control number 0910-
0513). This collection of information includes the requirements in 
Sec.  314.50(h) for submission of patent information in an NDA, an 
amendment, or a supplement, as described in Sec.  314.53. Section 
314.53 requires that an applicant submitting an NDA, an amendment, or a 
supplement, except as provided in Sec.  314.53(d)(2), submit on Forms 
FDA 3542a and 3542 the required patent information described in this 
section.
    We are not reestimating these approved burdens. Only the reporting 
burdens associated with the MMA's amendments to the FD&C Act and the 
proposed changes to parts 314 and 320 are estimated.
    Under section 505(b), (c), and (j) of the FD&C Act and this 
proposed rule, the following information would be submitted to FDA but 
is not currently approved by OMB under the PRA:
    Proposed Sec.  314.50(i)(1)(i)(C) would require a 505(b)(2) 
applicant to submit an appropriate patent certification or statement 
for each patent listed in the Orange Book for a drug product(s) that is 
pharmaceutically equivalent to the proposed drug product for which the 
505(b)(2) application is submitted. Proposed Sec.  314.54 would require 
a 505(b)(2) applicant to identify a pharmaceutically equivalent product 
as a listed drug relied upon and to comply with applicable regulatory 
requirements. Generally, 505(b)(2) applications submitted for a 
proposed drug product for which there is an approved pharmaceutical 
equivalent already cite the pharmaceutically equivalent product as a 
listed drug relied upon to support approval. Therefore, we are not 
estimating a new burden for proposed Sec.  314.54 at this time. Based 
on our experience reviewing 505(b)(2) applications, we estimate that 
proposed Sec.  314.50(i)(1)(i)(C) may result in approximately two 
instances per year in which an applicant is required to identify a 
pharmaceutically equivalent drug product as a listed drug relied upon 
and comply with applicable regulatory requirements (including 
submission of an appropriate patent certification or statement for each 
patent listed in the Orange Book for the pharmaceutically equivalent 
listed drug relied upon). Based on an estimated average of 2.6 patents 
by each NDA holder for listing in the Orange Book, we estimate that 
there will be 5.2 responses per year, and the burden hours associated 
with this requirement in proposed Sec.  314.50(i)(1)(i)(C) will be 
approximately 2 hours per response. If the patent certification 
submitted pursuant to proposed Sec.  314.50(i)(1)(i)(C) is a paragraph 
IV certification, the applicant also must comply with the requirements 
in Sec.  314.52 for notice of paragraph IV certification, which add

[[Page 6873]]

approximately 80 hours (15.33 hours per response) to the currently 
approved burden hours. This estimate reflects other proposals described 
in this section of the document that would reduce the currently 
approved burden for Sec.  314.52 from 16 hours per response to 15 hours 
per response, and the additional content requirement in proposed Sec.  
314.52(c) that would increase the estimated burden by 0.33 hours per 
response. As previously noted, we are not reestimating approved burdens 
in this document. Accordingly, the estimate provided for Sec.  
314.52(a), (b), (c), and (e) reflects the additional burden that may 
arise from the requirement in proposed Sec.  314.50(i)(1)(i)(C) if the 
505(b)(2) applicant submits a paragraph IV certification. We separately 
describe and estimate the burden of the additional content requirement 
in proposed Sec.  314.52(c) for the estimated average of seven 
505(b)(2) applications filed per year that contain one or more 
paragraph IV certification.
    Proposed Sec. Sec.  314.50(i)(6) and 314.94(a)(12)(viii) would 
require a 505(b)(2) or ANDA applicant to amend its patent certification 
from a paragraph IV certification to a paragraph III certification 
after the court enters a final decision from which no appeal has been 
or can be taken, or signs a settlement order or consent decree with a 
finding of infringement (unless the patent also is found invalid). 
Proposed Sec. Sec.  314.50(i)(6) and 314.94(a)(12)(viii) also would 
require a 505(b)(2) or ANDA applicant to submit an amended patent 
certification in certain circumstances after the NDA holder has 
requested to remove a patent or patent information from the list. Based 
on our experience and review of selected court decisions, we estimate 
that there are approximately 12 instances per year in which a party has 
submitted a court decision or order with a finding of infringement. In 
addition, there are approximately 24 instances per year in which the 
NDA holder has requested to remove a patent or patent information from 
the list and the patent or patent information has been removed. Based 
on our experience, we estimate that this requirement may result in 
approximately 36 and 108 instances per year in which an applicant 
amends its 505(b)(2) application or ANDA, respectively, to submit a 
revised patent certification, and the burden hours associated with this 
requirement will be approximately 2 hours per response. Proposed 
Sec. Sec.  314.50(i)(6)(iii)(A)(2) and 314.94(a)(12)(vi)(C)(1)(ii) 
would expressly codify the current requirement for a 505(b)(2) or ANDA 
applicant to submit a patent certification or statement if, after 
submission of the application, a new patent is issued by the PTO that 
in the opinion of the applicant and to the best of its knowledge, 
claims the listed drug or an approved use for such listed drug and for 
which information is required to be filed by the NDA holder. The burden 
hours associated with compliance with current provisions of Sec. Sec.  
314.50(i)(1) through (i)(6) and 314.94(a)(12)(i) through (a)(12)(viii) 
are described in the burden hours estimate currently approved under OMB 
control number 0910-0001.
    Proposed Sec. Sec.  314.52(a) and 314.95(a) would expand the list 
of acceptable delivery methods that may be used to send notice of 
paragraph IV certification to the NDA holder and each patent owner, and 
thereby reduce the burden on applicants to submit, under current 
Sec. Sec.  314.52(a) and (e), a request to FDA to use common alternate 
delivery methods. We receive approximately 205 written inquiries per 
year from 505(b)(2) or ANDA applicants requesting permission to send 
notice of paragraph IV certification by an overnight delivery service. 
Proposed Sec. Sec.  314.52(a) and 314.95(a) would eliminate the 
requirement to submit a request to use a designated delivery service, 
as defined in proposed Sec. Sec.  314.52(f) and 314.95(f). We estimate 
that approximately 95 percent of these written inquiries will no longer 
be required because the alternate delivery method would fall within the 
definition of a ``designated delivery service'' in proposed Sec. Sec.  
314.52(g) and 314.95(g).
    Proposed Sec. Sec.  314.52(c) and 314.95(c) would require that 
notice of paragraph IV certification contain a statement that the 
applicant has received the acknowledgment letter or the paragraph IV 
acknowledgment letter, as applicable. In addition, proposed Sec.  
314.52(c) would require that the notice of paragraph IV certification 
contain a statement that a 505(b)(2) application that contains any 
required bioavailability or bioequivalence data has been submitted by 
the applicant and filed by FDA, as required by section 505(b)(3)(D)(i) 
of the FD&C Act. We estimate that these additional content requirements 
for the notice of paragraph IV certification would increase the burden 
of providing notice of paragraph IV certification by approximately 20 
minutes. Based on an estimated average of 7 505(b)(2) applications 
filed per year that contain one or more paragraph IV certifications and 
209 ANDAs received per year that contain one or more paragraph IV 
certifications, we estimate that there will be 21 and 627 responses per 
year, and the burden hours associated with this requirement will be 
approximately 20 minutes per response.
    Proposed Sec. Sec.  314.52(d)(1) and 314.95(d)(1) would require 
notice of paragraph IV certification regardless of whether notice has 
already been provided for another paragraph IV certification contained 
in the 505(b)(2) application or ANDA or an amendment or supplement to 
the 505(b)(2) application or ANDA, as required by section 
505(b)(3)(B)(ii) and (j)(2)(B)(ii)(II) of the FD&C Act. Since enactment 
of the MMA, FDA has regulated directly from the statute and required 
notice of paragraph IV certification in these circumstances. Thus, the 
burden associated with this statutory requirement is reflected in the 
burden hours estimate for Sec. Sec.  314.52 and 314.95 currently 
approved under OMB control number 0910-0001.
    Proposed Sec. Sec.  314.52(e) and 314.95(e) would permit a 
505(b)(2) or ANDA applicant to submit a single amendment containing 
documentation of timely sending and receipt of notice of paragraph IV 
certification. Currently, an applicant is required to amend its 
505(b)(2) application or ANDA both at the time of sending notice of 
paragraph IV certification and after the notice was received by each 
patent owner and the NDA holder (see current Sec. Sec.  314.52(b) and 
(e) and 314.95(b) and (e)). Proposed Sec.  314.95(e) also would require 
an ANDA applicant to include in its amendment a dated printout of the 
Orange Book entry for the RLD. FDA has OMB approval for the burden 
hours estimate of 16 hours per response for the estimated 260 responses 
submitted annually to comply with Sec. Sec.  314.52 and 314.95 (see OMB 
control number 0910-0001). We estimate that 2 hours of the 16 hours per 
response are attributable to compliance with current Sec. Sec.  
314.52(b) and (e) and 314.95(b) and (e). We estimate that the burden 
hours associated with the requirement in proposed Sec. Sec.  314.52(e) 
and 314.95(e) (including submission of the dated printout of the Orange 
Book entry) would be approximately 1 hour per response for each of the 
estimated 7 and 209 responses per year by our updated estimate of 7 
505(b)(2) applicants and 209 ANDA applicants whose applications were 
filed or received, as applicable, by FDA and contained one or more 
paragraph IV certifications. Therefore, the proposal would reduce the 
currently approved burden for Sec. Sec.  314.52 and 314.95 by 1 hour.
    Proposed Sec.  314.53(c)(2) would decrease the patent information 
that NDA applicants are currently required to submit for listing in the 
Orange Book.

[[Page 6874]]

Proposed Sec.  314.53(c)(2) would require an NDA applicant to submit 
information on a previously submitted patent only if a patent is a 
reissued patent of a patent previously submitted for listing for the 
NDA or supplement. Proposed Sec.  314.53(c)(2) would require submission 
of patent information on whether a drug substance patent claims a 
polymorph only if such patent claims only a polymorph that is the same 
active ingredient described in the NDA or supplement. Proposed Sec.  
314.53(c)(2) also would provide that an applicant that submits 
information for a patent that claims either the drug substance or drug 
product and meets the requirements for patent listing on that basis is 
not required to provide information on whether that patent also claims 
the drug product or drug substance, respectively. The information 
collection resulting from current Sec.  314.50(h) (citing Sec.  314.53) 
and Form FDA 3542a has been approved by OMB under control number 0910-
0153 for FDA's estimate of 20 hours per response. We estimate the 
proposed revisions to our regulations will reduce the time needed to 
complete Form FDA 3542a by approximately 3 hours per response.
    Proposed Sec.  314.53(d)(2) would enable FDA to reduce duplicative 
submission of patent information and require such information only for 
a supplement to change the dosage form or route of administration, to 
change the strength, to change the drug product from prescription to 
OTC use, or to correct previously submitted patent information that 
differently or no longer claims the changed product.
    Proposed Sec.  314.53(f)(2) would expressly require correction or 
change of patent information if the NDA holder determines that a patent 
or patent claim no longer meets the statutory requirements for listing, 
if the NDA holder is required by court order to amend patent 
information or withdraw a patent from the list, or if the term of a 
listed patent is extended under 35 U.S.C. 156(e). We estimate that 
these corrections and changes of patent information would result in 
approximately 62 submissions of Form FDA 3542 or other written 
submission, as provided in proposed Sec.  314.53(f)(2)(iv), by 
approximately 39 NDA holders. We further estimate that the burden hours 
associated with the requirement in proposed Sec.  314.53(f)(2) would be 
approximately 1 hour per response.
    Section 505(b)(4)(A) and (j)(2)(D)(i) of the FD&C Act generally 
prohibit the submission of certain types of changes in an amendment or 
a supplement to a 505(b)(2) application or an ANDA, respectively. 
Proposed Sec. Sec.  314.60(e) and 314.70(h) would prohibit an applicant 
from amending or supplementing a 505(b)(2) application to seek approval 
of a drug that has been modified to have a different active ingredient, 
different route of administration, different dosage form, or certain 
differences in excipients that the drug proposed in the original 
submission of the 505(b)(2) application. These changes must be 
requested in a new 505(b)(2) application. This proposed requirement 
conforms with FDA's current policy regarding the types of proposed 
changes to a drug product that should be submitted as a separate 
application (see Separate Marketing Application Guidance). Accordingly, 
the burden associated with this statutory requirement is reflected in 
the burden hours estimate for Sec. Sec.  314.50 and 314.94 currently 
approved under OMB control number 0910-0001 for 505(b)(2) applications 
and ANDAs, respectively.
    Proposed Sec. Sec.  314.60(f), 314.70(i), 314.96(d), and 314.97(c) 
would require an applicant to submit a patent certification if approval 
is sought for either of the following types of amendments or 
supplements to a 505(b)(2) application or ANDA: (1) To add a new 
indication or other condition of use or (2) to add a new strength. 
Proposed Sec. Sec.  314.60(f) and 314.96(d) also would require an 
applicant to submit a patent certification if approval is sought for 
either of the following types of amendments to a 505(b)(2) application 
or ANDA: (1) To make other than minor changes in product formulation or 
(2) to change the physical form or crystalline structure of the active 
ingredient. Although currently the submission of a patent certification 
is required if, at any time before approval, the applicant learns that 
the previously submitted patent certification is no longer accurate 
with respect to the pending application or supplement, as amended (thus 
the burden hours are currently approved under OMB control number 0910-
0001), the patent certification requirements would be broadened under 
this proposed rule. We estimate that this requirement may result in 
approximately six and four instances per year in which an applicant is 
required to submit a patent certification with an amendment or 
supplement, respectively, to its 505(b)(2) application. We further 
estimate that this requirement may result in approximately 95 and 16 
instances per year in which an applicant is required to submit a patent 
certification with an amendment or supplement, respectively, to its 
ANDA. The burden hours associated with these requirements are estimated 
to be approximately 2 hours per response.
    Proposed Sec. Sec.  314.96(c) and 314.97(b) would prohibit an ANDA 
applicant from amending or supplementing an ANDA to seek approval of a 
drug referring to a listed drug that is different from the RLD 
identified in the ANDA. An applicant must submit a change of the RLD in 
a new ANDA. We estimate that approximately one ANDA applicant per year 
will be required to submit a new ANDA instead of submitting an 
amendment for a change of the RLD. We also estimate that approximately 
one ANDA applicant per year will be required to submit a new ANDA 
instead of submitting a supplement for a change of the RLD. We further 
estimate that the burden of submitting an ANDA and complying with 
applicable regulatory requirements, including any required study to 
demonstrate bioequivalence to the new RLD, will be approximately 288 
hours for each of the estimated two responses per year.
    Proposed Sec.  314.107(e) would expand the scope of the court 
actions and documented agreements related to a patent described in 
Sec.  314.107(b)(3) that are required to be submitted to FDA. Proposed 
Sec.  314.107(e) also would require submission of any court order 
pursuant to 35 U.S.C. 271(e)(4)(A) ordering that a 505(b)(2) 
application or ANDA may be approved no earlier than the date specified. 
FDA has OMB approval for the burden hours estimate of 30 minutes per 
response for the estimated 98 responses submitted annually by 25 
505(b)(2) or ANDA applicants to comply with Sec.  314.107(e) (see OMB 
control number 0910-0001). Based on our experience, we estimate that 
140 505(b)(2) and ANDA applicants will be required to submit a copy of 
a court action, documented agreement, or written notification of appeal 
in approximately 310 instances per year. We continue to estimate that 
the burden associated with submitting a copy of these documents to FDA 
is approximately 30 minutes per response.
    The estimated burden of the burden of this collection of 
information is described in Table 18.

[[Page 6875]]



                                 Table 18--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                   Number of                     Average burden
        21 CFR section             Number of     responses per   Total annual     per response      Total hours
                                  respondents     respondent       responses       (in hours)
----------------------------------------------------------------------------------------------------------------
314.50(i)(1)..................               2             2.6             5.2  2...............            10.4
314.50(i)(6)..................              36               1              36  2...............              72
314.52(a), (b), (c), and (e)..               2             2.6             5.2  15.33...........            79.7
314.52(c).....................               7               3              21  0.33 (20                       7
                                                                                 minutes)..
314.53(f).....................              39             1.5              62  1...............              62
314.60(f).....................               6               1               6  2...............              12
314.70(i).....................               4               1               4  2...............               8
314.94(a)(12).................             108               1             108  2...............             216
314.95(c).....................             209               3             627  0.33 (20                     209
                                                                                 minutes)..
314.96(c).....................               1               1               1  288.............             288
314.96(d).....................              95               1              95  2...............             190
314.97(b).....................               1               1               1  288.............             288
314.97(c).....................              16               1              16  2...............              32
314.107(e)....................             140             2.2             310  0.5 (30                      155
                                                                                 minutes)..
    Total Reporting Burden      ..............  ..............  ..............  ................          1629.1
     Hours.
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    We have submitted the information collection requirements of this 
rule to OMB for review. Interested persons are requested to send 
comments regarding information collection to the Office of Information 
and Regulatory Affairs, OMB (see ADDRESSES).

VI. Environmental Impact

    The Agency has determined under 21 CFR 25.30(h) and 25.31(a) and 
(g) that this action is of a type that does not individually or 
cumulatively have a significant effect on the human environment. 
Therefore, neither an environmental assessment nor an environmental 
impact statement is required.

VII. Effective Date

    FDA proposes that any final rule based on this proposal become 
effective 60 days after publication in the Federal Register.
    We intend to apply this rule, if finalized, to any new submission 
received by FDA on or after the effective date. This proposed rule 
provides sufficient notice to all interested parties, including NDA 
holders, NDA applicants (including 505(b)(2) applicants), and ANDA 
applicants to adjust their submissions and actions by the time we issue 
any final rule. However, we invite comments on how a final rule should 
be implemented.

VIII. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the proposed rule, if finalized, would not contain policies that would 
have substantial direct effects on the States, on the relationship 
between the National Government and the States, or on the distribution 
of power and responsibilities among the various levels of government. 
Accordingly, the Agency tentatively concludes that the proposed rule 
does not contain policies that have federalism implications as defined 
in the Executive order and, consequently, a federalism summary impact 
statement is not required.

IX. Request for Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) either electronic or written comments regarding this 
document. It is only necessary to send one set of comments. Identify 
comments with the docket number found in brackets in the heading of 
this document. Received comments may be seen in the Division of Dockets 
Management between 9 a.m. and 4 p.m., Monday through Friday, and will 
be posted to the docket at http://www.regulations.gov.

X. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES), and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday. 
(FDA has verified the Web site addresses, but we are not responsible 
for any subsequent changes to the Web sites after this document 
publishes in the Federal Register.)

    1. Preliminary Regulatory Impact Analysis, Initial Regulatory 
Flexibility Analysis, and Unfunded Mandates Reform Act Analysis for 
Abbreviated New Drug Applications and 505(b)(2) Applications; 
Proposed Rule, available at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.
    2. U.S. Department of Commerce, Bureau of the Census, Economic 
Census, Manufacturing Industry Series, Pharmaceutical Preparation 
Manufacturing, Table 4, EC02-311-325412 (RV), 2002.

List of Subjects

21 CFR Part 314

    Administrative practice and procedure, Confidential business 
information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 320

    Drugs, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, FDA proposes 
to amend 21 CFR parts 314 and 320 as follows:

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

0
1. The authority citation for 21 CFR part 314 is revised to read as 
follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 356, 
356a, 356b, 356c, 360cc, 371, 374, 379e.
0
2. Section 314.3 is revised to read as follows:


Sec.  314.3  Definitions.

    (a) The definitions and interpretations contained in section 201 of 
the Federal Food, Drug, and Cosmetic Act apply to

[[Page 6876]]

those terms when used in this part and part 320 of this chapter.
    (b) The following definitions of terms apply to this part and part 
320 of this chapter:
    180-day exclusivity period is the 180-day period beginning on the 
date of the first commercial marketing of the drug (including the 
commercial marketing of the reference listed drug) by any first 
applicant. The 180-day period ends on the day before the date on which 
an ANDA submitted by an applicant other than a first applicant could be 
approved.
    Abbreviated application, abbreviated new drug application, or ANDA 
is the application described under Sec.  314.94, including all 
amendments and supplements to the application.
    Acknowledgment letter is a written, postmarked communication from 
FDA to an applicant stating that the Agency has determined that a 
505(b)(2) application or ANDA is sufficiently complete to permit a 
substantive review. An acknowledgment letter indicates that the 
505(b)(2) application is regarded as filed or the ANDA is regarded as 
received.
    Act is the Federal Food, Drug, and Cosmetic Act (section 201 et 
seq. (21 U.S.C. 301 et seq.)).
    Active ingredient is any component that is intended to furnish 
pharmacological activity or other direct effect in the diagnosis, cure, 
mitigation, treatment, or prevention of disease, or to affect the 
structure or any function of the body of man or other animals. The term 
includes those components that may undergo chemical change in the 
manufacture of the drug product and be present in the drug product in a 
modified form intended to furnish the specified activity or effect.
    Active moiety is the molecule or ion, excluding those appended 
portions of the molecule that cause the drug to be an ester, salt 
(including a salt with hydrogen or coordination bonds), or other 
noncovalent derivative (such as a complex, chelate, or clathrate) of 
the molecule, responsible for the physiological or pharmacological 
action of the drug substance.
    ANDA holder is the applicant that owns an approved ANDA.
    Applicant is any person who submits an NDA (including a 505(b)(2) 
application) or ANDA or an amendment or supplement to an NDA or ANDA 
under this part to obtain FDA approval of a new drug and any person who 
owns an approved NDA (including a 505(b)(2) application) or ANDA.
    Application, new drug application, or NDA is the application 
described under Sec.  314.50, including all amendments and supplements 
to the application. An NDA refers to ``stand-alone'' applications 
submitted under section 505(b)(1) of the Federal Food, Drug, and 
Cosmetic Act and to 505(b)(2) applications.
    505(b)(2) application is an NDA submitted under section 505(b)(1) 
of the Federal Food, Drug, and Cosmetic Act for a drug for which the 
investigations described in section 505(b)(1)(A) of the Federal Food, 
Drug, and Cosmetic Act and relied upon by the applicant for approval of 
the NDA were not conducted by or for the applicant and for which the 
applicant has not obtained a right of reference or use from the person 
by or for whom the investigations were conducted.
    Approval letter is a written communication to an applicant from FDA 
approving an NDA or an ANDA.
    Assess the effects of the change is to evaluate the effects of a 
manufacturing change on the identity, strength, quality, purity, and 
potency of a drug product as these factors may relate to the safety or 
effectiveness of the drug product.
    Authorized generic drug is a listed drug, as defined in this 
section, that has been approved under section 505(c) of the Federal 
Food, Drug, and Cosmetic Act and is marketed, sold, or distributed 
directly or indirectly to the retail class of trade with labeling, 
packaging (other than repackaging as the listed drug in blister packs, 
unit doses, or similar packaging for use in institutions), product 
code, labeler code, trade name, or trademark that differs from that of 
the listed drug.
    Bioavailability is the rate and extent to which the active 
ingredient or active moiety is absorbed from a drug product and becomes 
available at the site of drug action. For drug products that are not 
intended to be absorbed into the bloodstream, bioavailability may be 
assessed by scientifically valid measurements intended to reflect the 
rate and extent to which the active ingredient or active moiety becomes 
available at the site of drug action.
    Bioequivalence is the absence of a significant difference in the 
rate and extent to which the active ingredient or active moiety in 
pharmaceutical equivalents or pharmaceutical alternatives becomes 
available at the site of drug action when administered at the same 
molar dose under similar conditions in an appropriately designed study. 
Where there is an intentional difference in rate (e.g., in certain 
extended release dosage forms), certain pharmaceutical equivalents or 
alternatives may be considered bioequivalent if there is no significant 
difference in the extent to which the active ingredient or moiety from 
each product becomes available at the site of drug action. This applies 
only if the difference in the rate at which the active ingredient or 
moiety becomes available at the site of drug action is intentional and 
is reflected in the proposed labeling, is not essential to the 
attainment of effective body drug concentrations on chronic use, and is 
considered medically insignificant for the drug. For drug products that 
are not intended to be absorbed into the bloodstream, bioequivalence 
may be assessed by scientifically valid measurements intended to 
reflect the rate and extent to which the active ingredient or active 
moiety becomes available at the site of drug action.
    Bioequivalence requirement is a requirement imposed by FDA for in 
vitro and/or in vivo testing of specified drug products that must be 
satisfied as a condition of marketing.
    Class 1 resubmission is the resubmission of an NDA or efficacy 
supplement, following receipt of a complete response letter, that 
contains one or more of the following: Final printed labeling, draft 
labeling, certain safety updates, stability updates to support 
provisional or final dating periods, commitments to perform 
postmarketing studies (including proposals for such studies), assay 
validation data, final release testing on the last lots used to support 
approval, minor reanalyses of previously submitted data, and other 
comparatively minor information.
    Class 2 resubmission is the resubmission of an NDA or efficacy 
supplement, following receipt of a complete response letter, that 
includes any item not specified in the definition of ``Class 1 
resubmission,'' including any item that would require presentation to 
an advisory committee.
    Commercial marketing is the introduction or delivery for 
introduction into interstate commerce of a drug product described in an 
approved ANDA, outside the control of the ANDA holder, except for 
investigational use under part 312 of this chapter, but does not 
include transfer of the drug product for reasons other than sale to 
parties identified in the approved ANDA.
    Complete response letter is a written communication to an applicant 
from FDA usually describing all of the deficiencies that the Agency has 
identified in an NDA or ANDA that must be satisfactorily addressed 
before it can be approved.
    Component is any ingredient intended for use in the manufacture of 
a drug product, including those that may not appear in such drug 
product.

[[Page 6877]]

    Date of approval is the date on the approval letter from FDA 
stating that the NDA or ANDA is approved. ``Date of approval'' refers 
only to a final approval and not to a tentative approval.
    Dosage form is the physical manifestation containing the active and 
inactive ingredients that delivers a dose of the drug product. This 
includes such factors as:
    (1) The physical appearance of the drug product,
    (2) The physical form of the drug product prior to dispensing to 
the patient,
    (3) The way the product is administered, and
    (4) The design features that affect frequency of dosing.
    Drug product is a finished dosage form, e.g., tablet, capsule, or 
solution that contains a drug substance, generally, but not 
necessarily, in association with one or more other ingredients.
    Drug substance is an active ingredient that is intended to furnish 
pharmacological activity or other direct effect in the diagnosis, cure, 
mitigation, treatment, or prevention of disease or to affect the 
structure or any function of the human body, but does not include 
intermediates used in the synthesis of such ingredient.
    Efficacy supplement is a supplement to an approved NDA proposing to 
make one or more related changes from among the following changes to 
product labeling:
    (1) Add or modify an indication or claim;
    (2) Revise the dose or dose regimen;
    (3) Provide for a new route of administration;
    (4) Make a comparative efficacy claim naming another drug product;
    (5) Significantly alter the intended patient population;
    (6) Change the marketing status from prescription to over-the-
counter use;
    (7) Provide for, or provide evidence of effectiveness necessary 
for, the traditional approval of a product originally approved under 
subpart H of part 314; or
    (8) Incorporate other information based on at least one adequate 
and well-controlled clinical study.
    FDA is the Food and Drug Administration.
    First applicant is an applicant that, on the first day on which a 
substantially complete ANDA containing a paragraph IV certification is 
submitted for approval of a drug, submits a substantially complete ANDA 
that contains, and for which the applicant lawfully maintains, a 
paragraph IV certification for the drug.
    Inactive ingredient is any component other than an active 
ingredient.
    Listed drug is a new drug product that has been approved under 
section 505(c) of the Federal Food, Drug, and Cosmetic Act for safety 
and effectiveness or under section 505(j) of the Federal Food, Drug, 
and Cosmetic Act, which has not been withdrawn or suspended under 
section 505(e)(1) through (e)(5) or section 505(j)(6) of the Federal 
Food, Drug, and Cosmetic Act, and which has not been withdrawn from 
sale for what FDA has determined are reasons of safety or 
effectiveness. Listed drug status is evidenced by the drug product's 
identification in the current edition of FDA's ``Approved Drug Products 
With Therapeutic Equivalence Evaluations'' (the list) as an approved 
drug. A drug product is deemed to be a listed drug on the date of the 
approval letter for the NDA or ANDA for that drug product.
    NDA holder is the applicant that owns an approved NDA.
    Newly acquired information is data, analyses, or other information 
not previously submitted to the Agency, which may include (but is not 
limited to) data derived from new clinical studies, reports of adverse 
events, or new analyses of previously submitted data (e.g., meta-
analyses) if the studies, events, or analyses reveal risks of a 
different type or greater severity or frequency than previously 
included in submissions to FDA.
    Original application, original NDA is a pending NDA for which FDA 
has never issued a complete response letter or approval letter, or an 
NDA that was submitted again after FDA had refused to file it or after 
it was withdrawn without being approved.
    Paragraph IV acknowledgment letter is a written, postmarked 
communication from FDA to an applicant stating that the Agency has 
determined that a 505(b)(2) application or ANDA containing a paragraph 
IV certification is sufficiently complete to permit a substantive 
review. A paragraph IV acknowledgment letter indicates that the 
505(b)(2) application is regarded as filed or the ANDA is regarded as 
received.
    Paragraph IV certification is a patent certification of invalidity, 
unenforceability, or noninfringement described in Sec.  
314.50(i)(1)(i)(A)(4) or Sec.  314.94(a)(12)(i)(A)(4).
    Patent owner is the owner of the patent for which information is 
submitted for an NDA.
    Pharmaceutical alternatives are drug products that contain the 
identical therapeutic moiety, or its precursor, but not necessarily in 
the same amount or dosage form or as the same salt or ester. Each such 
drug product individually meets either the identical or its own 
respective compendial or other applicable standard of identity, 
strength, quality, and purity, including potency and, where applicable, 
content uniformity, disintegration times, and/or dissolution rates.
    Pharmaceutical equivalents are drug products in identical dosage 
forms and route(s) of administration that contain identical amounts of 
the identical active drug ingredient, i.e., the same salt or ester of 
the same therapeutic moiety, or, in the case of modified release dosage 
forms that require a reservoir or overage or such forms as prefilled 
syringes where residual volume may vary, that deliver identical amounts 
of the active drug ingredient over the identical dosing period; do not 
necessarily contain the same inactive ingredients; and meet the 
identical compendial or other applicable standard of identity, 
strength, quality, and purity, including potency and, where applicable, 
content uniformity, disintegration times, and/or dissolution rates.
    Postmark is an independently verifiable evidentiary record of the 
date on which a document is transmitted, in an unmodifiable format, to 
another party. For postmarks made by the U.S. Postal Service or a 
designated delivery service, the date of transmission is the date on 
which the document is received by the domestic mail service of the U.S. 
Postal Service or by a designated delivery service. For postmarks 
documenting an electronic event, the date of transmission is the date 
(in a particular time zone) that FDA sends the electronic transmission 
on its host system as evidenced by a verifiable record. If the sender 
and the intended recipient are located in different time zones, it is 
the sender's time zone that provides the controlling date of electronic 
transmission.
    Reference listed drug is the listed drug identified by FDA as the 
drug product upon which an applicant relies in seeking approval of its 
ANDA.
    Reference standard is the drug product selected by FDA that an 
applicant seeking approval of an ANDA must use in conducting an in vivo 
bioequivalence study required for approval.
    Resubmission is submission by the applicant of all materials needed 
to fully address all deficiencies identified in the complete response 
letter. An NDA or ANDA for which FDA issued a complete response letter, 
but which was withdrawn before approval and later submitted again, is 
not a resubmission.
    Right of reference or use is the authority to rely upon, and 
otherwise

[[Page 6878]]

use, an investigation for the purpose of obtaining approval of an NDA, 
including the ability to make available the underlying raw data from 
the investigation for FDA audit, if necessary.
    Same drug product formulation is the formulation of the drug 
product submitted for approval and any formulations that have minor 
differences in composition or method of manufacture from the 
formulation submitted for approval, but are similar enough to be 
relevant to the Agency's determination of bioequivalence.
    Specification is the quality standard (i.e., tests, analytical 
procedures, and acceptance criteria) provided in an approved NDA or 
ANDA to confirm the quality of drug substances, drug products, 
intermediates, raw materials, reagents, components, in-process 
materials, container closure systems, and other materials used in the 
production of a drug substance or drug product. For the purpose of this 
definition, acceptance criteria means numerical limits, ranges, or 
other criteria for the tests described.
    Strength is the amount of drug substance contained in, delivered, 
or deliverable from a drug product, which includes:
    (1)(i) The total quantity of drug substance in mass or units of 
activity in a dosage unit or container closure (e.g., weight/unit dose, 
weight/volume or weight/weight in a container closure, or units/volume 
or units/weight in a container closure); and/or, as applicable.
    (ii) The concentration of the drug substance in mass or units of 
activity per unit volume or mass (e.g., weight/weight, weight/volume, 
or units/volume); or
    (2) Such other criteria the Agency establishes for determining the 
amount of drug substance contained in, delivered, or deliverable from a 
drug product if the weights and measures described in paragraph (i) of 
this definition do not apply (e.g., certain drug-device combination 
products for which the amount of drug substance is emitted per use or 
unit time).
    Substantially complete application is an ANDA that on its face is 
sufficiently complete to permit a substantive review and contains all 
the information required under section 505(j)(2)(A) of the Federal 
Food, Drug, and Cosmetic Act and Sec.  314.94.
    Tentative approval is notification that an NDA or ANDA otherwise 
meets the requirements for approval under the Federal Food, Drug, and 
Cosmetic Act, but cannot be approved because there is a 7-year period 
of orphan exclusivity for a listed drug under section 527 of the 
Federal Food, Drug, and Cosmetic Act and Sec.  316.31 of this chapter, 
or that a 505(b)(2) application or ANDA otherwise meets the 
requirements for approval under the Federal Food, Drug, and Cosmetic 
Act, but cannot be approved until the conditions in Sec.  
314.107(b)(1)(iii), (b)(3), or (c) are met; because there is a period 
of exclusivity for the listed drug under Sec.  314.108; because there 
is a period of pediatric exclusivity for the listed drug under section 
505A of the Federal Food, Drug, and Cosmetic Act, or because a court 
order pursuant to 35 U.S.C. 271(e)(4)(A) orders that the application 
may be approved no earlier than the date specified. A drug product that 
is granted tentative approval is not an approved drug and will not be 
approved until FDA issues an approval letter after any necessary 
additional review of the NDA or ANDA.
    The list is the list of approved drug products published in FDA's 
current ``Approved Drug Products With Therapeutic Equivalence 
Evaluations,'' available electronically on FDA's Web site at http://www.fda.gov/cder.
    Therapeutic equivalents are approved drug products that are 
pharmaceutical equivalents and for which bioequivalence has been 
demonstrated. Therapeutic equivalents can be expected to have the same 
clinical effect and safety profile when administered to patients under 
the conditions specified in the labeling.
0
3. Section 314.50 is amended by:
0
a. Removing from paragraph (a) introductory text, paragraphs (a)(5), 
(d)(1)(v), (d)(5)(v), and (d)(5)(vi)(a), paragraph (e)(2) introductory 
text, and paragraphs (f)(3), (g)(2), and (k) the word ``shall'' each 
time it appears and adding in its place the word ``must'';
0
b. Removing from paragraphs (a)(5), (b), (c)(1), (c)(2)(i), and 
(c)(2)(iv) through (c)(2)(viii), paragraph (d) introductory text, 
paragraphs (d)(1)(i), (d)(1)(ii)(a), (d)(1)(iii) through (d)(1)(v), 
(d)(3)(ii), and (d)(5)(iv), paragraph (e)(1)(i) introductory text, 
paragraph (e)(2), paragraph (f) introductory text, paragraphs (f)(1) 
through (f)(3), (g)(2), (j)(4)(i), (j)(4)(ii), and (k), paragraph (l) 
heading, paragraph (l)(1) introductory text, and paragraphs (l)(2) and 
(l)(4) the word ``application'' each time it appears and adding in its 
place ``NDA'';
0
c. Removing from paragraph (j) introductory text the word ``shall'' and 
adding in its place the word ``must'' and removing the phrase ``new 
drug application'' and adding in its place ``NDA''; and
0
d. Revising the section heading and section introductory text, 
paragraphs (a)(1) and (d)(5)(vi)(b), paragraph (e)(1) introductory 
text, paragraphs (f)(4), (g)(3), and (i), paragraph (j)(4) introductory 
text, the first two sentences of paragraph (j)(4)(iii), and paragraph 
(l)(3).
    The revisions read as follows:


Sec.  314.50  Content and format of an NDA.

    NDAs and supplements to approved NDAs are required to be submitted 
in the form and contain the information, as appropriate for the 
particular submission, required under this section. Three copies of the 
NDA are required: An archival copy, a review copy, and a field copy. An 
NDA for a new chemical entity will generally contain an application 
form, an index, a summary, five or six technical sections, case report 
tabulations of patient data, case report forms, drug samples, and 
labeling, including, if applicable, any Medication Guide required under 
part 208 of this chapter. Other NDAs will generally contain only some 
of those items, and information will be limited to that needed to 
support the particular submission. These include an NDA of the type 
described in section 505(b)(2) of the Federal Food, Drug, and Cosmetic 
Act, an amendment, and a supplement. The NDA is required to contain 
reports of all investigations of the drug product sponsored by the 
applicant, and all other information about the drug pertinent to an 
evaluation of the NDA that is received or otherwise obtained by the 
applicant from any source. FDA will maintain guidance documents on the 
format and content of NDAs to assist applicants in their preparation.
    (a) * * *
    (1) The name and address of the applicant; the date of the NDA; the 
NDA number if previously issued (for example, if the NDA is a 
resubmission or an amendment or supplement); the name of the drug 
product, including its established, proprietary, code, and chemical 
names; the dosage form and strength; the route of administration; the 
identification numbers of all INDs (as defined in Sec.  312.3(b) of 
this chapter) that are referenced in the NDA; the identification 
numbers of all drug master files and other applications under this part 
that are referenced in the NDA; and the drug product's proposed 
indications for use.
* * * * *
    (d) * * *
    (5) * * *
    (vi) * * *
    (b) The applicant must, under section 505(i) of the Federal Food, 
Drug, and Cosmetic Act, update periodically its pending NDA with new 
safety information learned about the drug that

[[Page 6879]]

may reasonably affect the statement of contraindications, warnings, 
precautions, and adverse reactions in the draft labeling and, if 
applicable, any Medication Guide required under part 208 of this 
chapter. These ``safety update reports'' must include the same kinds of 
information (from clinical studies, animal studies, and other sources) 
and must be submitted in the same format as the integrated summary in 
paragraph (d)(5)(vi)(a) of this section. In addition, the reports must 
include the case report forms for each patient who died during a 
clinical study or who did not complete the study because of an adverse 
event (unless this requirement is waived). The applicant must submit 
these reports:
    (1) 4 months after the initial submission;
    (2) In a resubmission following receipt of a complete response 
letter; and
    (3) At other times as requested by FDA. Before submitting the first 
such report, applicants are encouraged to consult with FDA regarding 
further details on its form and content.
* * * * *
    (e) * * * (1) Upon request from FDA, the applicant must submit the 
samples described below to the places identified in the Agency's 
request. FDA generally will ask applicants to submit samples directly 
to two or more Agency laboratories that will perform all necessary 
tests on the samples and validate the applicant's analytical 
procedures.
* * * * *
    (f) * * *
    (4) Applicants are invited to meet with FDA before submitting an 
NDA to discuss the presentation and format of supporting information. 
If the applicant and FDA agree, the applicant may submit tabulations of 
patient data and case report forms in an alternate form.
    (g) * * *
    (3) If an applicant who submits an NDA under section 505(b) of the 
Federal Food, Drug, and Cosmetic Act obtains a ``right of reference or 
use,'' as defined under Sec.  314.3(b), to an investigation described 
in clause (A) of section 505(b)(1) of the Federal Food, Drug, and 
Cosmetic Act, the applicant must include in its NDA a written statement 
signed by the owner of the data from each such investigation that the 
applicant may rely on in support of the approval of its NDA, and 
provide FDA access to, the underlying raw data that provide the basis 
for the report of the investigation submitted in its NDA.
* * * * *
    (i) Patent certification--(1) Contents. A 505(b)(2) application is 
required to contain the following:
    (i) Patents claiming drug substance, drug product, or method of 
use. (A) A certification with respect to each patent issued by the U.S. 
Patent and Trademark Office that, in the opinion of the applicant and 
to the best of its knowledge, claims the drug substance or drug product 
on which investigations that are relied upon by the applicant for 
approval of its 505(b)(2) application were conducted or that claims an 
approved use for such drug and for which information is required to be 
filed under section 505(b) and (c) of the Federal Food, Drug, and 
Cosmetic Act and Sec.  314.53. For each such patent, the applicant must 
provide the patent number and certify, in its opinion and to the best 
of its knowledge, one of the following circumstances:
    (1) That the patent information has not been submitted to FDA. The 
applicant must entitle such a certification ``Paragraph I 
Certification'';
    (2) That the patent has expired. The applicant must entitle such a 
certification ``Paragraph II Certification'';
    (3) The date on which the patent will expire. The applicant must 
entitle such a certification ``Paragraph III Certification''; or
    (4) That the patent is invalid, unenforceable, or will not be 
infringed by the manufacture, use, or sale of the drug product for 
which the 505(b)(2) application is submitted. The applicant must 
entitle such a certification ``Paragraph IV Certification''. This 
certification must be submitted in the following form:

    I, (name of applicant), certify that Patent No. ______ (is 
invalid, unenforceable, or will not be infringed by the manufacture, 
use, or sale of) (name of proposed drug product) for which this 
505(b)(2) application is submitted.

    The certification must be accompanied by a statement that the 
applicant will comply with the requirements under Sec.  314.52(a) with 
respect to providing a notice to each owner of the patent or its 
representative and to the holder of the approved NDA for the drug 
product which is claimed by the patent or a use of which is claimed by 
the patent and with the requirements under Sec.  314.52(b) with respect 
to sending the notice and under Sec.  314.52(c) with respect to the 
content of the notice.
    (B) If the drug on which investigations that are relied upon by the 
applicant were conducted is itself a licensed generic drug of a 
patented drug first approved under section 505(b) of the Federal Food, 
Drug, and Cosmetic Act, the appropriate patent certification under this 
section with respect to each patent that claims the first-approved 
patented drug or that claims an approved use for such a drug.
    (C) If, before the date of submission of the 505(b)(2) application, 
there is an approved drug product that is pharmaceutically equivalent 
to the drug product for which the 505(b)(2) application is submitted, 
an appropriate patent certification under this section with respect to 
each patent that claims the drug substance or drug product or that 
claims an approved use for such drug.
    (ii) No relevant patents. If, in the opinion of the applicant and 
to the best of its knowledge, there are no patents described in 
paragraph (i)(1)(i) of this section, a certification in the following 
form:

    In the opinion and to the best knowledge of (name of applicant), 
there are no patents that claim the drug or drugs on which 
investigations that are relied upon in this 505(b)(2) application 
were conducted or that claim a use of such drug or drugs.

    (iii) Method-of-use patent. (A) If information that is submitted 
under section 505(b) or (c) of the Federal Food, Drug, and Cosmetic Act 
and Sec.  314.53 is for a method-of-use patent, and the labeling for 
the drug product for which the applicant is seeking approval does not 
include any indications or other conditions of use that are covered by 
the use patent, a statement explaining that the method-of-use patent 
does not claim any of the proposed indications or other conditions of 
use.
    (B) If the labeling of the drug product for which the applicant is 
seeking approval includes an indication or other condition of use that, 
according to the patent information submitted under section 505(b) or 
(c) of the Federal Food, Drug, and Cosmetic Act and Sec.  314.53 or in 
the opinion of the applicant, is claimed by a use patent, the applicant 
must submit an applicable certification under paragraph (i)(1)(i) of 
this section.
    (2) [Reserved]
    (3) Licensing agreements. If a 505(b)(2) application is for a drug 
or method of using a drug claimed by a patent and the applicant has a 
licensing agreement with the patent owner, the applicant must submit a 
certification under paragraph (i)(1)(i)(A)(4) of this section 
(``Paragraph IV Certification'') as to that patent and a statement that 
it has been granted a patent license. If the patent owner consents to 
approval of the 505(b)(2) application (if otherwise justified) as of a 
specific date, the 505(b)(2) application must contain a written 
statement from the patent owner that it has a licensing agreement with

[[Page 6880]]

the applicant and that it consents to approval of the 505(b)(2) 
application as of a specific date.
    (4) Untimely filing of patent information. If a patent described in 
paragraph (i)(1)(i) of this section is issued and the holder of the 
approved NDA for the patented drug does not file with FDA the required 
information on the patent within 30 days of issuance of the patent, an 
applicant who submitted a 505(b)(2) application that, before the 
submission of the patent information, contained an appropriate patent 
certification is not required to submit an amended certification to 
address the patent that is late-listed with respect to the pending 
505(b)(2) application. Except as provided in Sec.  314.53(f)(1), an NDA 
holder's amendment to the description of the approved method(s) of use 
claimed by the patent will be considered untimely filing of patent 
information if:
    (i) The amendment is submitted more than 30 days after patent 
issuance and it is not related to a corresponding change in approved 
product labeling; or
    (ii) The amendment is submitted more than 30 days after a 
corresponding change in approved product labeling. An applicant whose 
505(b)(2) application is filed after the NDA holder's untimely filing 
of patent information or whose 505(b)(2) application was previously 
filed but did not contain an appropriate patent certification at the 
time of the patent submission must submit a certification under 
paragraph (i)(1)(i) of this section or a statement under paragraph 
(i)(1)(iii) of this section as to that patent.
    (5) Disputed patent information. If an applicant disputes the 
accuracy or relevance of patent information submitted to FDA, the 
applicant may seek a confirmation of the correctness of the patent 
information in accordance with the procedures under Sec.  314.53(f). 
Unless the patent information is withdrawn or changed, the applicant 
must submit an appropriate certification for each relevant patent.
    (6) Amended certifications. A certification submitted under 
paragraphs (i)(1)(i) through (i)(1)(iii) of this section may be amended 
at any time before the approval of the 505(b)(2) application. An 
applicant must submit an amended certification as an amendment to a 
pending 505(b)(2) application. If an applicant with a pending 505(b)(2) 
application voluntarily makes a patent certification for an untimely 
filed patent, the applicant may withdraw the patent certification for 
the untimely filed patent. Once an amendment for the change in 
certification has been submitted, the 505(b)(2) application will no 
longer be considered to be one containing the prior certification.
    (i) After finding of infringement. An applicant who has submitted a 
paragraph IV certification and is sued for patent infringement must 
submit an amendment to change its certification if a court enters a 
final decision from which no appeal has been or can be taken, or signs 
a settlement order or consent decree in the action that includes a 
finding that the patent is infringed, unless the final decision, 
settlement order, or consent decree also finds the patent to be 
invalid. In its amendment, the applicant must certify under paragraph 
(i)(1)(i)(A)(3) of this section that the patent will expire on a 
specific date or, with respect to a patent claiming a method of use, 
the applicant may instead provide a statement under paragraph 
(i)(1)(iii) of this section if the applicant amends its 505(b)(2) 
application such that the applicant is no longer seeking approval for a 
method of use claimed by the patent.
    (ii) After request to remove a patent or patent information from 
the list. If the list reflects that an NDA holder has requested that a 
patent be removed from the list and no ANDA applicant is eligible for 
180-day exclusivity based on a paragraph IV certification to that 
patent, the patent will be removed and any applicant with a pending 
505(b)(2) application (including a tentatively approved 505(b)(2) 
application) who has made a certification with respect to such patent 
must submit an amendment to withdraw its certification. In the 
amendment, the applicant must state the reason for withdrawing the 
certification (that the patent has been removed from the list). If the 
list reflects that an NDA holder has requested that a patent be removed 
from the list and one or more first applicants are eligible for 180-day 
exclusivity based on a paragraph IV certification to that patent, the 
patent shall remain listed until any 180-day exclusivity is 
extinguished. A 505(b)(2) applicant is not required to provide or 
maintain a certification to a patent that remains listed only for 
purposes of a first applicant's 180-day exclusivity for its ANDA. Once 
an amendment to withdraw the certification has been submitted, the 
505(b)(2) application will no longer be considered to be one containing 
a paragraph IV certification to the patent. If removal of a patent from 
the list results in there being no patents listed for the listed 
drug(s) identified in the 505(b)(2) application, the applicant must 
submit an amended certification reflecting that there are no listed 
patents.
    (iii) Other amendments. (A) Except as provided in paragraphs (i)(4) 
and (i)(6)(iii)(B) of this section:
    (1) An applicant must amend a submitted certification if, at any 
time before the approval of the 505(b)(2) application, the applicant 
learns that the submitted certification is no longer accurate; and
    (2) An applicant must submit a certification or statement under 
paragraph (i)(1) of this section if, after submission of the 505(b)(2) 
application, a new patent is issued by the U.S. Patent and Trademark 
Office that, in the opinion of the applicant and to the best of its 
knowledge, claims a listed drug relied upon or that claims an approved 
use for such listed drug for which information is required to be filed 
under section 505(b) and (c) of the Federal Food, Drug, and Cosmetic 
Act and Sec.  314.53.
    (B) An applicant is not required to submit a supplement to change a 
submitted certification when information on an otherwise applicable 
patent is submitted after the approval of the 505(b)(2) application, 
except as provided in Sec.  314.70(i).
    (j) * * *
    (4) If the applicant claims exclusivity under Sec.  314.108(b)(4) 
or (b)(5), the following information to show that the NDA contains 
``new clinical investigations'' that are ``essential to approval of the 
application or supplement'' and ``were conducted or sponsored by the 
applicant'':
* * * * *
    (iii) * * * If the applicant was the sponsor named in the Form FDA 
1571 for an IND under which the new clinical investigation(s) that is 
essential to the approval of its NDA was conducted, identification of 
the IND by number. If the applicant was not the sponsor of the IND 
under which the clinical investigation(s) was conducted, a 
certification that the applicant or its predecessor in interest 
provided substantial support for the clinical investigation(s) that is 
essential to the approval of its NDA, and information supporting the 
certification. * * *
* * * * *
    (l) * * *
    (3) Field copy. The applicant must submit a field copy of the NDA 
that contains the technical section described in paragraph (d)(1) of 
this section, a copy of the application form required under paragraph 
(a) of this section, a copy of the summary required under paragraph (c) 
of this section, and a certification that the field copy is a true copy 
of the technical section described in paragraph (d)(1) of this section

[[Page 6881]]

contained in the archival and review copies of the NDA.
* * * * *
0
4. Section 314.52 is revised to read as follows:


Sec.  314.52  Notice of certification of invalidity or noninfringement 
of a patent.

    (a) Notice of certification. For each patent that claims the listed 
drug or drugs relied upon or that claims a use for such listed drug or 
drugs and for which the applicant submits a paragraph IV certification, 
the applicant must send notice of such certification by registered or 
certified mail, return receipt requested, or by a designated delivery 
service, as defined in paragraph (g) of this section to each of the 
following persons:
    (1) Each owner of the patent that is the subject of the 
certification or the representative designated by the owner to receive 
the notice. The name and address of the patent owner or its 
representative may be obtained from the U.S. Patent and Trademark 
Office; and
    (2) The holder of the approved NDA under section 505(b) of the 
Federal Food, Drug, and Cosmetic Act for each drug product which is 
claimed by the patent or a use of which is claimed by the patent and 
for which the applicant is seeking approval, or, if the NDA holder does 
not reside or maintain a place of business within the U.S., the NDA 
holder's attorney, agent, or other authorized official. The name and 
address of the NDA holder or its attorney, agent, or authorized 
official may be obtained from the Orange Book Staff, Office of Generic 
Drugs, 7620 Standish Pl., Rockville, MD 20855.
    (3) This paragraph does not apply to a use patent that does not 
claim a use for which the applicant is seeking approval.
    (4) An applicant may send notice by an alternative method only if 
FDA has agreed in advance that the method will produce an acceptable 
form of documentation.
    (b) Sending the notice. (1) Except as provided under paragraph (d) 
of this section, the applicant must send the notice required by 
paragraph (a) of this section on or after the date it receives a 
paragraph IV acknowledgment letter from FDA, but not later than 20 days 
after the date of the postmark on the paragraph IV acknowledgment 
letter. The 20-day clock described in this paragraph begins on the day 
after the date of the postmark on the paragraph IV acknowledgment 
letter. When the 20th day falls on Saturday, Sunday, or a Federal 
holiday, the 20th day will be the next day that is not a Saturday, 
Sunday, or Federal holiday.
    (2) Any notice required by paragraph (a) of this section is invalid 
if it is sent before the applicant's receipt of a paragraph IV 
acknowledgment letter. The applicant will not have complied with this 
paragraph until it sends valid notice.
    (3) At the same time it sends the notice required by paragraph (a) 
of this section, the applicant must submit to FDA an amendment to its 
505(b)(2) application that includes a statement certifying that the 
notice has been provided to each person identified under paragraph (a) 
of this section and that the notice met the content requirement under 
paragraph (c) of this section. A copy of the notice itself need not be 
submitted to the Agency.
    (c) Content of a notice. In the notice, the applicant must cite 
section 505(b)(3)(D) of the Federal Food, Drug, and Cosmetic Act and 
must include, but is not limited to, the following information:
    (1) A statement that a 505(b)(2) application that contains any 
required bioavailability or bioequivalence studies has been submitted 
by the applicant and filed by FDA.
    (2) The NDA number.
    (3) A statement that the applicant has received the paragraph IV 
acknowledgment letter for the 505(b)(2) application.
    (4) The established name, if any, as defined in section 502(e)(3) 
of the Federal Food, Drug, and Cosmetic Act, of the proposed drug 
product.
    (5) The active ingredient, strength, and dosage form of the 
proposed drug product.
    (6) The patent number and expiration date of each patent on the 
list alleged to be invalid, unenforceable, or not infringed.
    (7) A detailed statement of the factual and legal basis of the 
applicant's opinion that the patent is not valid, unenforceable, or 
will not be infringed. The applicant must include in the detailed 
statement:
    (i) For each claim of a patent alleged not to be infringed, a full 
and detailed explanation of why the claim is not infringed.
    (ii) For each claim of a patent alleged to be invalid or 
unenforceable, a full and detailed explanation of the grounds 
supporting the allegation.
    (8) If the applicant alleges that the patent will not be infringed 
and the applicant may later decide to file a civil action for 
declaratory judgment in accordance with section 505(c)(3)(D) of the 
Federal Food, Drug, and Cosmetic Act, then the notice must be 
accompanied by an offer of confidential access to the 505(b)(2) 
application for the sole and limited purpose of evaluating possible 
infringement of the patent that is the subject of the paragraph IV 
certification.
    (9) If the applicant does not reside or have a place of business in 
the United States, the name and address of an agent in the United 
States authorized to accept service of process for the applicant.
    (d) Amendment or supplement to a 505(b)(2) application. (1) If, 
after receipt of an acknowledgment letter or paragraph IV 
acknowledgment letter, an applicant submits an amendment or supplement 
to its 505(b)(2) application that includes a paragraph IV 
certification, the applicant must send the notice required by paragraph 
(a) of this section at the same time that the amendment or supplement 
to the 505(b)(2) application is submitted to FDA, regardless of whether 
the applicant has already given notice with respect to another such 
certification contained in the 505(b)(2) application or in an amendment 
or supplement to the 505(b)(2) application.
    (2) If, before receipt of a paragraph IV acknowledgment letter, an 
applicant submits a paragraph IV certification in an amendment, the 
applicant must send the notice required by paragraph (a) of this 
section in accordance with the procedures in paragraph (b) of this 
section.
    (3) An applicant that submits an amendment or supplement to seek 
approval of a different strength must provide notice of any paragraph 
IV certification in accordance with paragraphs (d)(1) or (d)(2) of this 
section, as applicable.
    (e) Documentation of timely sending and receipt of notice. The 
applicant must amend its 505(b)(2) application to provide documentation 
of the date of receipt of the notice required under paragraph (a) of 
this section by each person provided the notice. The amendment must be 
submitted to FDA within 30 days after the last date on which notice was 
received by a person described in paragraph (a) of this section. The 
applicant's amendment also must include documentation that its notice 
was sent on a date that complies with the timeframe required by 
paragraph (b) or paragraph (d) of this section, as applicable. FDA will 
accept, as adequate documentation of the date the notice was sent, a 
copy of the registered mail receipt, certified mail receipt, or receipt 
from a designated delivery service, as defined in paragraph (g) of this 
section. FDA will accept as adequate documentation of the date of 
receipt a return receipt, a signature proof of delivery by a designated

[[Page 6882]]

delivery service, or a letter acknowledging receipt by the person 
provided the notice. An applicant may rely on another form of 
documentation only if FDA has agreed to such documentation in advance. 
A copy of the notice itself need not be submitted to the Agency.
    (f) Approval. If the requirements of this section are met, the 
Agency will presume the notice to be complete and sufficient and will 
count the day following the date of receipt of the notice by the patent 
owner or its representative and by the approved NDA holder as the first 
day of the 45-day period provided for in section 505(c)(3)(C) of the 
Federal Food, Drug, and Cosmetic Act. FDA may, if the applicant amends 
its 505(b)(2) application with a written statement that a later date 
should be used, count from such later date.
    (g) Designated delivery services. (1) For purposes of this section, 
the term ``designated delivery service'' is any delivery service 
provided by a trade or business that the Agency determines:
    (i) Is available to the general public throughout the United 
States;
    (ii) Records electronically to its database, kept in the regular 
course of its business, or marks on the cover in which any item 
referred to in this section is to be delivered, the date on which such 
item was given to such trade or business for delivery; and
    (iii) Provides overnight or 2-day delivery service throughout the 
United States.
    (2) FDA will periodically issue guidance regarding designated 
delivery services that meet these criteria.
0
5. Section 314.53 is revised to read as follows:


Sec.  314.53  Submission of patent information.

    (a) Who must submit patent information. This section applies to any 
applicant who submits to FDA an NDA or an amendment to it under section 
505(b) of the Federal Food, Drug, and Cosmetic Act and Sec.  314.50 or 
a supplement to an approved NDA under Sec.  314.70, except as provided 
in paragraph (d)(2) of this section.
    (b) Patents for which information must be submitted and patents for 
which information must not be submitted--(1) General requirements. An 
applicant described in paragraph (a) of this section must submit the 
required information, on the required FDA declaration form, set forth 
in paragraph (c) of this section for each patent that claims the drug 
or a method of using the drug that is the subject of the NDA or 
amendment or supplement to it and with respect to which a claim of 
patent infringement could reasonably be asserted if a person not 
licensed by the owner of the patent engaged in the manufacture, use, or 
sale of the drug product. For purposes of this part, such patents 
consist of drug substance (active ingredient) patents, drug product 
(formulation and composition) patents, and method-of-use patents. For 
patents that claim the drug substance, the applicant must submit 
information only on those patents that claim the drug substance that is 
the subject of the pending or approved NDA or that claim a drug 
substance that is the same as the active ingredient that is the subject 
of the approved or pending NDA. For patents that claim only a polymorph 
that is the same as the active ingredient described in the approved or 
pending NDA, the applicant must certify in the required FDA declaration 
form that the applicant has test data, as set forth in paragraph (b)(2) 
of this section, demonstrating that a drug product containing the 
polymorph will perform the same as the drug product described in the 
NDA. For patents that claim a drug product, the applicant must submit 
information only on those patents that claim a drug product, as is 
defined in Sec.  314.3, that is described in the pending or approved 
application. For patents that claim a method of use, the applicant must 
submit information only on those patents that claim indications or 
other conditions of use for which approval is sought or has been 
granted in the NDA. The applicant must separately identify each pending 
or approved method of use and related patent claim(s). For approved 
NDAs, the applicant submitting the method-of-use patent must identify 
with specificity the section of the approved labeling that corresponds 
to the method of use claimed by the patent submitted. If the scope of 
the method-of-use claim(s) of the patent does not cover every use of 
the drug, the applicant must only identify the specific portion(s) of 
the indication or other condition of use claimed by the patent. Process 
patents, patents claiming packaging, patents claiming metabolites, and 
patents claiming intermediates are not covered by this section, and 
information on these patents must not be submitted to FDA.
    (2) Test data for submission of patent information for patents that 
claim only a polymorph. The test data, referenced in paragraph (b)(1) 
of this section, must include the following:
    (i) A full description of the polymorphic form of the drug 
substance, including its physical and chemical characteristics and 
stability; the method of synthesis (or isolation) and purification of 
the drug substance; the process controls used during manufacture and 
packaging; and such specifications and analytical methods as are 
necessary to assure the identity, strength, quality, and purity of the 
polymorphic form of the drug substance;
    (ii) The executed batch record for a drug product containing the 
polymorphic form of the drug substance and documentation that the batch 
was manufactured under current good manufacturing practice 
requirements;
    (iii) Demonstration of bioequivalence between the executed batch of 
the drug product that contains the polymorphic form of the drug 
substance and the drug product as described in the NDA;
    (iv) A list of all components used in the manufacture of the drug 
product containing the polymorphic form and a statement of the 
composition of the drug product; a statement of the specifications and 
analytical methods for each component; a description of the 
manufacturing and packaging procedures and in-process controls for the 
drug product; such specifications and analytical methods as are 
necessary to assure the identity, strength, quality, purity, and 
bioavailability of the drug product, including release and stability 
data complying with the approved product specifications to demonstrate 
pharmaceutical equivalence and comparable product stability; and
    (v) Comparative in vitro dissolution testing on 12 dosage units 
each of the executed test batch and the NDA product.
    (c) Reporting requirements--(1) General requirements. An applicant 
described in paragraph (a) of this section must submit the required 
patent information described in paragraph (c)(2) of this section for 
each patent that meets the requirements described in paragraph (b) of 
this section. We will not accept the patent information unless it is 
submitted on the appropriate form, Form FDA 3542 or 3542a, and contains 
the information required in paragraph (c)(2) of this section. These 
forms may be obtained on the Internet at http://www.fda.gov by 
searching for ``forms''.
    (2) Drug substance (active ingredient), drug product (formulation 
or composition), and method-of-use patents--(i) Original declaration. 
For each patent that claims a drug substance (active ingredient), drug 
product (formulation and composition), or method of use, the applicant 
must submit Form FDA 3542a. The following information and verification 
is required, subject to the exceptions listed in paragraph (c)(2)(i)(S) 
of this section:
    (A) NDA number;

[[Page 6883]]

    (B) Name of NDA sponsor;
    (C) Trade name (or proposed trade name) of new drug;
    (D) Active ingredient(s) of new drug;
    (E) Strength(s) of new drug;
    (F) Dosage form of new drug;
    (G) U.S. patent number, issue date, and expiration date of patent 
submitted;
    (H) The patent owner's name, full address, phone number and, if 
available, fax number and email address;
    (I) The name, full address, phone number and, if available, fax 
number and email address of an agent or representative who resides or 
maintains a place of business within the United States authorized to 
receive notice of patent certification under section 505(b)(3) and 
(j)(2)(B) of the Federal Food, Drug, and Cosmetic Act and Sec. Sec.  
314.52 and 314.95 (if patent owner or NDA applicant or holder does not 
reside or have a place of business within the United States);
    (J) Information on whether the patent is a reissued patent of a 
patent submitted previously for listing for the NDA or supplement;
    (K) Information on whether the expiration date is a new expiration 
date if the patent had been submitted previously for listing;
    (L) Information on whether the patent is a product-by-process 
patent in which the product claimed is novel;
    (M) Information on the drug substance (active ingredient) patent, 
including the following:
    (1) Whether the patent claims the drug substance that is the active 
ingredient in the drug product described in the NDA or supplement;
    (2) Whether the patent claims only a polymorph that is the same 
active ingredient that is described in the pending NDA or supplement;
    (3) Whether the applicant has test data, described in paragraph 
(b)(2) of this section, demonstrating that a drug product containing 
only the polymorph will perform the same as the drug product described 
in the NDA or supplement, and a description of the polymorphic form(s) 
claimed by the patent for which such test data exist;
    (4) Whether the patent claims only a metabolite of the active 
ingredient; and
    (5) Whether the patent claims only an intermediate;
    (N) Information on the drug product (composition/formulation) 
patent, including the following:
    (1) Whether the patent claims the drug product for which approval 
is being sought, as defined in Sec.  314.3; and
    (2) Whether the patent claims only an intermediate;
    (O) Information on each method-of-use patent, including the 
following:
    (1) Whether the patent claims one or more methods of using the drug 
product for which use approval is being sought and a description of 
each pending method of use or related indication and related patent 
claim of the patent being submitted;
    (2) Identification of the specific section(s) of the proposed 
labeling for the drug product that corresponds to the method of use 
claimed by the patent submitted (if the scope of the method-of-use 
claim(s) of the patent does not cover every use of the drug, the 
applicant must only identify the specific portion(s) of the indication 
or other condition of use claimed by the patent); and
    (3) An applicant that submits information for a patent that claims 
one or more methods of using the drug product must also submit 
information described in either paragraph (c)(2)(i)(M) or (c)(2)(i)(N) 
of this section, regarding whether that patent also claims either the 
drug substance (active ingredient) or the drug product (composition/
formulation).
    (P) Whether there are no relevant patents that claim the drug 
substance (active ingredient), drug product (formulation or 
composition), or method(s) of use, for which the applicant is seeking 
approval and with respect to which a claim of patent infringement could 
reasonably be asserted if a person not licensed by the owner of the 
patent engaged in the manufacture, use, or sale of the drug product;
    (Q) A signed verification that states:

    The undersigned declares that this is an accurate and complete 
submission of patent information for the NDA, amendment, or 
supplement pending under section 505 of the Federal Food, Drug, and 
Cosmetic Act. This time-sensitive patent information is submitted 
pursuant to 21 CFR 314.53. I attest that I am familiar with 21 CFR 
314.53 and this submission complies with the requirements of the 
regulation. I verify under penalty of perjury that the foregoing is 
true and correct.;

    and
    (R) Information on whether the applicant, patent owner or attorney, 
agent, representative, or other authorized official signed the form; 
the name of the person; and the full address, phone number and, if 
available, the fax number and email address.
    (S) Exceptions to required submission of patent information:
    (1) If an applicant submits the information described in paragraph 
(c)(2)(i)(M) of this section for a patent that claims the drug 
substance (active ingredient) and meets the requirements for listing on 
that basis, then the applicant is not required to provide the 
information described in paragraph (c)(2)(i)(N) of this section on 
whether that patent also claims the drug product (composition/
formulation).
    (2) If an applicant submits the information described in paragraph 
(c)(2)(i)(N) of this section for a patent that claims the drug product 
(composition/formulation) and meets the requirements for listing on 
that basis, then the applicant is not required to provide the 
information described in paragraph (c)(2)(i)(M) of this section on 
whether that patent also claims the drug substance (active ingredient).
    (ii) Submission of patent information upon and after approval. 
Within 30 days after the date of approval of its NDA or supplement, the 
applicant must submit Form FDA 3542 for each patent that claims the 
drug substance (active ingredient), drug product (formulation and 
composition), or approved method of use. FDA will rely only on the 
information submitted on this form and will not list or publish patent 
information if the patent declaration is incomplete or indicates the 
patent is not eligible for listing. Patent information must also be 
submitted for patents issued after the date of approval of the NDA as 
required in paragraph (c)(2)(ii) of this section. As described in 
paragraph (d)(3) of this section, to be timely filed, patent 
information for patents issued after the date of approval of the NDA 
must be submitted to FDA within 30 days of the date of issuance of the 
patent. If the applicant submits the required patent information within 
the 30 days, but we notify an applicant that a declaration form is 
incomplete or shows that the patent is not eligible for listing, the 
applicant must submit an acceptable declaration form within 15 days of 
FDA notification to be considered timely filed. The following 
information and verification statement is required, subject to the 
exceptions listed in paragraph (c)(2)(ii)(T) of this section:
    (A) NDA number;
    (B) Name of NDA sponsor;
    (C) Trade name of new drug;
    (D) Active ingredient(s) of new drug;
    (E) Strength(s) of new drug;
    (F) Dosage form of new drug;
    (G) Approval date of NDA or supplement;
    (H) U.S. patent number, issue date, and expiration date of patent 
submitted;
    (I) The patent owner's name, full address, phone number and, if 
available, fax number and email address;
    (J) The name, full address, phone number and, if available, fax 
number and email address of an agent or representative who resides or 
maintains

[[Page 6884]]

a place of business within the United States authorized to receive 
notice of patent certification under section 505(b)(3) and (j)(2)(B) of 
the Federal Food, Drug, and Cosmetic Act and Sec. Sec.  314.52 and 
314.95 (if patent owner or NDA applicant or holder does not reside or 
have a place of business within the United States);
    (K) Information on whether the patent is a reissued patent of a 
patent submitted previously for listing for the NDA or supplement;
    (L) Information on whether the expiration date is a new expiration 
date if the patent had been submitted previously for listing;
    (M) Information on whether the patent is a product-by-process 
patent in which the product claimed is novel;
    (N) Information on the drug substance (active ingredient) patent, 
including the following:
    (1) Whether the patent claims the drug substance that is the active 
ingredient in the drug product described in the approved NDA;
    (2) Whether the patent claims only a polymorph that is the same as 
the active ingredient that is described in the approved NDA;
    (3) Whether the applicant has test data, described in paragraph 
(b)(2) of this section, demonstrating that a drug product containing 
only the polymorph will perform the same as the drug product described 
in the approved NDA and a description of the polymorphic form(s) 
claimed by the patent for which such test data exist;
    (4) Whether the patent claims only a metabolite of the active 
ingredient; and
    (5) Whether the patent claims only an intermediate;
    (O) Information on the drug product (composition/formulation) 
patent, including the following:
    (1) Whether the patent claims the approved drug product as defined 
in Sec.  314.3; and
    (2) Whether the patent claims only an intermediate;
    (P) Information on each method-of-use patent, including the 
following:
    (1) Whether the patent claims one or more approved methods of using 
the approved drug product and a description of each approved method of 
use or indication and related patent claim of the patent being 
submitted;
    (2) Identification of the specific section(s) of the approved 
labeling for the drug product that corresponds to the method of use 
claimed by the patent submitted (if the scope of the method-of-use 
claim(s) of the patent does not cover every use of the drug, the 
applicant must only identify the specific portion(s) of the indication 
or other condition of use claimed by the patent);
    (3) The description of the patented method of use as required for 
publication (which must contain adequate information to assist 
505(b)(2) and ANDA applicants in determining whether a listed method-
of-use patent claims a use for which the 505(b)(2) or ANDA applicant is 
not seeking approval; for example, if the scope of the method-of-use 
claim(s) of the patent does not cover every approved use of the drug, 
then the description of the patented method of use must contain only 
the specific portion(s) of the indication or other method of use 
claimed by the patent); and
    (4) An applicant that submits information for a patent that claims 
one or more methods of using the drug product must also submit 
information described in either paragraph (c)(2)(ii)(N) or 
(c)(2)(ii)(O) of this section, regarding whether that patent also 
claims either the drug substance (active ingredient) or the drug 
product (composition/formulation).
    (Q) Whether there are no relevant patents that claim the approved 
drug substance (active ingredient), the approved drug product 
(formulation or composition), or approved method(s) of use and with 
respect to which a claim of patent infringement could reasonably be 
asserted if a person not licensed by the owner of the patent engaged in 
the manufacture, use, or sale of the drug product;
    (R) A signed verification that states:

    The undersigned declares that this is an accurate and complete 
submission of patent information for the NDA, amendment, or 
supplement approved under section 505 of the Federal Food, Drug, and 
Cosmetic Act. This time-sensitive patent information is submitted 
pursuant to 21 CFR 314.53. I attest that I am familiar with 21 CFR 
314.53 and this submission complies with the requirements of the 
regulation. I verify under penalty of perjury that the foregoing is 
true and correct.;

    and
    (S) Information on whether the applicant, patent owner or attorney, 
agent, representative, or other authorized official signed the form; 
the name of the person; and the full address, phone number and, if 
available, the fax number and email address.
    (T) Exceptions to required submission of patent information:
    (1) If an applicant submits the information described in paragraph 
(c)(2)(ii)(N) of this section for a patent that claims the drug 
substance (active ingredient) and meets the requirements for listing on 
that basis, then the applicant is not required to provide the 
information described in paragraph (c)(2)(ii)(O) of this section on 
whether that patent also claims the drug product (composition/
formulation).
    (2) If an applicant submits the information described in paragraph 
(c)(2)(ii)(O) of this section for a patent that claims the drug product 
(composition/formulation) and meets the requirements for listing on 
that basis, then the applicant is not required to provide the 
information described in paragraph (c)(2)(ii)(N) of this section on 
whether that patent also claims the drug substance (active ingredient).
    (3) No relevant patents. If the applicant believes that there are 
no relevant patents that claim the drug substance (active ingredient), 
drug product (formulation or composition), or the method(s) of use for 
which the applicant has received approval, and with respect to which a 
claim of patent infringement could reasonably be asserted if a person 
not licensed by the owner of the patent engaged in the manufacture, 
use, or sale of the drug product, the applicant will verify this 
information in the appropriate forms, Form FDA 3542 or 3542a.
    (4) Authorized signature. The declarations required by this section 
must be signed by the applicant or patent owner, or the applicant's or 
patent owner's attorney, agent (representative), or other authorized 
official.
    (d) When and where to submit patent information--(1) Original NDA. 
An applicant must submit with its original NDA submitted under this 
part, including a 505(b)(2) application, the information described in 
paragraph (c) of this section on each drug substance (ingredient), drug 
product (formulation and composition), and method-of-use patent issued 
before the NDA is filed with FDA and for which patent information is 
required to be submitted under this section. If a patent is issued 
after the NDA is filed with FDA but before the NDA is approved, the 
applicant shall, within 30 days of the date of issuance of the patent, 
submit the required patent information in an amendment to the NDA under 
Sec.  314.60.
    (2) Supplements. (i) An applicant must submit patent information 
required under paragraph (c) of this section for a patent that claims 
the drug substance, drug product, or method of use for which approval 
is sought in any of the following supplements:
    (A) To change the dosage form or route of administration;
    (B) To change the strength; or
    (C) To change the drug product from prescription use to over-the-
counter use.

[[Page 6885]]

    (ii) If the applicant submits a supplement for a change other than 
one of the changes listed under paragraph (d)(2)(i) of this section 
(for example, to change the formulation, to add a new indication or 
other condition of use, or to make any other patented change regarding 
the drug substance, drug product, or any method of use), the following 
patent information submission requirements apply:
    (A) If existing patents for which information has already been 
submitted to FDA for the product approved in the original NDA claim the 
changed product, the applicant is not required to resubmit this patent 
information unless the description of the patented method of use would 
change upon approval of the supplement, and FDA will continue to list 
this patent information for the product;
    (B) If one or more existing patents for which information has 
already been submitted to FDA no longer claim the changed product, the 
applicant must submit a request to remove that patent information from 
the list at the time of approval of the supplement;
    (C) If one or more existing drug substance (active ingredient), 
drug product (formulation and composition), or method-of-use patents 
claim the changed product for which approval is sought in the 
supplement and such patent information has not been submitted to FDA, 
the applicant must submit the patent information required under 
paragraph (c) of this section.
    (3) Newly issued patents. If a patent is issued for a drug 
substance, drug product, or method of use after an NDA is approved, the 
applicant must submit to FDA, as described in paragraph (d)(4) of this 
section, the required patent information within 30 days of the date of 
issuance of the patent. If the required patent information is not 
submitted within 30 days of the issuance of the patent, FDA will list 
the patent, but patent certifications will be governed by the 
provisions regarding untimely filed patents at Sec. Sec.  314.50(i)(4) 
and (i)(6) and 314.94(a)(12)(vi) and (a)(12)(viii).
    (4) Submission of Forms FDA 3542a and 3542.
    (i) Patent information submitted with the filing of an NDA, 
amendment, or supplement. The applicant must submit patent information 
required by paragraphs (c)(1) and (c)(2)(i) of this section and Sec.  
314.50(h) or Sec.  314.70(f) on Form FDA 3542a to the Central Document 
Room, Center for Drug Evaluation and Research, Food and Drug 
Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266. Form 
FDA 3542a should not be submitted to the Orange Book Staff in the 
Office of Generic Drugs.
    (ii) Patent information submitted upon and after approval of an NDA 
or supplement. The applicant must submit patent information required by 
paragraphs (c)(1) and (c)(2)(ii) of this section on Form FDA 3542 to 
the Office of Generic Drugs, OGD Document Room, Attention: Orange Book 
Staff, 7620 Standish Pl., Rockville, MD 20855.
    (5) Submission date. Patent information will be considered to be 
submitted to FDA for purposes of paragraph (d)(3) of this section as of 
the earlier of the date the information submitted on Form FDA 3542 is 
date-stamped by the Office of Generic Drugs, Document Room, or 
officially received electronically by FDA through the Electronic 
Submissions Gateway.
    (6) Identification. Each submission of patent information, except 
information submitted with an original NDA, must bear prominent 
identification as to its contents, i.e., ``Patent Information,'' or, if 
submitted after approval of an NDA, ``Time-Sensitive Patent 
Information.''
    (e) Public disclosure of patent information. FDA will publish in 
the list the patent number and expiration date of each patent that is 
required to be, and is, submitted to FDA by an applicant, and for each 
use patent, the approved indications or other conditions of use covered 
by a patent. FDA will publish such patent information upon approval of 
the NDA, or, if the patent information is submitted by the applicant 
after approval of an NDA as provided under paragraph (d)(2) of this 
section, as soon as possible after the submission to the Agency of the 
patent information. A request for copies of the submitted patent 
information must be sent in writing to the Division of Freedom of 
Information (ELEM-1029), Food and Drug Administration, 12420 Parklawn 
Dr., Element Bldg., Rockville, MD 20857. This information, and requests 
for delisting patents, will be subject to public disclosure.
    (f) Correction or change of patent information--(1) Requests by 
persons other than the NDA holder. If any person disputes the accuracy 
or relevance of patent information submitted to the Agency under this 
section and published by FDA in the list, or believes that an NDA 
holder has failed to submit required patent information, that person 
must first notify the Agency in a written or electronic communication 
titled ``314.53(f) Patent Listing Dispute'' that states the grounds for 
disagreement. Such notification should be directed to the Office of 
Generic Drugs, OGD Document Room, Attention: Orange Book Staff, 7620 
Standish Pl., Rockville, MD 20855. The Agency will then request of the 
applicable NDA holder that the correctness of the patent information or 
omission of patent information be confirmed within 30 days. For listed 
patents that claim an approved method of using the drug product, FDA 
will request that the NDA holder confirm the correctness of its 
description of the approved indication or method of use that has been 
included as the ``Use Code'' in the Orange Book, and provide 
information on the specific approved use claimed by the patent that 
enables the Agency to make a determination in accordance with section 
505(b)(2)(B) or 505(j)(2)(C)(viii) of the Federal Food, Drug, and 
Cosmetic Act. Unless the NDA holder withdraws or amends its patent 
information in response to FDA's request, the Agency will not change 
the patent information in the list. If the NDA holder does not change 
the patent information submitted to FDA, a 505(b)(2) application or an 
ANDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act 
submitted for a drug that is claimed by a patent for which information 
has been submitted must, despite any disagreement as to the correctness 
of the patent information, contain an appropriate certification for 
each listed patent. However, if there is insufficient information to 
make a determination in accordance with section 505(b)(2)(B) or 
505(j)(2)(C)(viii) of the Federal Food, Drug, and Cosmetic Act, and the 
NDA holder has confirmed the correctness of its description of the 
specific approved use claimed by the patent, the Agency will review the 
proposed labeling for the 505(b)(2) application or ANDA with deference 
to the 505(b)(2) or ANDA applicant's interpretation of the scope of the 
patent.
    (2) Requests by the NDA holder.--(i) Patents or patent claims that 
no longer meet the statutory requirements for listing. If the NDA 
holder determines that a patent or patent claim no longer meets the 
requirements for listing in section 505(b)(1) or 505(c)(2) of the 
Federal Food, Drug, and Cosmetic Act (including if there has been a 
judicial finding of invalidity for a listed patent, from which no 
appeal has been or can be taken), the NDA holder is required to 
promptly notify FDA to withdraw the patent or patent information and 
request that the patent or patent information be removed from the list. 
If the NDA holder is required by court order to amend patent 
information or withdraw a patent from the list, it must submit a copy 
of the order, within 14 days of the date the order was entered, to the 
Office of

[[Page 6886]]

Generic Drugs, OGD Document Room, Attention: Orange Book Staff, 7620 
Standish Pl., Rockville, MD 20855. FDA will remove a patent from the 
list if there is no first applicant eligible for 180-day exclusivity or 
upon the expiration of the 180-day exclusivity period of a first 
applicant.
    (ii) Patent term restoration. If the term of a listed patent is 
extended under 35 U.S.C. 156(e), the NDA holder must submit on Form FDA 
3542 a correction to the expiration date of the patent. This correction 
must be submitted within 30 days of receipt of a certificate of 
extension as described in 35 U.S.C. 156(e)(1) or documentation of an 
extension of the term of the patent as described in 35 U.S.C. 
156(e)(2).
    (iii) Submission of corrections or changes to patent information. 
Corrections or changes to previously submitted patent information, 
other than withdrawal of a patent and requests to remove a patent from 
the list, must be submitted on Form FDA 3542 or 3542a, as appropriate. 
We will not accept the corrections or changes unless they are submitted 
on the appropriate forms.
    (iv) Submission of patent withdrawals and requests to remove a 
patent from the list. Withdrawal of a patent and requests to remove a 
patent from the list must be submitted to the same addresses described 
in paragraph (d)(4) of this section, except that the withdrawal or 
request to remove a patent from the list is not required to be 
submitted on Form FDA 3542 and may be submitted by letter. Withdrawal 
of a patent and a request to delist a patent must contain the following 
information:
    (A) The NDA number to which the request applies;
    (B) Each product(s) approved in the NDA to which the request 
applies; and
    (C) The patent number.
    6. Section 314.54 is amended by removing the word ``shall'' and 
adding in its place the word ``must'' in paragraph (a)(1) introductory 
text and paragraph (a)(1)(i) and by revising the section heading, 
paragraph (a) introductory text, and paragraphs (a)(1)(iii), 
(a)(1)(vi), (a)(4), and (b) to read as follows:


Sec.  314.54  Procedure for submission of a 505(b)(2) application 
requiring investigations for approval of a new indication for, or other 
change from, a listed drug.

    (a) The Federal Food, Drug, and Cosmetic Act does not permit 
approval of an ANDA for a new indication, nor does it permit approval 
of other changes in a listed drug if investigations, other than 
bioavailability or bioequivalence studies, are essential to the 
approval of the change. Any person seeking approval of a drug product 
that represents a modification of a listed drug (e.g., a new indication 
or new dosage form) and for which investigations, other than 
bioavailability or bioequivalence studies, are essential to the 
approval of the changes may, except as provided in paragraph (b) of 
this section, submit a 505(b)(2) application. This 505(b)(2) 
application need contain only that information needed to support the 
modification(s) of the listed drug.
    (1) * * *
    (iii) Identification of each listed drug for which FDA has made a 
finding of safety and effectiveness and on which finding the applicant 
relies in seeking approval of its proposed drug product by established 
name, if any, proprietary name, dosage form, strength, route of 
administration, name of listed drug's application holder, and listed 
drug's approved NDA number. The listed drug or drugs identified as 
relied upon must include any approved drug product that:
    (A) Is pharmaceutically equivalent to the drug product for which 
the 505(b)(2) application is submitted; and
    (B) Was approved before the 505(b)(2) application was submitted.
* * * * *
    (vi) Any patent certification or statement required under section 
505(b)(2) of the Federal Food, Drug, and Cosmetic Act with respect to 
any relevant patents that claim the listed drug or drugs on which 
investigations relied on by the applicant for approval of the 
application were conducted, or that claim a use for the listed drug or 
drug(s).
* * * * *
    (4) The applicant must submit a field copy of the 505(b)(2) 
application that contains the technical section described in Sec.  
314.50(d)(1), a copy of the information required under Sec.  314.50(a) 
and (c), and certification that the field copy is a true copy of the 
technical section described in Sec.  314.50(d)(1) contained in the 
archival and review copies of the 505(b)(2) application.
    (b) A 505(b)(2) application may not be submitted under this section 
for a drug product whose only difference from a listed drug is that:
    (1) The extent to which its active ingredient(s) is absorbed or 
otherwise made available to the site of action is less than that of the 
listed drug; or
    (2) The rate at which its active ingredient(s) is absorbed or 
otherwise made available to the site of action is unintentionally less 
than that of the listed drug.
0
7. Section 314.60 is amended by:
0
a. Removing the word ``application'' each time it appears and adding in 
its place ``NDA'';
0
b. Removing ``(505)(c)(3)(D)(ii)'' in paragraphs (c)(1)(i) and (c)(2) 
and adding in its place ``(505)(c)(3)(E)(ii)'';
0
c. Adding paragraph headings in paragraphs (a), (b), and (c);
0
d. Revising the section heading and paragraph (d); and
0
e. Adding new paragraphs (e) and (f).
    The revisions read as follows:


Sec.  314.60  Amendments to an unapproved NDA, supplement, or 
resubmission.

    (a) Submission of NDA. * * *
    (b) Submission of major amendment. * * *
    (c) Limitation on certain amendments. * * *
    (d) Field copy. The applicant must submit a field copy of each 
amendment to a section of the NDA described in Sec.  314.50(d)(1). The 
applicant must include in its submission of each such amendment to FDA 
a statement certifying that a field copy of the amendment has been sent 
to the applicant's home FDA district office.
    (e) Different drug. An applicant may not amend a 505(b)(2) 
application to seek approval of a drug that is a different drug from 
the drug in the original submission of the 505(b)(2) application. For 
purposes of this section, a drug is a different drug if it has been 
modified to have a different active ingredient, different route of 
administration, different dosage form, or difference in excipients that 
requires either a separate clinical study to establish safety or 
effectiveness or, for topical products, that requires a separate in 
vivo demonstration of bioequivalence. However, notwithstanding the 
limitation described in this paragraph, an applicant may amend the 
505(b)(2) application to seek approval of a different strength.
    (f) Patent certification requirements. An amendment to a 505(b)(2) 
application is required to contain patent certifications described in 
Sec.  314.50(i) if approval is sought for any of the following types of 
amendments:
    (1) To add a new indication or other condition of use;
    (2) To add a new strength;
    (3) To make other than minor changes in product formulation; or
    (4) To change the physical form or crystalline structure of the 
active ingredient.
0
8. Section 314.70 is amended by:
0
a. Removing the word ``application'' each time it appears and adding in 
its place ``NDA'';

[[Page 6887]]

0
b. Removing the words ``cover letter'' in paragraph (a)(6), and adding 
in their place the word ``submission'';
0
c. Removing the words ``and its mailing cover'' in paragraph (b)(4);
0
d. Revising the section heading and paragraph (f); and
0
e. Adding paragraphs (h) and (i).
    The revisions read as follows:


Sec.  314.70  Supplements and other changes to an approved NDA.

* * * * *
    (f) Patent information. The applicant must comply with the patent 
information requirements under section 505(c)(2) of the Federal Food, 
Drug, and Cosmetic Act and Sec.  314.53.
* * * * *
    (h) Different drug. An applicant may not supplement a 505(b)(2) 
application to seek approval of a drug that is a different drug from 
the drug in the approved 505(b)(2) application. For purposes of this 
section, a drug is a different drug if it has been modified to have a 
different active ingredient, different route of administration, 
different dosage form, or difference in excipients that requires either 
a separate clinical study to establish safety or effectiveness or, for 
topical products, that requires a separate in vivo demonstration of 
bioequivalence. However, notwithstanding the limitation described in 
this paragraph, an applicant may supplement the 505(b)(2) application 
to seek approval of a different strength.
    (i) Patent certification requirements. (1) Except as provided in 
paragraph (i)(2) of this section, a supplement to a 505(b)(2) 
application is required to contain patent certifications described in 
Sec.  314.50(i) if approval is sought for either of the following types 
of supplements:
    (i) To add a new indication or other condition of use; or
    (ii) To add a new strength.
    (2) A supplement to a 505(b)(2) application that only seeks 
approval to add a new indication or other condition of use is required 
to contain patent certifications described in Sec.  314.50(i) only for 
patents that are identified as claiming an approved use. If a method-
of-use patent is identified as also claiming the drug substance or drug 
product, the patent certification also must address the drug substance 
and/or drug product claims.
0
9. Section 314.90 is amended by removing the word ``application'' each 
time it appears and adding in its place ``NDA'' and by adding paragraph 
(c) to read as follows:


Sec.  314.90  Waivers.

* * * * *
    (c) If FDA grants the applicant's waiver request with respect to a 
requirement under Sec. Sec.  314.50 through 314.81, the waived 
requirement will not constitute a basis for refusal to approve an NDA 
under Sec.  314.125.
0
10. Section 314.93 is amended by:
0
a. Removing the words ``abbreviated new drug applications'' in 
paragraph (a) and adding in their place ``ANDAs'';
0
b. Removing the words ``abbreviated new drug application'' in 
paragraphs (b), (c), and (e)(3) and adding in their place ``ANDA'';
0
c. Removing the word ``or'' from the end of paragraph (e)(1)(iv) ;
0
d. Removing ``reasons.'' in paragraph (e)(1)(v) and adding in its place 
``reasons; or'';
0
e. Adding paragraph (e)(1)(vi);
0
f. Redesignating paragraph (f) as paragraph (f)(1); and
0
g. Adding paragraph (f)(2).
    The revisions read as follows:


Sec.  314.93  Petition to request a change from a listed drug.

* * * * *
    (e) * * *
    (1) * * *
    (vi) A drug product is approved in an NDA for the change described 
in the petition.
* * * * *
    (f) * * *
    (2) If, after approval of a petition and before approval of an ANDA 
submitted pursuant to the approved petition, a drug product is approved 
in an NDA for the change described in the petition, the petition and 
the listed drug identified in the petition can no longer be the basis 
for ANDA submission, irrespective of whether FDA has withdrawn approval 
of the petition. A person seeking approval for such drug product must 
submit a new ANDA that identifies the pharmaceutically equivalent 
reference listed drug as the basis for ANDA submission and comply with 
applicable regulatory requirements.
0
11. Section 314.94 is amended by:
0
a. Removing the words ``abbreviated application'' in paragraphs 
(a)(5)(ii)(A), (a)(6)(ii), (d)(1)(i), and (d)(4) each time they appear 
and adding in their place ``ANDA'';
0
b. Removing the word ``shall'' in paragraphs (a)(9)(i) through 
(a)(9)(iv), (a)(12)(i)(A)(1) through (a)(12)(i)(A)(3), and (a)(12)(vii) 
each time it appears and adding in its place the word ``must'';
0
c. Removing and reserving paragraph (a)(12)(iv); and
0
d. Revising the section heading and the introductory text, paragraph 
(a) heading and introductory text, paragraphs (a)(1) and (a)(2), 
paragraph (a)(3) heading and introductory text, paragraphs (a)(3)(i), 
(a)(3)(iii), the first sentence of paragraph (a)(7)(ii), paragraphs 
(a)(7)(iii), (a)(8)(i),(a)(9)(v), paragraph (a)(12)(i)(A) introductory 
text, paragraphs (a)(12)(i)(A)(4), (a)(12)(i)(B), (a)(12)(iii)(A), 
(a)(12)(iii)(B), (a)(12)(v), (a)(12)(vi), (a)(12)(viii), (a)(13), (b), 
paragraph (d) heading, paragraph (d)(1) introductory text, and 
paragraphs (d)(2) and (d)(5).
    The revisions read as follows:


Sec.  314.94  Content and format of an ANDA.

    ANDAs are required to be submitted in the form and contain the 
information required under this section. Three copies of the 
application are required, an archival copy, a review copy, and a field 
copy. FDA will maintain guidance documents on the format and content of 
applications to assist applicants in their preparation.
    (a) ANDAs. Except as provided in paragraph (b) of this section, the 
applicant must submit a complete archival copy of the ANDA that 
includes the following:
    (1) Application form. The applicant must submit a completed and 
signed application form that contains the information described under 
Sec.  314.50(a)(1), (a)(3), (a)(4), and (a)(5). The applicant must 
state whether the submission is an ANDA under this section or a 
supplement to an ANDA under Sec.  314.97.
    (2) Table of contents. The archival copy of the ANDA is required to 
contain a table of contents that shows the volume number and page 
number of the contents of the submission.
    (3) Basis for ANDA submission. An ANDA must refer to a listed drug. 
Ordinarily, that listed drug will be the drug product selected by the 
Agency as the reference standard for conducting bioequivalence testing. 
The application must contain:
    (i) The name of the reference listed drug, including its dosage 
form and strength. For an ANDA based on an approved petition under 
Sec.  10.30 of this chapter or Sec.  314.93, the reference listed drug 
must be the same as the listed drug approved in the petition.
* * * * *
    (iii) For an ANDA based on an approved petition under Sec.  10.30 
of this chapter or Sec.  314.93, a reference to the FDA-assigned docket 
number for the petition and a copy of FDA's correspondence approving 
the petition.
* * * * *
    (7) * * *
    (ii) If the ANDA is submitted pursuant to a petition approved under 
Sec.  314.93,

[[Page 6888]]

the results of any bioavailability or bioequivalence testing required 
by the Agency, or any other information required by the Agency to show 
that the active ingredients of the proposed drug product are of the 
same pharmacological or therapeutic class as those in the reference 
listed drug and that the proposed drug product can be expected to have 
the same therapeutic effect as the reference listed drug. * * *
* * * * *
    (iii) For each in vivo or in vitro bioequivalence study contained 
in the ANDA:
    (A) A description of the analytical and statistical methods used in 
each study; and
    (B) With respect to each study involving human subjects, a 
statement that it either was conducted in compliance with the 
institutional review board regulations in part 56 of this chapter, or 
was not subject to the regulations under Sec.  56.104 or Sec.  56.105 
of this chapter, and that it was conducted in compliance with the 
informed consent regulations in part 50 of this chapter.
    (8) Labeling--(i) Listed drug labeling. A copy of the currently 
approved labeling (including, if applicable, any Medication Guide 
required under part 208 of this chapter) for the listed drug referred 
to in the ANDA, if the ANDA relies on a reference listed drug.
* * * * *
    (9) * * *
    (v) Inactive ingredient changes permitted in drug products intended 
for topical use. Generally, a drug product intended for topical use, 
solutions for aerosolization or nebulization, and nasal solutions must 
contain the same inactive ingredients as the reference listed drug 
identified by the applicant under paragraph (a)(3) of this section. 
However, an ANDA may include different inactive ingredients provided 
that the applicant identifies and characterizes the differences and 
provides information demonstrating that the differences do not affect 
the safety or efficacy of the proposed drug product.
* * * * *
    (12) Patent certification--(i) Patents claiming drug, drug product, 
or method of use. (A) A certification with respect to each patent 
issued by the U.S. Patent and Trademark Office that, in the opinion of 
the applicant and to the best of its knowledge, claims the reference 
listed drug or that claims a use of such listed drug for which the 
applicant is seeking approval under section 505(j) of the Federal Food, 
Drug, and Cosmetic Act and for which information is required to be 
filed under section 505(b) and (c) of the Federal Food, Drug, and 
Cosmetic Act and Sec.  314.53. For each such patent, the applicant must 
provide the patent number and certify, in its opinion and to the best 
of its knowledge, one of the following circumstances:
* * * * *
    (4) That the patent is invalid, unenforceable, or will not be 
infringed by the manufacture, use, or sale of the drug product for 
which the ANDA is submitted. The applicant shall entitle such a 
certification ``Paragraph IV Certification''. This certification must 
be submitted in the following form:

    I, (name of applicant), certify that Patent No. ____________(is 
invalid, unenforceable, or will not be infringed by the manufacture, 
use, or sale of) (name of proposed drug product) for which this 
application is submitted.


The certification must be accompanied by a statement that the applicant 
will comply with the requirements under Sec.  314.95(a) with respect to 
providing a notice to each owner of the patent or their representatives 
and to the holder of the approved application for the listed drug, with 
the requirements under Sec.  314.95(b) with respect to sending the 
notice, and with the requirements under Sec.  314.95(c) with respect to 
the content of the notice.

    (B) If the ANDA refers to a listed drug that is itself a licensed 
generic product of a patented drug first approved under section 505(b) 
of the Federal Food, Drug, and Cosmetic Act, the appropriate patent 
certification under paragraph (a)(12)(i) of this section with respect 
to each patent that claims the first-approved patented drug or that 
claims a use for such drug.
* * * * *
    (iii) Method-of-use patent. (A) If patent information is submitted 
under section 505(b) or (c) of the Federal Food, Drug, and Cosmetic Act 
and Sec.  314.53 for a patent claiming a method of using the listed 
drug, and the labeling for the drug product for which the applicant is 
seeking approval does not include any indications or other conditions 
of use that are covered by the use patent, a statement explaining that 
the method-of-use patent does not claim any of the proposed indications 
or other conditions of use.
    (B) If the labeling of the drug product for which the applicant is 
seeking approval includes an indication or other condition of use that, 
according to the patent information submitted under section 505(b) or 
(c) of the Federal Food, Drug, and Cosmetic Act and Sec.  314.53 or in 
the opinion of the applicant, is claimed by a use patent, an applicable 
certification under paragraph (a)(12)(i) of this section.
    (iv) [Reserved]
    (v) Licensing agreements. If the ANDA is for a drug or method of 
using a drug claimed by a patent and the applicant has a licensing 
agreement with the patent owner, a paragraph IV certification as to 
that patent and a statement that it has been granted a patent license.
    (vi) Untimely filing of patent information. If a patent on the 
listed drug is issued and the holder of the approved NDA for the listed 
drug does not file with FDA the required information on the patent 
within 30 days of issuance of the patent, an applicant who submitted an 
ANDA for that drug that contained an appropriate patent certification 
before the submission of the patent information is not required to 
submit an amended certification to address the patent that is late-
listed with respect to the pending ANDA. Except as provided in Sec.  
314.53(f)(1), an NDA holder's amendment to the description of the 
approved method(s) of use claimed by the patent will be considered 
untimely filing of patent information if:
    (A) The amendment is submitted more than 30 days after patent 
issuance and it is not related to a corresponding change in approved 
product labeling; or
    (B) The amendment is submitted more than 30 days after a 
corresponding change in approved product labeling. An applicant whose 
ANDA is submitted after the NDA holder's untimely filing of patent 
information, or whose pending ANDA was previously submitted but did not 
contain an appropriate patent certification at the time of the patent 
submission, must submit a certification under paragraph (a)(12)(i) of 
this section or a statement under paragraph (a)(12)(iii) of this 
section as to that patent.
* * * * *
    (viii) Amended certifications. A certification submitted under 
paragraphs (a)(12)(i) through (a)(12)(iii) of this section may be 
amended at any time before the date of approval of the ANDA. If an 
applicant with a pending ANDA voluntarily makes a patent certification 
for an untimely filed patent, the applicant may withdraw the patent 
certification for the untimely filed patent. An applicant must submit 
an amended certification as an amendment to a pending ANDA. Once an 
amendment is submitted to change a certification, the ANDA will no 
longer be considered to contain the prior certification.

[[Page 6889]]

    (A) After finding of infringement. An applicant who has submitted a 
paragraph IV certification and is sued for patent infringement must 
submit an amendment to change its certification if a court enters a 
final decision from which no appeal has been or can be taken, or signs 
a settlement order or consent decree in the action that includes a 
finding that the patent is infringed, unless the final decision, 
settlement order, or consent decree also finds the patent to be 
invalid. In its amendment, the applicant must certify under paragraph 
(a)(12)(i)(A)(3) of this section that the patent will expire on a 
specific date. Once an amendment for the change has been submitted, the 
ANDA will no longer be considered to be one containing a paragraph IV 
certification to the patent. If a final judgment finds the patent to be 
invalid and infringed, an amended certification is not required.
    (B) After request to remove a patent or patent information from the 
list. If the list reflects that an NDA holder has requested that a 
patent be removed from the list and no ANDA applicant is eligible for 
180-day exclusivity based on a paragraph IV certification to that 
patent, the patent will be removed and any applicant with a pending 
ANDA (including a tentatively approved application) who has made a 
certification with respect to such patent must submit an amendment to 
withdraw its certification. In the amendment, the applicant must state 
the reason for withdrawing the certification (that the patent is or has 
been removed from the list). If the list reflects that an NDA holder 
has requested that a patent be removed from the list and one or more 
first applicants are eligible for 180-day exclusivity based on a 
paragraph IV certification to that patent, the patent shall remain 
listed until any 180-day exclusivity is extinguished. If one or more 
first applicants are eligible for 180-day exclusivity based on a 
paragraph IV certification to a patent that has been reissued, then the 
first applicant must submit a paragraph IV certification to the 
reissued patent within 30 days of listing to have lawfully maintained 
its paragraph IV certification for purposes of eligibility for 180-day 
exclusivity. After any applicable 180-day exclusivity has been 
extinguished, the patent will be removed and any applicant with a 
pending ANDA (including a tentatively approved application) who has 
made a certification with respect to such patent must submit an 
amendment to withdraw its certification. Once an amendment to withdraw 
the certification has been submitted, the ANDA will no longer be 
considered to be one containing a paragraph IV certification to the 
patent. If removal of a patent from the list results in there being no 
patents listed for the listed drug identified in the ANDA, the 
applicant must submit an amended certification reflecting that there 
are no listed patents.
    (C) Other amendments. (1) Except as provided in paragraphs 
(a)(12)(vi) and (a)(12)(viii)(C)(2) of this section:
    (i) An applicant must amend a submitted certification if, at any 
time before the date of approval of the ANDA, the applicant learns that 
the submitted certification is no longer accurate; and
    (ii) An applicant must submit a certification or statement under 
paragraph (a)(12)(i) of this section if, after submission of the ANDA, 
a new patent is issued by the U.S. Patent and Trademark Office that, in 
the opinion of the applicant and to the best of its knowledge, claims 
the reference listed drug or that claims an approved use for such 
reference listed drug and for which information is required to be filed 
under section 505(b) and (c) of the Federal Food, Drug, and Cosmetic 
Act and Sec.  314.53. For a paragraph IV certification, the 
certification must not be submitted earlier than the first working day 
after the day the patent is published in the list.
    (2) An applicant is not required to submit a supplement to change a 
submitted certification when information on a patent on the listed drug 
is submitted after the approval of the ANDA, except as provided in 
Sec.  314.97(c).
    (13) Financial certification or disclosure statement. An ANDA must 
contain a financial certification or disclosure statement as required 
by part 54 of this chapter.
    (b) Drug products subject to the Drug Efficacy Study Implementation 
(DESI) review. If the ANDA is for a duplicate of a drug product that is 
subject to FDA's DESI review (a review of drug products approved as 
safe between 1938 and 1962) or other DESI-like review and the drug 
product evaluated in the review is a listed drug, the applicant must 
comply with the provisions of paragraph (a) of this section.
    (c) [Reserved]
    (d) Format of an ANDA. (1) The applicant must submit a complete 
archival copy of the ANDA as required under paragraphs (a) and (c) of 
this section. FDA will maintain the archival copy during the review of 
the ANDA to permit individual reviewers to refer to information that is 
not contained in their particular technical sections of the ANDA, to 
give other Agency personnel access to the ANDA for official business, 
and to maintain in one place a complete copy of the ANDA.
* * * * *
    (2) For ANDAs, the applicant must submit a review copy of the ANDA 
that contains two separate sections. One section must contain the 
information described under paragraphs (a)(2) through (a)(6), (a)(8), 
and (a)(9) of this section, and section 505(j)(2)(A)(vii) of the 
Federal Food, Drug, and Cosmetic Act and a copy of the analytical 
procedures and descriptive information needed by FDA's laboratories to 
perform tests on samples of the proposed drug product and to validate 
the applicant's analytical procedures. The other section must contain 
the information described under paragraphs (a)(3), (a)(7), and (a)(8) 
of this section. Each of the sections in the review copy is required to 
contain a copy of the application form described under Sec.  314.50(a).
* * * * *
    (5) The applicant must submit a field copy of the ANDA that 
contains the technical section described in paragraph (a)(9) of this 
section, a copy of the application form required under paragraph (a)(1) 
of this section, and a certification that the field copy is a true copy 
of the technical section described in paragraph (a)(9) of this section 
contained in the archival and review copies of the ANDA.
0
12. Section 314.95 is revised to read as follows:


Sec.  314.95  Notice of certification of invalidity or noninfringement 
of a patent.

    (a) Notice of certification. For each patent that claims the listed 
drug or that claims a use for such listed drug for which the applicant 
is seeking approval and for which the applicant submits a paragraph IV 
certification, the applicant must send notice of such certification by 
registered or certified mail, return receipt requested, or by a 
designated delivery service, as defined in paragraph (g) of this 
section to each of the following persons:
    (1) Each owner of the patent which is the subject of the 
certification or the representative designated by the owner to receive 
the notice. The name and address of the patent owner or its 
representative may be obtained from the U.S. Patent and Trademark 
Office; and
    (2) The holder of the approved NDA under section 505(b) of the 
Federal Food, Drug, and Cosmetic Act for the listed drug that is 
claimed by the patent and for which the applicant is seeking approval 
or, if the NDA holder does not reside or maintain a place of business

[[Page 6890]]

within the United States, the NDA holder's attorney, agent, or other 
authorized official. The name and address of the NDA holder or its 
attorney, agent, or authorized official may be obtained from the Orange 
Book Staff, Office of Generic Drugs, 7620 Standish Pl., Rockville, MD 
20855.
    (3) This paragraph does not apply to a use patent that does not 
claim a use for which the applicant is seeking approval.
    (4) An applicant may send notice by an alternative method only if 
FDA has agreed in advance that the method will produce an acceptable 
form of documentation.
    (b) Sending the notice. (1) Except as provided under paragraph (d) 
of this section, the applicant must send the notice required by 
paragraph (a) of this section on or after the date it receives an 
acknowledgment letter or a paragraph IV acknowledgment letter from FDA, 
but not later than 20 days after the date of the postmark on the 
acknowledgment letter. The 20-day clock described in this paragraph 
begins on the day after the date of the postmark on the paragraph IV 
acknowledgment letter. When the 20th day falls on Saturday, Sunday, or 
a Federal holiday, the 20th day will be the next day that is not a 
Saturday, Sunday, or Federal holiday.
    (2) Any notice required by paragraph (a) of this section is invalid 
if it is sent before the applicant's receipt of an acknowledgment 
letter or a paragraph IV acknowledgment letter, or before the first 
working day after the day the patent is published in the list. The 
applicant will not have complied with this paragraph until it sends 
valid notice.
    (3) At the same time it sends the notice required by paragraph (a) 
of this section, the applicant must submit to FDA an amendment to its 
ANDA that includes a statement certifying that the notice has been 
provided to each person identified under paragraph (a) of this section 
and that the notice met the content requirements under paragraph (c) of 
this section. A copy of the notice itself need not be submitted to the 
Agency.
    (c) Contents of a notice. In the notice, the applicant must cite 
section 505(j)(2)(B)(iv) of the Federal Food, Drug, and Cosmetic Act 
and must include, but is not limited to, the following information:
    (1) A statement that FDA has received an ANDA submitted by the 
applicant containing any required bioavailability or bioequivalence 
data or information.
    (2) The ANDA number.
    (3) A statement that the applicant has received the acknowledgment 
letter or paragraph IV acknowledgment letter for the ANDA.
    (4) The established name, if any, as defined in section 502(e)(3) 
of the Federal Food, Drug, and Cosmetic Act, of the proposed drug 
product.
    (5) The active ingredient, strength, and dosage form of the 
proposed drug product.
    (6) The patent number and expiration date of each listed patent for 
the reference listed drug alleged to be invalid, unenforceable, or not 
infringed.
    (7) A detailed statement of the factual and legal basis of the 
applicant's opinion that the patent is not valid, unenforceable, or 
will not be infringed. The applicant must include in the detailed 
statement:
    (i) For each claim of a patent alleged not to be infringed, a full 
and detailed explanation of why the claim is not infringed.
    (ii) For each claim of a patent alleged to be invalid or 
unenforceable, a full and detailed explanation of the grounds 
supporting the allegation.
    (8) If the applicant alleges that the patent will not be infringed 
and the applicant may later decide to file a civil action for 
declaratory judgment in accordance with section 505(j)(5)(C) of the 
Federal Food, Drug, and Cosmetic Act, then the notice must be 
accompanied by an offer of confidential access to the ANDA for the sole 
and limited purpose of evaluating possible infringement of the patent 
that is the subject of the paragraph IV certification.
    (9) If the applicant does not reside or have a place of business in 
the United States, the name and address of an agent in the United 
States authorized to accept service of process for the applicant.
    (d) Amendment or supplement to an ANDA. (1) If, after receipt of a 
paragraph IV acknowledgment letter, an applicant submits an amendment 
or supplement to its ANDA that includes a paragraph IV certification, 
the applicant must send the notice required by paragraph (a) of this 
section at the same time that the amendment or supplement to the ANDA 
is submitted to FDA, regardless of whether the applicant has already 
given notice with respect to another such certification contained in 
the application or in an amendment or supplement to the application.
    (2) If, before receipt of an acknowledgment letter or a paragraph 
IV acknowledgment letter, an applicant submits an amendment to its ANDA 
that includes a paragraph IV certification, the applicant must send the 
notice required by paragraph (a) of this section in accordance with the 
procedures in paragraph (b) of this section. If an ANDA applicant's 
notice of its paragraph IV certification is timely provided in 
accordance with paragraph (b) of this section, FDA will base its 
determination of whether the applicant is a first applicant on the date 
of submission of the amendment containing the paragraph IV 
certification.
    (3) An applicant that submits an amendment or supplement to seek 
approval of a different strength must provide notice of any paragraph 
IV certification in accordance with paragraph (d)(1) or (d)(2) of this 
section, as applicable.
    (e) Documentation of timely sending and receipt of notice. The 
applicant must amend its ANDA to provide documentation of the date of 
receipt of the notice required under paragraph (a) of this section by 
each person provided the notice. The amendment must be submitted to FDA 
within 30 days after the last date on which notice was received by a 
person described in paragraph (a) of this section. The applicant's 
amendment also must include documentation that its notice was sent on a 
date that complies with the timeframe required by paragraph (b) or 
paragraph (d) of this section, as applicable, and a dated printout of 
the entry for the reference listed drug in FDA's ``Approved Drug 
Products With Therapeutic Equivalence Evaluations'' (the list) that 
includes the patent that is the subject of the paragraph IV 
certification. FDA will accept, as adequate documentation of the date 
the notice was sent, a copy of the registered mail receipt, certified 
mail receipt, or receipt from a designated delivery service, as defined 
in paragraph (g) of this section. FDA will accept as adequate 
documentation of the date of receipt a return receipt, signature proof 
of delivery by a designated delivery service, or a letter acknowledging 
receipt by the person who provided the notice. An applicant may rely on 
another form of documentation only if FDA has agreed to such 
documentation in advance. A copy of the notice itself need not be 
submitted to the Agency.
    (f) Approval. If the requirements of this section are met, FDA will 
presume the notice to be complete and sufficient, and it will count the 
day following the date of receipt of the notice by the patent owner or 
its representative and by the approved application holder as the first 
day of the 45-day period provided for in section 505(j)(5)(B)(iii) of 
the Federal Food, Drug, and Cosmetic Act. FDA may, if the applicant 
provides a written statement to FDA that a later date should be used, 
count from such later date.

[[Page 6891]]

    (g) Designated delivery services. (1) For purposes of this section, 
the term ``designated delivery service'' means any delivery service 
provided by a trade or business that the Agency determines:
    (i) Is available to the general public throughout the United 
States;
    (ii) Records electronically to its database, kept in the regular 
course of its business, or marks on the cover in which any item 
referred to in this section is to be delivered, the date on which such 
item was given to such trade or business for delivery; and
    (iii) Provides overnight or 2-day delivery service throughout the 
United States.
    (2) FDA will periodically issue guidance regarding designated 
delivery services that meet these criteria.
0
13. Section 314.96 is amended by:
0
a. Revising the section heading;
0
b. Removing from the heading of paragraph (a) and from paragraph (a)(1) 
the words ``abbreviated new drug application'' and adding in their 
place ``ANDA'';
0
c. Removing from paragraph (a)(1) ``320.1(g)'' and adding in its place 
``314.3'';
0
d. Removing from paragraph (b) the word ``shall'' each time it appears 
and adding in its place the word ``must'';
0
e. Adding a heading to paragraph (b); and
0
f. Adding paragraphs (c) and (d).
    The revisions read as follows:


Sec.  314.96  Amendments to an unapproved ANDA.

* * * * *
    (b) Field copy. * * *
    (c) Different listed drug. An applicant may not amend an ANDA to 
seek approval of a drug referring to a listed drug that is different 
from the reference listed drug identified in the ANDA. This paragraph 
applies if, at any time before the approval of the ANDA, a different 
listed drug is approved that is the pharmaceutical equivalent to the 
product in the ANDA and is designated as a reference listed drug. This 
paragraph also applies if changes are proposed in an amendment to the 
ANDA such that the proposed product is a pharmaceutical equivalent to a 
different listed drug than the reference listed drug identified in the 
ANDA. A change of the reference listed drug must be submitted in a new 
ANDA. However, notwithstanding the limitation described in this 
paragraph, an applicant may amend the ANDA to seek approval of a 
different strength.
    (d) Patent certification requirements. An amendment to an ANDA is 
required to contain patent certifications described in Sec.  
314.94(a)(12) if approval is sought for any of the following types of 
amendments:
    (1) To add a new indication or other condition of use;
    (2) To add a new strength;
    (3) To make other than minor changes in product formulation; or
    (4) To change the physical form or crystalline structure of the 
active ingredient.
0
14. Section 314.97 is revised to read as follows:


Sec.  314.97  Supplements and other changes to an approved ANDA.

    (a) General requirements. The applicant must comply with the 
requirements of Sec. Sec.  314.70 and 314.71 regarding the submission 
of supplemental applications and other changes to an approved ANDA.
    (b) Different listed drug. An applicant may not supplement an ANDA 
to seek approval of a drug referring to a listed drug that is different 
from the current reference listed drug identified in the ANDA. This 
paragraph applies if changes are proposed in a supplement to the ANDA 
such that the proposed product is a pharmaceutical equivalent to a 
different listed drug than the reference listed drug identified in the 
ANDA. A change of reference listed drug must be submitted in a new 
ANDA. However, notwithstanding the limitation described in this 
paragraph, an applicant may supplement the ANDA to seek approval of a 
different strength.
    (c) Patent certification requirements. A supplement to an ANDA is 
required to contain patent certifications described in Sec.  
314.94(a)(12) if approval is sought for either of the following types 
of supplements:
    (1) To add a new indication or other condition of use; or
    (2) To add a new strength.
0
15. Section 314.99 is revised to read as follows:


Sec.  314.99  Other responsibilities of an applicant of an ANDA.

    (a) An applicant must comply with the requirements of Sec.  314.65 
regarding withdrawal by the applicant of an unapproved ANDA and Sec.  
314.72 regarding a change in ownership of an ANDA.
    (b) An applicant may ask FDA to waive under this section any 
requirement that applies to the applicant under Sec. Sec.  314.92 
through 314.99. The applicant must comply with the requirements for a 
waiver under Sec.  314.90. If FDA grants the applicant's waiver request 
with respect to a requirement under Sec. Sec.  314.92 through 314.99, 
the waived requirement will not constitute a basis for refusal to 
approve an ANDA under Sec.  314.127.
0
16. Section 314.101 is revised to read as follows:


Sec.  314.101  Filing an NDA and receiving an ANDA.

    (a) Filing an NDA. (1) Within 60 days after FDA receives an NDA, 
the Agency will determine whether the NDA may be filed. The filing of 
an NDA means that FDA has made a threshold determination that the NDA 
is sufficiently complete to permit a substantive review.
    (2) If FDA finds that none of the reasons in paragraphs (d) and (e) 
of this section for refusing to file the NDA applies, the Agency will 
file the NDA and notify the applicant in writing. In the case of a 
505(b)(2) application that contains a paragraph IV certification, the 
applicant will be notified via a paragraph IV acknowledgment letter. 
The date of filing will be the date 60 days after the date FDA received 
the NDA. The date of filing begins the 180-day period described in 
section 505(c) of the Federal Food, Drug, and Cosmetic Act. This 180-
day period is called the ``filing clock.''
    (3) If FDA refuses to file the NDA, the Agency will notify the 
applicant in writing and state the reason under paragraph (d) or (e) of 
this section for the refusal. If FDA refuses to file the NDA under 
paragraph (d) of this section, the applicant may request in writing 
within 30 days of the date of the Agency's notification an informal 
conference with the Agency about whether the Agency should file the 
NDA. If, following the informal conference, the applicant requests that 
FDA file the NDA (with or without amendments to correct the 
deficiencies), the Agency will file the NDA over protest under 
paragraph (a)(2) of this section, notify the applicant in writing, and 
review it as filed. If the NDA is filed over protest, the date of 
filing will be the date 60 days after the date the applicant requested 
the informal conference. The applicant need not resubmit a copy of an 
NDA that is filed over protest. If FDA refuses to file the NDA under 
paragraph (e) of this section, the applicant may amend the NDA and 
resubmit it, and the Agency will make a determination under this 
section whether it may be filed.
    (b) Receiving an ANDA. (1) An ANDA will be reviewed after it is 
submitted to determine whether the ANDA may be received. Receipt of an 
ANDA means that FDA has made a threshold determination that the ANDA is 
substantially complete.

[[Page 6892]]

    (2) If FDA finds that none of the reasons in paragraphs (d) and (e) 
of this section for considering the ANDA not to have been received 
applies, the ANDA is substantially complete and the Agency will receive 
the ANDA and notify the applicant in writing. If an ANDA is determined 
to be substantially complete, the date of submission is considered to 
be the date of receipt. In the case of an ANDA that contains a 
paragraph IV certification, the applicant will be notified via a 
paragraph IV acknowledgment letter.
    (3) If FDA considers the ANDA not to have been received under 
paragraph (d) or (e) of this section, FDA will notify the applicant. 
The applicant may then:
    (i) Withdraw the ANDA under Sec.  314.99; or
    (ii) Amend the ANDA to correct the deficiencies; or
    (iii) Take no action, in which case FDA will refuse to receive the 
ANDA.
    (4) If, after an ANDA has been received under paragraph (b)(2) of 
this section, FDA determines that the applicant did not send notice of 
a paragraph IV certification as required under Sec.  314.95 within the 
timeframe specified in paragraph (b) or (d) of that section, the date 
that the ANDA was submitted will be deemed to be delayed by the number 
of days by which the timeframe required by Sec.  314.95(b) or (d) was 
exceeded. When the date as delayed falls on Saturday, Sunday, or a 
Federal holiday, the filing date will be the next day that is not a 
Saturday, Sunday, or a Federal holiday.
    (c) [Reserved]
    (d) Application deficiencies. FDA may refuse to file an NDA or may 
not consider an ANDA to be received if any of the following applies:
    (1) The NDA or ANDA does not contain a completed application form.
    (2) The NDA or ANDA is not submitted in the form required under 
Sec.  314.50 or Sec.  314.94.
    (3) The NDA or ANDA is incomplete because it does not on its face 
contain information required under section 505(b) or section 505(j) of 
the Federal Food, Drug, and Cosmetic Act and Sec.  314.50 or Sec.  
314.94.
    (4) The applicant fails to submit a complete environmental 
assessment that addresses each of the items specified in the applicable 
format under Sec.  25.40 of this chapter or fails to provide sufficient 
information to establish that the requested action is subject to 
categorical exclusion under Sec.  25.30 or Sec.  25.31 of this chapter.
    (5) The NDA or ANDA does not contain an accurate and complete 
English translation of each part of the application that is not in 
English.
    (6) The NDA or ANDA does not contain a statement for each 
nonclinical laboratory study that it was conducted in compliance with 
the requirements set forth in part 58 of this chapter or, for each 
study not conducted in compliance with part 58 of this chapter, a brief 
statement of the reason for the noncompliance.
    (7) The NDA or ANDA does not contain a statement for each clinical 
study that it was conducted in compliance with the institutional review 
board regulations in part 56 of this chapter or was not subject to 
those regulations, and that it was conducted in compliance with the 
informed consent regulations in part 50 of this chapter or, if the 
study was subject to but was not conducted in compliance with those 
regulations, the NDA or ANDA does not contain a brief statement of the 
reason for the noncompliance.
    (8) The drug product that is the subject of the submission is 
already covered by an approved NDA or ANDA and the applicant of the 
submission:
    (i) Has an approved NDA or ANDA for the same drug product; or
    (ii) Is merely a distributor and/or repackager of the already 
approved drug product.
    (9) The NDA is submitted as a 505(b)(2) application for a drug that 
is a duplicate of a listed drug and is eligible for approval under 
section 505(j) of the Federal Food, Drug, and Cosmetic Act.
    (e) Regulatory deficiencies. The Agency will refuse to file an NDA 
or will consider an ANDA not to have been received if any of the 
following applies:
    (1) The drug product is subject to licensing by FDA under the 
Public Health Service Act (42 U.S.C. 201 et seq.) and subchapter F of 
this chapter.
    (2) Submission of a 505(b)(2) application or an ANDA for the active 
moiety is not permitted under Sec.  314.108(b)(2).
    (f) Outcome of FDA review. (1) Within 180 days after the date of 
filing, plus the period of time the review period was extended (if 
any), FDA will either:
    (i) Approve the NDA; or
    (ii) Issue a notice of opportunity for a hearing if the applicant 
asked FDA to provide it an opportunity for a hearing on an NDA in 
response to a complete response letter.
    (2) Within 180 days after the date of receipt, plus the period of 
time the review clock was extended (if any), FDA will either approve or 
disapprove the ANDA. If FDA disapproves the ANDA, FDA will issue a 
notice of opportunity for hearing if the applicant asked FDA to provide 
it an opportunity for a hearing on an ANDA in response to a complete 
response letter.
    (3) This paragraph does not apply to NDAs or ANDAs that have been 
withdrawn from FDA review by the applicant.
0
17. Section 314.105 is revised to read as follows:


Sec.  314.105  Approval of an NDA and an ANDA.

    (a) FDA will approve an NDA and send the applicant an approval 
letter if none of the reasons in Sec.  314.125 for refusing to approve 
the NDA applies. An NDA is approved on the date of the issuance of the 
approval letter. FDA will issue a tentative approval letter if an NDA 
otherwise meets the requirements for approval under the Federal Food, 
Drug, and Cosmetic Act, but cannot be approved because there is a 7-
year period of orphan exclusivity for the listed drug under section 527 
of the Federal Food, Drug, and Cosmetic Act and Sec.  316.31, or if a 
505(b)(2) application otherwise meets the requirements for approval 
under the Federal Food, Drug, and Cosmetic Act, but cannot be approved 
until the conditions in Sec.  314.107(b)(3) or (c) are met; because 
there is a period of exclusivity for the listed drug under Sec.  
314.108; or because there is a period of pediatric exclusivity for the 
listed drug under section 505A of the Federal Food, Drug, and Cosmetic 
Act. A drug product that is granted tentative approval is not an 
approved drug and will not be approved until FDA issues an approval 
after any necessary additional review of the NDA. FDA's tentative 
approval of a drug product is based on information available to FDA at 
the time of the tentative approval letter (i.e., information in the 
505(b)(2) application and the status of current good manufacturing 
practices of the facilities used in the manufacturing and testing of 
the drug product) and is therefore subject to change on the basis of 
new information that may come to FDA's attention. A new drug product 
may not be marketed until the date of the approval letter.
    (b) FDA will approve an NDA and issue the applicant an approval 
letter on the basis of draft labeling if the only deficiencies in the 
NDA concern editorial or similar minor deficiencies in the draft 
labeling. Such approval will be conditioned upon the applicant 
incorporating the specified labeling changes exactly as directed, and 
upon the applicant submitting to FDA a copy of the final printed 
labeling prior to marketing.
    (c) FDA will approve an NDA after it determines that the drug meets 
the

[[Page 6893]]

statutory standards for safety and effectiveness, manufacturing and 
controls, and labeling, and an ANDA after it determines that the drug 
meets the statutory standards for manufacturing and controls, labeling, 
and, where applicable, bioequivalence. While the statutory standards 
apply to all drugs, the many kinds of drugs that are subject to the 
statutory standards and the wide range of uses for those drugs demand 
flexibility in applying the standards. Thus FDA is required to exercise 
its scientific judgment to determine the kind and quantity of data and 
information an applicant is required to provide for a particular drug 
to meet the statutory standards. FDA makes its views on drug products 
and classes of drugs available through guidance documents, 
recommendations, and other statements of policy.
    (d) FDA will approve an ANDA and send the applicant an approval 
letter if none of the reasons in Sec.  314.127 for refusing to approve 
the ANDA applies. The date of approval is the date of the issuance of 
the Agency's approval letter. FDA will issue a tentative approval 
letter if an ANDA otherwise meets the requirements for approval under 
the Federal Food, Drug, and Cosmetic Act, but cannot be approved 
because there is a 7-year period of orphan exclusivity for the listed 
drug under section 527 of the Federal Food, Drug, and Cosmetic Act and 
Sec.  316.31, or cannot be approved until the conditions in Sec.  
314.107(b)(3) or (c) are met; because there is a period of exclusivity 
for the listed drug under Sec.  314.108; or because there is a period 
of pediatric exclusivity for the listed drug under section 505A of the 
Federal Food, Drug, and Cosmetic Act. A drug product that is granted 
tentative approval is not an approved drug and will not be approved 
until FDA issues an approval after any necessary additional review of 
the ANDA. FDA's tentative approval of a drug product is based on 
information available to FDA at the time of the tentative approval 
letter (i.e., information in the ANDA and the status of current good 
manufacturing practices of the facilities used in the manufacturing and 
testing of the drug product) and is therefore subject to change on the 
basis of new information that may come to FDA's attention. A new drug 
product may not be marketed until the date of the approval letter.
0
18. Section 314.107 is revised to read as follows:


Sec.  314.107  Date of approval of a 505(b)(2) application or ANDA.

    (a) General. A drug product may be introduced or delivered for 
introduction into interstate commerce when the 505(b)(2) application or 
ANDA for the drug product is approved. A 505(b)(2) application or ANDA 
for a drug product is approved on the date FDA issues an approval 
letter under Sec.  314.105 for the 505(b)(2) application or ANDA.
    (b) Effect of patent(s) on the listed drug. As described in 
paragraphs (b)(1) and (b)(2) of this section, the status of patents 
listed for the listed drug(s) relied upon or reference listed drug, as 
applicable, must be considered in determining the first possible date 
of approval of a 505(b)(2) application or ANDA. The criteria in 
paragraphs (b)(1) and (b)(2) of this section will be used to determine, 
for each relevant patent, the date that patent will no longer prevent 
approval. The first possible date of approval will be calculated for 
each patent, and the 505(b)(2) application or ANDA may be approved on 
the last applicable date.
    (1) Timing of approval based on patent certification or statement. 
If none of the reasons in Sec.  314.125 or Sec.  314.127 for refusing 
to approve the application applies, and none of the reasons in 
paragraph (d) of this section for delaying approval applies, the 
505(b)(2) application or ANDA may be approved as follows:
    (i) Immediately, if the applicant certifies under Sec.  314.50(i) 
or Sec.  314.94(a)(12) that:
    (A) The applicant is aware of a relevant patent but the patent 
information required under section 505(b) or (c) of the Federal Food, 
Drug, and Cosmetic Act has not been submitted to FDA; or
    (B) The relevant patent has expired; or
    (C) The relevant patent is invalid, unenforceable, or will not be 
infringed, except as provided in paragraphs (b)(3) and (c) of this 
section, and the 45-day period provided for in section 505(c)(3)(C) and 
(j)(5)(B)(iii) of the Federal Food, Drug, and Cosmetic Act has expired; 
or
    (D) There are no relevant patents.
    (ii) Immediately, if the applicant submits an appropriate statement 
under Sec.  314.50(i) or Sec.  314.94(a)(12) explaining that a method-
of-use patent does not claim an indication or other condition of use 
for which the applicant is seeking approval.
    (iii) On the date specified, if the applicant certifies under Sec.  
314.50(i) or Sec.  314.94(a)(12) that the relevant patent will expire 
on a specified date.
    (2) Patent information filed after submission of 505(b)(2) 
application or ANDA. If the holder of the approved NDA for the listed 
drug submits patent information required under Sec.  314.53 after the 
date on which the 505(b)(2) application or ANDA was submitted to FDA, 
the 505(b)(2) applicant or ANDA applicant must comply with the 
requirements of Sec.  314.50(i)(4) and (i)(6) and Sec.  
314.94(a)(12)(vi) and (a)(12)(viii) regarding amendment of its patent 
certification or statement. If the applicant submits an amendment 
certifying under Sec.  314.50(i)(1)(i)(A)(4) or Sec.  
314.94(a)(12)(i)(A)(4) that the relevant patent is invalid, 
unenforceable, or will not be infringed, and complies with the 
requirements of Sec.  314.52 or Sec.  314.95, the 505(b)(2) application 
or ANDA may be approved immediately upon submission of documentation of 
receipt of notice of paragraph IV certification under Sec.  314.52(e) 
or Sec.  314.95(e). The 45-day period provided for in section 
505(c)(3)(C) and (j)(5)(B)(iii) of the Federal Food, Drug, and Cosmetic 
Act does not apply in these circumstances.
    (3) Disposition of patent litigation--(i) Approval upon expiration 
of 30-month period or 7\1/2\ years from date of reference product 
approval. (A) Except as provided in paragraphs (b)(3)(ii) through 
(b)(3)(viii) of this section, if, with respect to patents for which 
required information was submitted under Sec.  314.53 before the date 
on which the 505(b)(2) application or ANDA was submitted to FDA 
(excluding an amendment or supplement to the 505(b)(2) application or 
ANDA), the applicant certifies under Sec.  314.50(i) or Sec.  
314.94(a)(12) that the relevant patent is invalid, unenforceable, or 
will not be infringed, and the patent owner or its representative or 
the exclusive patent licensee brings suit for patent infringement 
within 45 days of receipt of the notice of certification from the 
applicant under Sec.  314.52 or Sec.  314.95, the 505(b)(2) application 
or ANDA may be approved 30 months after the later of the date of the 
receipt of the notice of certification by any owner of the listed 
patent or by the NDA holder who is an exclusive patent licensee (or 
their representatives) unless the court has extended or reduced the 
period because of a failure of either the plaintiff or defendant to 
cooperate reasonably in expediting the action; or
    (B) If the patented drug product qualifies for 5 years of exclusive 
marketing under Sec.  314.108(b)(2) and the patent owner or its 
representative or the exclusive patent licensee brings suit for patent 
infringement during the 1-year period beginning 4 years after the date 
the patented drug was approved and within 45 days of receipt of the 
notice of certification from the applicant under Sec.  314.52 or Sec.  
314.95, the 505(b)(2) application or ANDA may be approved at the 
expiration of 7\1/2\ years from the date of approval of the NDA for the 
patented drug product.

[[Page 6894]]

    (ii) Federal district court decision of invalidity, 
unenforceability, or non-infringement. If before the expiration of the 
30-month period, or 7\1/2\ years where applicable, the district court 
decides that the patent is invalid, unenforceable, or not infringed 
(including any substantive determination that there is no cause of 
action for patent infringement or invalidity), the 505(b)(2) 
application or ANDA may be approved on:
    (A) The date on which the court enters judgment reflecting the 
decision; or
    (B) The date of a settlement order or consent decree signed and 
entered by the court stating that the patent that is the subject of the 
certification is invalid or not infringed.
    (iii) Appeal of Federal district court judgment of infringement. If 
before the expiration of the 30-month period, or 7\1/2\ years where 
applicable, the district court decides that the patent has been 
infringed, and if the judgment of the district court is appealed, the 
505(b)(2) application or ANDA may be approved on:
    (A) The date on which the mandate is issued by the court of appeals 
entering judgment that the patent is invalid or not infringed 
(including any substantive determination that there is no cause of 
action for patent infringement or invalidity); or
    (B) The date of a settlement order or consent decree signed and 
entered by the court of appeals stating that the patent that is the 
subject of the certification is invalid or not infringed.
    (iv) Affirmation or non-appeal of Federal district court judgment 
of infringement. If before the expiration of the 30-month period, or 
7\1/2\ years where applicable, the district court decides that the 
patent has been infringed, and if the judgment of the district court is 
not appealed or is affirmed, the 505(b)(2) application or ANDA may be 
approved no earlier than the date specified by the district court in an 
order under 35 U.S.C. 271(e)(4)(A).
    (v) Grant of preliminary injunction by Federal district court. If 
before the expiration of the 30-month period, or 7\1/2\ years where 
applicable, the district court grants a preliminary injunction 
prohibiting the applicant from engaging in the commercial manufacture 
or sale of the drug product until the court decides the issues of 
patent validity and infringement, and if the court later decides that 
the patent is invalid, unenforceable, or not infringed, the 505(b)(2) 
application or ANDA may be approved as provided in paragraph (b)(3)(ii) 
of this section. If the court decides that the patent has been 
infringed, the 505(b)(2) application or ANDA may be approved as 
provided in paragraph (b)(3)(iii) or (b)(3)(iv) of this section, 
whichever is applicable.
    (vi) Written consent to approval by patent owner or exclusive 
patent licensee. If before the expiration of the 30-month period, or 
7\1/2\ years where applicable, the patent owner or the exclusive patent 
licensee (or their representatives) agrees in writing that the 
505(b)(2) application or ANDA may be approved any time on or after the 
date of the consent, approval may be granted on or after that date.
    (vii) Court order terminating 30-month or 7\1/2\ year period. If 
before the expiration of the 30-month period, or 7\1/2\ years where 
applicable, the court enters an order requiring the 30-month or 7\1/2\-
year period to be terminated, the 505(b)(2) application or ANDA may be 
approved in accordance with the court's order.
    (viii) Court order of dismissal without a finding of infringement. 
If before the expiration of the 30-month period, or 7\1/2\ years where 
applicable, the court enters an order of dismissal, with or without 
prejudice, without a finding of infringement, the 505(b)(2) application 
or ANDA may be approved on or after the date of the order.
    (4) Tentative approval. FDA will issue a tentative approval letter 
when tentative approval is appropriate in accordance with paragraphs 
(b)(3) or (e)(1)(vi) of this section. In order for a 505(b)(2) 
application or ANDA to be approved under paragraph (b)(3) of this 
section, the applicant must receive an approval letter from the Agency. 
Tentative approval of an application does not constitute ``approval'' 
of an application and cannot, absent an approval letter from the 
Agency, result in an approval under paragraph (b)(3) of this section.
    (c) Subsequent ANDA submission. (1) If an ANDA contains a paragraph 
IV certification for a relevant patent and the ANDA is not that of a 
first applicant, the ANDA is regarded as the ANDA of a subsequent 
applicant. The ANDA of a subsequent applicant will not be approved 
during the period when any first applicant is eligible for 180-day 
exclusivity or during the 180-day exclusivity period of a first 
applicant. Any applicable 180-day exclusivity period cannot extend 
beyond the expiration of the patent upon which the 180-day exclusivity 
period was based.
    (2) For purposes of paragraph (c)(1) of this section, a first 
applicant must submit correspondence to its ANDA notifying FDA within 
30 days of the date of first commercial marketing of its drug product. 
If an applicant does not notify FDA, as required in this paragraph, of 
this date, the date of first commercial marketing will be deemed to be 
the date of the drug product's approval.
    (d) Delay due to exclusivity. The Agency will also delay the 
approval of a 505(b)(2) application or an ANDA if delay is required by 
the exclusivity provisions in Sec.  314.108, Sec.  316.31, or section 
505A of the Federal Food, Drug, and Cosmetic Act. When the approval of 
a 505(b)(2) application or ANDA is delayed under this section and Sec.  
314.108, Sec.  316.31, or section 505A of the Federal Food, Drug, and 
Cosmetic Act, the 505(b)(2) application or ANDA will be approved on the 
latest of the days specified under this section and Sec.  314.108, 
Sec.  316.31, or section 505A of the Federal Food, Drug, and Cosmetic 
Act, as applicable.
    (e) Notification of court actions or documented agreement. (1) The 
applicant must submit the following information to FDA, as applicable:
    (i) A copy of any judgment by the court (district court or mandate 
of the court of appeals) or settlement order or consent decree signed 
and entered by the court (district court or court of appeals) finding a 
patent described in paragraph (b)(3) of this section invalid, 
unenforceable, or not infringed, or finding the patent valid and 
infringed;
    (ii) Written notification of whether or not any action by the court 
described in paragraph (e)(1)(i) of this section has been appealed 
within the time permitted for an appeal;
    (iii) A copy of any order entered by the court terminating the 30-
month or 7\1/2\-year period described in paragraphs (b)(3)(i) and 
(b)(3)(ii) of this section;
    (iv) A copy of any documented agreement described in paragraph 
(b)(3)(vi) of this section;
    (v) A copy of any preliminary injunction described in paragraph 
(b)(3)(v) of this section, and a copy of any subsequent court order 
lifting the injunction; and
    (vi) A copy of any court order pursuant to 35 U.S.C. 271(e)(4)(A) 
ordering that a 505(b)(2) application or ANDA may be approved no 
earlier than the date specified (irrespective of whether the injunction 
relates to a patent described in paragraph (b)(3) of this section).
    (2) All information required by paragraph (e)(1) of this section 
must be sent to the Office of Generic Drugs (HFD-600) or to the 
appropriate division in the Office of New Drugs within 14 days of the 
date of entry by the court, the date of appeal or expiration of the 
time for appeal, or the

[[Page 6895]]

date of documented agreement, as applicable.
    (f) Forty-five day period after receipt of notice of paragraph IV 
certification--(1) Computation of 45-day time clock. The 45-day clock 
described in paragraph (b)(3) of this section as to each recipient 
required to receive notice of paragraph IV certification under Sec.  
314.52 or Sec.  314.95 begins on the day after the date of receipt of 
the applicant's notice of paragraph IV certification by the recipient. 
When the 45th day falls on Saturday, Sunday, or a Federal holiday, the 
45th day will be the next day that is not a Saturday, Sunday, or a 
Federal holiday.
    (2) Notification of filing of legal action. (i) The 505(b)(2) or 
ANDA applicant must notify FDA in writing within 14 days of the filing 
of any legal action filed within 45 days of receipt of the notice of 
paragraph IV certification by any recipient. A 505(b)(2) applicant must 
send the notification to the appropriate division in the Office of New 
Drugs reviewing the 505(b)(2) application. An ANDA applicant must send 
the notification to FDA's Office of Generic Drugs (HFD-600). The 
notification to FDA of the legal action must include:
    (A) The 505(b)(2) application or ANDA number.
    (B) The name of the 505(b)(2) or ANDA applicant.
    (C) The established name of the drug product or, if no established 
name exists, the name(s) of the active ingredient(s), the drug 
product's strength, and dosage form.
    (D) A statement that an action for patent infringement, identified 
by the court, case number, and the patent number(s) of the patent(s) at 
issue in the action, has been filed in an appropriate court on a 
specified date.
    (ii) A patent owner or NDA holder (or their representatives) may 
also notify FDA of the filing of any legal action for patent 
infringement. The notice should contain the information and be sent to 
the offices or divisions described in paragraph (f)(2)(i) of this 
section.
    (iii) If the 505(b)(2) or ANDA applicant, the patent owner(s), the 
NDA holder, or their representatives do not notify FDA in writing 
before the expiration of the 45-day time period or the completion of 
the Agency's review of the 505(b)(2) application or ANDA, whichever 
occurs later, that a legal action for patent infringement was filed 
within 45 days of receipt of the notice of paragraph IV certification, 
the 505(b)(2) application or ANDA may be approved upon expiration of 
the 45-day period (if the 505(b)(2) or ANDA applicant confirms that a 
legal action for patent infringement has not been filed) or upon 
completion of the Agency's review of the 505(b)(2) application or ANDA, 
whichever is later.
    (3) Waiver. If the patent owner or NDA holder who is an exclusive 
patent licensee (or their representatives) waives its opportunity to 
file a legal action for patent infringement within 45 days of a receipt 
of the notice of certification and the patent owner or NDA holder who 
is an exclusive patent licensee (or their representatives) submits to 
FDA a valid waiver before the 45 days elapse, the 505(b)(2) application 
or ANDA may be approved upon completion of the Agency's review of the 
application. FDA will only accept a waiver in the following form:

    (Name of patent owner or NDA holder who is an exclusive patent 
licensee or their representatives) has received notice from (name of 
applicant) under (section 505(b)(3) or 505(j)(2)(B) of the Federal 
Food, Drug, and Cosmetic Act) and does not intend to file an action 
for patent infringement against (name of applicant) concerning the 
drug (name of drug) before (date on which 45 days elapses). (Name of 
patent owner or NDA holder who is an exclusive patent licensee) 
waives the opportunity provided by (section 505(c)(3)(C) or 
505(j)(5)(B)(iii) of the Federal Food, Drug, and Cosmetic Act) and 
does not object to FDA's approval of (name of applicant)'s 
(505(b)(2) application or ANDA) for (name of drug) with an approval 
date on or after the date of this submission.

    (g) Conversion of approval to tentative approval. If FDA issues an 
approval letter in error or a court enters an order requiring, in the 
case of an already approved 505(b)(2) application or ANDA, that the 
date of approval be delayed, FDA will convert the approval to a 
tentative approval if appropriate.

0
19. Section 314.108 is amended by:
0
a. Revising paragraph (a) introductory text and the definitions of 
``Approved under section 505(b)'', ``Essential to approval'', and ``New 
chemical entity'';
0
b. Removing from paragraph (a) the definitions of ``Active moiety'', 
``Date of approval'', and ``FDA'';
0
c. Adding alphabetically to paragraph (a) the definition of 
``Bioavailability study''; and
0
d. Revising paragraph (b).
    The revisions read as follows:


Sec.  314.108  New drug product exclusivity.

    (a) Definitions. The definitions at Sec.  314.3 and the following 
definitions of terms apply to this section:
    Approved under section 505(b) means an NDA submitted under section 
505(b) and approved on or after October 10, 1962, or an application 
that was ``deemed approved'' under section 107(c)(2) of Public Law 87-
781.
    Bioavailability study means a study to determine the 
bioavailability or the pharmacokinetics of a drug.
* * * * *
    Essential to approval means, with regard to an investigation, that 
there are no other data available that could support approval of the 
NDA.
    New chemical entity means a drug that contains no active moiety 
that has been approved by FDA in any other NDA submitted under section 
505(b) of the Federal Food, Drug, and Cosmetic Act.
* * * * *
    (b) Submission of and date of approval of a 505(b)(2) application 
or ANDA.
    (1) [Reserved]
    (2) If a drug product that contains a new chemical entity was 
approved after September 24, 1984, in an NDA submitted under section 
505(b) of the Federal Food, Drug, and Cosmetic Act, no person may 
submit a 505(b)(2) application or ANDA under section 505(j) of the 
Federal Food, Drug, and Cosmetic Act for a drug product that contains 
the same active moiety as in the new chemical entity for a period of 5 
years from the date of approval of the first approved NDA, except that 
the 505(b)(2) application or ANDA may be submitted after 4 years if it 
contains a certification of patent invalidity or noninfringement 
described in Sec.  314.50(i)(1)(i)(A)(4) or Sec.  
314.94(a)(12)(i)(A)(4).
    (3) The approval of a 505(b)(2) application or ANDA described in 
paragraph (b)(2) of this section will occur as provided in Sec.  
314.107(b)(1) or (b)(2), unless the owner of a patent that claims the 
drug, the patent owner's representative, or exclusive licensee brings 
suit for patent infringement against the applicant during the 1-year 
period beginning 48 months after the date of approval of the NDA for 
the new chemical entity and within 45 days after receipt of the notice 
described at Sec.  314.52 or Sec.  314.95, in which case, approval of 
the 505(b)(2) application or ANDA will occur as provided in Sec.  
314.107(b)(3).
    (4) If an NDA:
    (i) Was submitted under section 505(b) of the Federal Food, Drug, 
and Cosmetic Act;
    (ii) Was approved after September 24, 1984;
    (iii) Was for a drug product that contains an active moiety that 
has been previously approved in another NDA under section 505(b) of the 
Federal Food, Drug, and Cosmetic Act; and
    (iv) Contained reports of new clinical investigations (other than 
bioavailability

[[Page 6896]]

studies) conducted or sponsored by the applicant that were essential to 
approval of the application, for a period of 3 years after the date of 
approval of the application, the Agency will not approve a 505(b)(2) 
application or an ANDA for the conditions of approval of the original 
NDA, or an ANDA submitted pursuant to an approved petition under 
section 505(j)(2)(C) of the Federal Food, Drug, and Cosmetic Act that 
relies on the information supporting the conditions of approval of an 
original NDA.
    (5) If a supplemental NDA:
    (i) Was approved after September 24, 1984; and
    (ii) Contained reports of new clinical investigations (other than 
bioavailability studies) that were conducted or sponsored by the 
applicant that were essential to approval of the supplemental NDA, for 
a period of 3 years after the date of approval of the supplemental 
application, the Agency will not approve a 505(b)(2) application or an 
ANDA for a change, or an ANDA submitted pursuant to an approved 
petition under section 505(j)(2)(C) of the Federal Food, Drug, and 
Cosmetic Act that relies on the information supporting a change 
approved in the supplemental NDA.
0
20. Section 314.125 is amended by:
0
a. Removing the word ``application'' wherever it appears in the section 
heading, paragraph (a) introductory text, and paragraphs (a)(2), 
(b)(7), (b)(9), (b)(10), (b)(12), and (b)(14) through (b)(18) and 
adding in its place ``NDA'';
0
b. Revising paragraph (b) introductory text; and
0
c. Adding paragraph (b)(19).
    The revisions read as follows:


Sec.  314.125  Refusal to approve an NDA.

* * * * *
    (b) FDA may refuse to approve an NDA for any of the following 
reasons, unless the requirement has been waived under Sec.  314.90:
* * * * *
    (19) The 505(b)(2) application failed to contain a patent 
certification or statement with respect to each listed patent for an 
approved drug product that:
    (i) Is pharmaceutically equivalent to the drug product for which 
the 505(b)(2) application is submitted; and
    (ii) Was approved before the 505(b)(2) application was submitted.
* * * * *
0
21. Section 314.127 is amended by:
0
a. Removing the words ``abbreviated application'' and ``abbreviated new 
drug application'' wherever they appear in paragraphs (a) and (b) and 
adding in their place ``ANDA'';
0
b. Revising the section heading and paragraph (a) introductory text; 
and
0
c. Adding paragraph (a)(14).
    The revisions read as follows:


Sec.  314.127  Refusal to approve an ANDA.

    (a) FDA will refuse to approve an ANDA for a new drug under section 
505(j) of the Federal Food, Drug, and Cosmetic Act for any of the 
following reasons, unless the requirement has been waived under Sec.  
314.99:
* * * * *
    (14) For an ANDA submitted pursuant to an approved suitability 
petition, an NDA subsequently has been approved for the change 
described in the suitability petition.
* * * * *

PART 320--BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS

0
22. The authority citation for part 320 continues to read as follows:

    Authority:  21 U.S.C. 321, 351, 352, 355, 371.
0
23. Section 320.1 is revised to read as follows:


Sec.  320.1  Definitions.

    The definitions contained in Sec.  314.3 of this chapter apply to 
those terms when used in this part.
0
24. Section 320.23 is amended by:
0
a. Revising the last sentence in paragraph (a)(1);
0
b. Removing the word ``shall'' in paragraph (a)(2) and adding in its 
place the word ``must'';
0
c. Redesignating paragraph (b) as paragraph (b)(1); and
0
d. Adding new paragraph (b)(2).
    The revisions read as follows:


Sec.  320.23  Basis for measuring in vivo bioavailability or 
demonstrating bioequivalence.

    (a)(1) * * * For drug products that are not intended to be absorbed 
into the bloodstream, bioavailability may be assessed by scientifically 
valid measurements intended to reflect the rate and extent to which the 
active ingredient or active moiety becomes available at the site of 
action.
* * * * *
    (b) * * *
    (2) For drug products that are not intended to be absorbed into the 
bloodstream, bioequivalence may be demonstrated by scientifically valid 
methods that are expected to detect a significant difference between 
the drug and the listed drug in safety and therapeutic effect.

    Dated: January 23, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-01666 Filed 2-5-15; 8:45 am]
BILLING CODE 4164-01-P


