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

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:

Final rule.

SUMMARY:

The Food and Drug Administration (FDA, the Agency, or we) is issuing a final rule 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 final rule implements 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 final rule also amends certain regulations regarding 505(b)(2) applications and ANDAs to facilitate compliance with and efficient enforcement of the FD&C Act.

DATES:

This rule is effective December 5, 2016.

ADDRESSES:

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 final rule 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:

With regard to the final rule:

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.

With regard to the information collection:

FDA PRA Staff, Office of Operations, Food and Drug Administration, Three White Flint North 10A63, 11601 Landsdown St., North Bethesda, MD 20852,

PRAStaff@fda.hhs.gov

.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary

A. Purpose of the Final Rule

B. Summary of the Major Provisions of the Final Rule

C. Legal Authority

D. Costs and Benefits

II. Table of Abbreviations and Acronyms Commonly Used in This Document

III. Background

A. History of This Rulemaking

B. General Overview of the Final Rule

IV. Legal Authority

V. Comments on the Proposed Rule and FDA Response

A. Definitions (§ 314.3(b))

B. Submission of Patent Information (§ 314.53)

C. Patent Certification (§§ 314.50(i) and 314.94(a)(12))

D. Notice of Paragraph IV Certification (§§ 314.52 and 314.95)

E. Amended Patent Certifications (§§ 314.50(i)(6) and 314.94(a)(12)(viii))

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

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 (§§ 314.60, 314.70, 314.96, and 314.97)

H. 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 (§ 314.54)

I. Petition to Request a Change From a Listed Drug (§ 314.93)

J. Filing an NDA and Receiving an ANDA (§ 314.101)

K. Approval of an NDA and ANDA (§ 314.105)

L. Refusal To Approve an NDA or ANDA (§§ 314.125 and 314.127 and Related Provisions in §§ 314.90 and 314.99)

M. Date of Approval of a 505(b)(2) Application or ANDA (§ 314.107)

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

O. Miscellaneous

P. Technical Amendments

VI. Effective Date

VII. Economic Analysis of Impacts

VIII. Analysis of Environmental Impact

IX. Paperwork Reduction Act of 1995

X. Federalism

XI. References

I. Executive Summary

I.A. Purpose of the Final Rule

This rule implements portions of Title XI of the MMA and revises and clarifies 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.

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 since its enactment. Based on this experience, FDA is amending its regulations to implement portions of the MMA that pertain to 30-month stays and other matters not related to forfeiture of 180-day exclusivity.

FDA is amending 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 clarifying requirements for the NDA holder's description of the specific approved method of use claimed by the patent (the “use code”) required for publication in FDA's “Approved Drug Products With Therapeutic Equivalence Evaluations” (commonly known as the Orange Book) to address overbroad or ambiguous use codes that may delay approval of generic drugs. This clarification 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. We also are revising the regulations to codify the types of court decisions and other actions that will terminate a 30-month stay of approval on a 505(b)(2) application or ANDA. Finally, we are updating the regulations to codify FDA's current practice and policy and thereby promote transparency.

I.B. Summary of the Major Provisions of the Final Rule

I.B.1. Submission of Patent Information

The rule revises and streamlines 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.

We are codifying our longstanding 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 address overbroad or ambiguous use codes, we are expressly requiring that if the method(s) of use claimed by the patent does not cover an indication or other approved condition of use in its entirety, the NDA holder's use code must describe only the specific approved method of use claimed by the patent for which a claim of patent infringement could reasonably be asserted if a person not licensed by the patent owner engaged in the manufacture, use, or sale of the drug product.

I.B.2. Timing of Submission of Patent Information

We are expressly describing 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 (21 U.S.C. 355(c)(2)), 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 expanding 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 are not submitted: (1) Within 30 days of patent issuance; (2) within 30 days of approval of a corresponding change to product labeling; or (3) within 30 days of a decision by the U.S. Patent and Trademark Office (USPTO) or a Federal court that is specific to the patent and alters the construction of a method-of-use claim(s) of the patent. This revision to our regulations is intended to reduce delays in approval related to overbroad or ambiguous patent use codes.

In addition, we are establishing that the submission date of patent information provided by an NDA holder after approval will be the earlier of the date on which Form FDA 3542 is date-stamped by the Central Document Room or officially received by FDA in an electronic format. These revisions are intended to facilitate prompt listing in the Orange Book and to remove any ambiguity about the date of submission in light of the implications of untimely filed patent information for the patent certification obligations of 505(b)(2) and ANDA applicants that rely upon the listed drug.

I.B.3. Correction or Change of Patent Information

We are clarifying and improving the procedures that govern challenges to the accuracy or relevance of the NDA holder's submission of patent information to the Agency. These procedures allow a person (including a 505(b)(2) or ANDA applicant) to request, for example, that an NDA holder confirm that a previously submitted use code complies with current requirements. We are establishing a 30-day timeframe in which the NDA holder will be required to substantively respond to the patent listing dispute and verify the accuracy and completeness of the response. We intend to take an incremental approach and evaluate whether FDA's revisions to the regulations on submission of method-of-use patent information and patent listing dispute procedures adequately address the problem of overbroad and ambiguous use codes before we determine whether a process to review a proposed labeling carve-out with deference to the 505(b)(2) and/or ANDA applicant(s)' interpretation of the scope of the patent is also needed.

In addition, we are expressly requiring 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 revisions facilitate implementation of the MMA provision related to patent withdrawal and efficient enforcement of the FD&C Act.

I.B.4. Notice of Paragraph IV Certification—Timing

We are revising our regulations to clearly delineate the two limitations on the timeframe 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 longstanding practice regarding premature notice) and (2) the date, established by MMA, by which notice must be given to be considered timely.

For an original application, a 505(b)(2) applicant must send notice of a paragraph IV certification on or after the date on which the 505(b)(2) application is filed and an ANDA applicant must send notice of a paragraph IV certification on or after the date on which it receives a “paragraph IV acknowledgment letter” from FDA stating that the application is sufficiently complete to permit a substantive review. Both 505(b)(2) and ANDA applicants must send notice of a paragraph IV certification not later than 20 days after the date of the “postmark” (as defined in this final rule) on the paragraph IV acknowledgment letter.

For an amendment or supplement, an applicant must send notice of a paragraph IV certification contained in an amendment to a 505(b)(2) application (that has been filed) or ANDA (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 establishing 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. 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. 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.

I.B.5. Notice of Paragraph IV Certification—Content and Methods

We are revising 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 are also expanding the acceptable methods of sending notice of a paragraph IV

certification beyond registered or certified mail to include “designated delivery services.” This reduces the burden on 505(b)(2) and ANDA applicants who currently must submit requests to the Agency to send notice by common alternate delivery methods.

I.B.6. Amended Patent Certifications

We are clarifying 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 are also clarifying the circumstances and timeframe 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 rule codifies 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 the 180-day exclusivity period based on that patent has expired or has been extinguished, and exempting 505(b)(2) applicants from providing or maintaining a certification to withdrawn patents. In addition, the rule expressly codifies the current requirement for a 505(b)(2) or ANDA applicant to submit a patent certification to a timely filed, newly issued patent that claims the listed drug or an approved method of using such drug.

I.B.7. Patent Certification Requirements for Amendments

We are clarifying and augmenting the patent certification requirements for amendments to 505(b)(2) applications and ANDAs to ensure that certain types of changes to the drug product are accompanied by an appropriate patent certification (or recertification) or statement. An appropriate patent certification (or recertification) or statement is required to accompany an amendment to add a new indication or other condition of use, to add a new strength, to make other-than-minor changes in product formulation, or to change the physical form or crystalline structure of the active ingredient. The regulations continue to require that a patent certification be amended if, at any time before approval, the applicant learns that the previously submitted patent certification or statement is no longer accurate.

I.B.8. Limitation on Submission of Certain Amendments and Supplements to a 505(b)(2) Application or ANDA

We are codifying 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.

I.B.9. 505(b)(2) Applications

We are requiring a 505(b)(2) applicant to identify one pharmaceutically equivalent drug product approved in an NDA, if one or more is approved before the original 505(b)(2) application is submitted, 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 certification obligations that would have applied if the proposed product could have been approved in an ANDA.

I.B.10. Date of Approval of a 505(b)(2) Application or ANDA

The rule describes, 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 revising 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.

We are clarifying 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 (or its representative(s)). This 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 codifying 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 are also addressing other scenarios in which a 30-month 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 in each pending suit for patent infringement brought within 45 days of receipt of the notice of paragraph IV certification. These clarifications are intended to avoid unnecessary delays in approval of 505(b)(2) applications and ANDAs 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).

I.B.11. Notification of Commercial Marketing

We are updating 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 is required to submit correspondence to its ANDA notifying FDA within 30 days of the date of first commercial marketing of the drug product. If a first applicant does not notify FDA within this timeframe, we are deeming 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.

I.B.12. Notification of Court Actions or Written Consent to Approval

We are expanding the scope of documentation that an applicant must submit to FDA regarding patent-related court actions and written consent to approval to ensure that FDA is promptly advised of information that may affect the timing of approval of a 505(b)(2) application or ANDA.

I.C. Legal Authority

Title XI of the MMA and sections 505, 505A, 505E, and 527 of the FD&C Act (21 U.S.C. 355, 355a, 355f, 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 rule.

I.D. Costs and Benefits

Many provisions of this final rule codify current practice, but some elements will lead to changes that generate additional benefits and costs. The table summarizes the benefits and costs of this final rule. The estimated annualized monetized benefits of this final rule are $215,247 at a 3 percent or 7 percent discount rate, while the estimated annualized monetized costs are $266,947 at a 3 percent discount rate and $275,925 at a 7 percent discount rate. We have also identified, but are

unable to quantify, additional impacts from changes to submitted patent information.

Summary of Benefits and Costs

Benefits

Costs

One-time (Year 1) Cost for Reading the Rule

NA

$466,450

Annually Recurring Compliance Costs or Savings (Years 1-10)

$215,247

213,858

Present Value at 3 Percent

1,836,098

2,277,116

Present Value at 7 Percent

1,511,803

1,937,983

Annualized Value at 3 Percent

215,247

266,947

Annualized Value at 7 Percent

215,247

275,925

NA = Not Applicable.

II. Table of Abbreviations and Acronyms Commonly Used in This Document

Abbreviation

What it means

ANDA

Abbreviated New Drug Application.

CDER

Center for Drug Evaluation and Research.

CFR

Code of Federal Regulations.

CSA

Controlled Substances Act.

ESG

Electronic Submissions Gateway.

FD&C Act

Federal Food, Drug, and Cosmetic Act.

FDA

U.S. Food and Drug Administration.

FDASIA

Food and Drug Administration Safety and Innovation Act.

FOIA

Freedom of Information Act.

FR

Federal Register.

FTC

U.S. Federal Trade Commission.

GAIN

Generating Antibiotic Incentives Now.

GDUFA

Generic Drug User Fee Amendments of 2012.

IRTNMTA

Improving Regulatory Transparency for New Medical Therapies Act.

MMA

Medicare Prescription Drug, Improvement, and Modernization Act of 2003.

NDA

New Drug Application.

OGD

Office of Generic Drugs (in FDA's Center for Drug Evaluation and Research).

OMB

U.S. Office of Management and Budget.

OND

Office of New Drugs (in FDA's Center for Drug Evaluation and Research).

Orange Book

FDA's “Approved Drug Products With Therapeutic Equivalence Evaluations”.

OTC

Over-the-counter.

RLD

Reference Listed Drug.

U.S.

United States.

U.S.C.

United States Code.

USPS

United States Postal Service.

USPTO

U.S. Patent and Trademark Office.

III. Background

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).

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 relied upon by the applicant for approval of the NDA comes from investigations that were 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) (see section 505(b)(2) of the FD&C Act; compare section 505(b)(1) of the FD&C Act for “stand-alone” NDAs).

An ANDA contains 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, conditions of use, dosage form, route of administration, strength, and (with certain permissible differences) labeling, among other characteristics. An ANDA applicant also must demonstrate that its proposed drug product is bioequivalent to the RLD (see section 505(j) of the FD&C Act; compare section 505(j)(2)(C) for “petitioned ANDAs”). 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 submitted under section 505(b)(1) of the FD&C Act.

The timing of approval for a 505(b)(2) application and an ANDA (including a petitioned ANDA) is subject to certain patent and marketing exclusivity protections. An NDA applicant is required to submit information on any patent that claims the drug that is the subject of the NDA or that 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) and (c)(2) of the FD&C Act). Upon approval of an NDA under section 505(c) of the FD&C Act, we publish certain patent information provided by the NDA holder in the Orange Book, available electronically on FDA's Web site at

http://www.fda.gov/cder

.

A 505(b)(2) application and ANDA must include an appropriate patent certification or statement for each patent that claims the listed drug(s) relied upon or RLD, respectively, or a method of using such drug and for which information is required to be filed under section 505(b) or 505(c) of the FD&C Act. The 505(b)(2) or ANDA applicant must submit one or more of the following certifications or statements:

• That such patent information has not been filed (a paragraph I certification);

• that such patent has expired (a paragraph II certification);

• the date on which such patent will expire (a paragraph III certification);

• that such 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 or ANDA is submitted (a paragraph IV certification);

• that there are no patents that claim the listed drug(s) or that claim a use of such drug (a “no relevant patents” statement, which is submitted instead of a patent certification); or

• that a method-of-use patent does not claim a use for which the 505(b)(2) or ANDA applicant is seeking approval (a 505(b)(2)(B) or (j)(2)(A)(viii) statement).

An applicant that submits a paragraph IV certification is required to give notice of the paragraph IV certification to the NDA holder 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)(iii) 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).

III.A. History of This Rulemaking

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 505(b)(2) applications and ANDAs. Title XI of the MMA addressed two key concerns identified in an FTC report on “Generic Drug Entry Prior to Patent Expiration: An FTC Study” (July 2002) (Ref. 1) 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 505(b)(2) application or ANDA). 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 certain 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.

Section 1102 of the MMA altered the conditions under which a 180-day period of marketing exclusivity attaches 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), 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.

On February 6, 2015, we published a proposed rule to implement portions of the MMA that pertain to 30-month stays and other matters not related to forfeiture of 180-day exclusivity, and make our regulations governing 505(b)(2) applications and ANDAs consistent with the MMA's amendments to the FD&C Act (80 FR 6802, February 6, 2015; see also “Abbreviated New Drug Applications and 505(b)(2) Applications; Correction,” 80 FR 13289, March 13, 2015). In addition, the proposed rule would amend the regulations in parts 314 and 320 (21 CFR parts 314 and 320) 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. We will determine whether additional rulemaking related to 180-day exclusivity is necessary in the future.

FDA provided 120 days for public comment on the proposed rule, including a 30-day extension of the original comment period (see “Abbreviated New Drug Applications and 505(b)(2) Applications; Extension of Comment Period,” 80 FR 22953, April 24, 2015). We received 13 comment letters on the proposed rule by the close of the comment period, each containing 1 or more comments on 1 or more issues. We received comments from pharmaceutical industry associations, brand and generic drug manufacturers, law firms, and a law student. Based on the comments received, FDA is finalizing the proposed rule with certain revisions and technical amendments.

III.B. General Overview of the Final Rule

This final rule implements portions of Title XI of the MMA and revises and clarifies FDA regulations relating to 505(b)(2) applications and ANDAs. The final rule reflects our consideration of comments on the proposed rule, recent court decisions, and legislative enactments, and incorporates several clarifying revisions and technical amendments. Table 1 summarizes the substantive changes from the proposed rule to the final rule.

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BILLING CODE 4164-01-C

IV. Legal Authority

The MMA and sections 505, 505A, 505E, 527, and 701 (21 U.S.C. 355, 355a, 355f, 360cc, and 371) of the FD&C Act provide the principal legal authority for this final rule. Section 505(b) of the FD&C Act describes the contents of an NDA, including a 505(b)(2) application, and describes patent listing and patent certification requirements for NDAs. 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 certain patent and marketing exclusivity protections. Section 505(j) also describes the availability of 180-day exclusivity for a first applicant. Section 505(x) describes the date of approval of an NDA for which FDA intends to recommend controls under the Controlled Substances Act (CSA). Section 701(a) of the FD&C Act provides FDA with the authority to issue regulations for the efficient enforcement of the FD&C Act.

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 505E of the FD&C Act describes the availability of an exclusivity period extension for certain designated qualified infectious disease products. 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, 505E, 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 final rule.

V. Comments on the Proposed Rule and FDA Response

We received 13 comment letters on the proposed rule by the close of the comment period, each containing 1 or

more comments on 1 or more issues. We received comments from pharmaceutical industry associations, brand and generic drug manufacturers, law firms, and a law student. Several comments made general remarks supporting the proposed rule without focusing on a particular proposed provision.

We describe and respond to specific comments in sections V.A through V.O. We have numbered each comment to help distinguish between different comments. We have grouped similar comments together under the same number, and, in some cases, we have separated different issues discussed in the same comment and designated them as distinct comments for purposes of our responses. The number assigned to each comment or comment topic is purely for organizational purposes and does not signify the comment's value or importance or the order in which comments were received. We also received comments on topics related to 505(b)(2) applications and ANDAs that are outside the scope of the proposed rule, including, for example, issues related to forfeiture of eligibility for 180-day exclusivity and the Drug Efficacy Study Implementation, and we are not addressing these comments at this time. We are currently implementing the 180-day exclusivity provisions of the MMA directly from the statute and will determine whether additional rulemaking is necessary in the future.

V.A. Definitions (§ 314.3(b))

We proposed to amend § 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 in the context of implementing section 505(b) and (j) of the FD&C Act. We also proposed amendments to § 314.3(b) to conform with other changes in the proposed rule (80 FR 6802), and to incorporate new definitions. We received a general comment expressing support for FDA's efforts to clarify and update various definitions that are necessary for the efficient enforcement of the Hatch-Waxman Amendments. We received no comments on our proposed definitions of “180-day exclusivity period,” “abbreviated new drug application or ANDA,” “active ingredient,” “ANDA holder,” “component,” “inactive ingredient,” “NDA holder,” “new drug application or NDA,” “original NDA,” “paragraph IV certification,” “patent owner,” “reference standard,” “strength,” and “therapeutic equivalents.” We also received no comments on our proposed revisions to the current definitions of “abbreviated application,” “act,” “applicant,” “application,” “listed drug,” and “the list.” In addition, we received no comments on our proposed relocation of the definition of “active moiety” that currently is in § 314.108(a) to § 314.3(b). Finally, we received no comments on our proposed relocation of the definitions that currently are in § 320.1(a) and (c) through (g) to § 314.3(b), our proposed deletion of § 320.1(b), and our proposed revisions to the definitions of “bioavailability” and “bioequivalence.” Therefore, we are finalizing these definitions without change, except for the technical amendment to the definition of “listed drug” described in section V.A.3 (Response 4) and the technical amendments to the definitions of “original NDA,” “resubmission,” and “therapeutic equivalents” described in section V.P.1. We also describe a technical amendment to the definition of “505(b)(2) application” in section V.P.3 and the addition of the defined term “Agency” in section V.P.1.

V.A.1. Definitions of “Acknowledgment Letter” and “Paragraph IV Acknowledgment Letter”

We proposed to establish a definition of the term “paragraph IV acknowledgment letter” and the related term “acknowledgment letter” to facilitate implementation of the MMA's requirement for a 505(b)(2) or ANDA applicant 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 application has been filed (see section 505(b)(3)(B)(i) and (j)(2)(B)(ii)(I) of the FD&C Act and section V.A.6). We proposed to define “paragraph IV acknowledgment letter” to mean 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. For 505(b)(2) applications and ANDAs that do not contain a paragraph IV certification, we proposed to define “acknowledgment letter” to mean 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 “acknowledgment letter” or “paragraph IV acknowledgment letter” would indicate that the 505(b)(2) application is regarded as filed or the ANDA is regarded as received (see proposed § 314.3(b)).

As explained in the proposed rule, the “paragraph IV acknowledgment letter” for 505(b)(2) applications that rely on the Agency's finding of safety and/or effectiveness for a listed drug and contain a paragraph IV certification would be the filing communication that generally is sent to the 505(b)(2) applicant not later than 14 calendar days after the 60-day filing date and sometimes is referred to as the “74-day letter” (see 80 FR 6802 at 6811 and 6814 to 6815). Unlike the paragraph IV acknowledgment letter for ANDAs, the filing communication is typically sent by the Office of New Drugs (OND) in the Center for Drug Evaluation and Research (CDER) in a franked envelope that may not bear a postmark made by the U.S. Postal Service (USPS). For purposes of § 314.52(b) and (c) only, we proposed that the “date of the postmark” on the “paragraph IV acknowledgment letter” would be considered to be four 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 USPS (see definition of “postmark” in proposed § 314.3). In the proposed rule, we explained that if OND were to send the filing communication via electronic transmission in the future, then our proposed definition of a “postmark” that documents an electronic event would apply (see proposed § 314.3(b) and section V.A.6).

In the following paragraphs, we discuss a comment on these proposed definitions. We also received a comment that agrees with the proposed definition of “paragraph IV acknowledgment letter” and the inclusion of this term in revised § 314.101(b)(2). After considering these comments, we are revising the definition of “acknowledgment letter” to delete the reference to 505(b)(2) applications, thereby limiting the applicability of this term to ANDAs. We are finalizing the definition of “paragraph IV acknowledgment letter” without change.

(Comment 1) One comment requests that FDA clarify whether the terms “acknowledgment letter,” “acceptance for filing letter,” and “paragraph IV acknowledgment letter” can be used interchangeably to refer to the letter sent to applicants for ANDAs that contain a paragraph IV certification.

(Response 1) FDA separately defines the terms “acknowledgment letter” and “paragraph IV acknowledgment letter” for ANDAs because the “paragraph IV acknowledgment letter” contains

information on certain regulatory requirements associated with a paragraph IV certification. For administrative reasons, it had been FDA's practice to send an “acknowledgment letter” rather than a “paragraph IV acknowledgment letter” to an ANDA applicant if an original ANDA contained a patent certification or statement other than a paragraph IV certification, and the applicant submitted an amendment containing a paragraph IV certification before the ANDA has been received for substantive review. Accordingly, we proposed to use both terms in the regulations where appropriate (see proposed § 314.95). Upon further consideration, we are modifying our administrative practices to send a “paragraph IV acknowledgment letter” to an ANDA applicant if the ANDA contains a paragraph IV certification at any time prior to receipt of the ANDA. We are making conforming revisions to § 314.95(b)(1) and (2), (c)(3), and (d)(2) to remove the reference to an “acknowledgment letter.” We are retaining a revised definition of the term “acknowledgment letter” in § 314.3(b) because FDA's Office of Generic Drugs (OGD) will continue to send “acknowledgment letters” for ANDAs that do not contain a paragraph IV certification at the time of receipt (see,

e.g.,

section V.D.1.b). (The defined term “acknowledgment letter” for ANDAs differs from the informal use of this term for NDAs, which acknowledges the submission of an NDA before the Agency has determined whether the NDA can be filed.) FDA no longer uses the term “acceptance for filing letter,” which is an informal term that previously was used to describe an acknowledgment letter for an ANDA.

FDA has concluded that that it is unnecessary to distinguish between an “acknowledgment letter” and a “paragraph IV acknowledgment letter” for a 505(b)(2) application. If the 505(b)(2) application contains a paragraph IV certification at any time before the 505(b)(2) application is filed, the filing communication that FDA sends to NDA applicants also will be the “paragraph IV acknowledgment letter” for 505(b)(2) applicants for purposes of determining the date by which notice of paragraph IV certification must be sent (see § 314.52). We are making a conforming revision to § 314.52(d) to remove the reference to an “acknowledgment letter” (see section V.D.1.b).

V.A.2. Definition of “Commercial Marketing”

We proposed 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 (21 CFR part 312), but that does not include transfer of the drug product for reasons other than sale to parties identified in the approved ANDA (see proposed § 314.3(b)). In the following paragraphs, we discuss three comments on this proposed definition. After considering these comments, we are making editorial corrections to clarify the types of transfers of the drug product for reasons other than sale that fall within the exception to commercial marketing. We also are making amendments to clarify that the definition of commercial marketing includes the introduction or delivery for introduction into interstate commerce of the reference listed drug by the ANDA applicant.

(Comment 2) One comment recommends clarifying that commercial marketing does not include transfer of the drug product to a third-party logistics provider or contractor who is not identified in the ANDA, provided that the transfer does not take the drug product outside the control of the ANDA holder (

e.g.,

transfer of the drug product for storage or further distribution only as the ANDA holder may direct in the future). This comment also suggests revising the structure of the definition to improve clarity. Another comment maintains that the proposed definition would limit business flexibility, given that an ANDA applicant's transfer of the drug product to a re-packager (

e.g.,

to facilitate packaging validation or preparation for product launch) would be considered commercial marketing because re-packagers are not identified in ANDAs.

(Response 2) FDA declines to expand the exception to commercial marketing to include transfer of the drug product, outside the control of the ANDA applicant, for reasons other than sale to third parties not identified in the ANDA. FDA's amended definition of “commercial marketing” creates a bright-line rule for establishing the date of first commercial marketing of the drug by any first applicant for purposes of determining the start of the 180-day exclusivity period (see section 505(j)(5)(B)(iv)(I) of the FD&C Act and § 314.107(c)(2)). The amended definition also facilitates implementation of the statutory provision by which a first applicant may forfeit eligibility for 180-day exclusivity due to failure to market the drug by the timeframe described in the statute (see section 505(j)(5)(D)(i)(I) of the FD&C Act).

Under the amended definition in § 314.3(b), “commercial marketing” of the drug product refers to a transfer of the drug product outside the control of the ANDA applicant, subject to specified exceptions, and thus does not include a transfer of the drug product within the control of the ANDA applicant. As we explained in the proposed rule, the amended definition is intended to clarify that the ANDA applicant's shipment of a drug product described in an 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 (80 FR 6802 at 6812). Among other things, an ANDA holder would be required to identify a packager or re-packager in a supplement to the ANDA if different equipment or facilities are used that have a moderate potential to have an adverse effect on factors that may relate to the safety and effectiveness of the drug product (see 21 U.S.C. 356a and § 314.70(c); compare § 314.70(d)). We also note that storage and distribution facilities often are identified in ANDAs (see,

e.g.,

draft guidance for industry entitled “Pre-Launch Activities Importation Requests (PLAIR)” (July 2013) at 3, available at

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

). Accordingly, we do not expect the amended definition to have a significant impact on ANDA applicants' business arrangements with third parties.

FDA agrees that the definition of “commercial marketing” should be revised further for clarity. We also are making amendments to remove the reference to an “approved” ANDA and to further clarify that the definition of commercial marketing includes an ANDA applicant's commercial marketing of the reference listed drug, including an authorized generic drug (see section 505(j)(5)(B)(iv)(I) of the FD&C Act). As revised, commercial marketing is the introduction or delivery for introduction into interstate commerce of a drug product described in an ANDA, outside the control of the ANDA applicant, except that the term does not include transfer of the drug product for investigational use under part 312 of this chapter or transfer of the

drug product to parties identified in the ANDA for reasons other than sale. Commercial marketing includes the introduction or delivery for introduction into interstate commerce of the reference listed drug by the ANDA applicant.

(Comment 3) One comment agrees with the proposed definition of “commercial marketing” but recommends specifically excluding charitable donations of drug product.

(Response 3) FDA disagrees with the recommendation to exclude charitable donations of drug product from the definition of “commercial marketing.” A drug product is introduced or delivered for introduction into interstate commerce, outside the control of the ANDA applicant, when an ANDA applicant donates the drug product to a charitable institution or organization (

e.g.,

a nonprofit hospital or health care entity). This introduction or delivery for introduction into interstate commerce subjects the donated drug product to applicable statutory and regulatory requirements, including, but not limited to, requirements intended to ensure that the drug product is not adulterated or misbranded (see,

e.g.,

21 U.S.C. 331, 351, and 352). Moreover, even if the charitable institution or organization is identified in the ANDA, a charitable donation of drug product is not necessarily a transfer of the drug product for reasons other than sale, given that there are circumstances in which a donated drug product may be sold (see 21 U.S.C. 353(c)(3)(B) and 21 CFR 203.22). FDA does not believe the definition of “commercial marketing” will impact charitable donation of drug product, given that charitable donation of drug product met the criteria for commercial marketing under the previous definition in § 314.107(c)(4). The comment does not provide any explanation for the proposed change, and we do not believe that the proposed change is necessary.

V.A.3. Definition of “Date of Approval”

We proposed to move the definition of “date of approval” from § 314.108(a) to § 314.3(b) with several revisions. We proposed that the date of approval would mean the date on the approval letter from FDA stating that the NDA or ANDA is approved (see proposed § 314.3(b)). Our proposed revisions broadened the definition to include the date of approval for an ANDA, and incorporated the defined term “approval letter.” We also proposed to remove the caveat that the date of approval is the date on the approval 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.

In the following paragraphs, we discuss two comments that disagree with these proposed changes. After these comments were submitted, Congress enacted the Improving Regulatory Transparency for New Medical Therapies Act (IRTNMTA) (Pub. L. 114-89), which addresses the primary concern expressed by comments regarding the proposed revision to the definition. We are finalizing the definition with technical amendments to incorporate IRTNMTA.

(Comment 4) Two comments recommend that FDA retain the former definition of “date of approval” in § 314.108 because the definition addresses circumstances in which the date on the approval letter for an NDA is not the same as the date on which an applicable exclusivity period begins to run. The comments contend that the qualifying phrase “as long as approval of such [final printed] labeling or materials is not expressly required” in the former definition of “date of approval” is not reflected elsewhere in the Agency's regulations. Moreover, the comments assert that the proposed revision to the definition would effectively reduce the exclusivity period for certain approved drug products that cannot be commercially marketed until the Drug Enforcement Administration (DEA) has scheduled the drug as a controlled substance or until FDA has approved a proprietary name (where the name is necessary for the safe use of the drug). The comments maintain that FDA did not clearly describe and invite comment on these effects of the proposed revision to the definition.

(Response 4) We disagree with comments recommending that we retain the former definition of “date of approval” in § 314.108. As we explained in the proposed rule, FDA's regulations in § 314.105(b) specifically address the circumstances in which FDA will approve an NDA and issue the applicant an approval letter on the basis of draft labeling. Since publication of the proposed rule, FDA has determined that an ANDA also may be approved on the basis of draft labeling, provided that the only deficiencies in the draft labeling are editorial or similarly minor in nature (see guidance for industry entitled “Acceptability of Draft Labeling to Support ANDA Approval” (October 2015), available at

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

) (superseding FDA's former policy that final printed labeling is required for approval of an ANDA). If draft labeling deficiencies have not yet been resolved and are more than “editorial or similar minor deficiencies,” then the appropriate action is a complete response letter (see §§ 314.125(b) and 314.110). In the exceptional circumstances in which FDA has not yet approved a proprietary name for a proposed drug product and determines that the product cannot be marketed without a proprietary name, the applicant should receive a complete response letter (compare Letter from Janet Woodcock, M.D., Director, CDER, to Anil Hiteshi, Spectrum Pharmaceuticals, Inc., dated February 24, 2015, regarding Docket No. FDA-2014-P-1615, available at

http://www.regulations.gov

) (denying request for revision of the approval date because the approval letter expressly stated that Spectrum could market the product with labeling bearing only the established name until a proprietary name could be agreed upon). Accordingly, it is unnecessary to address any requirements for approval of final printed labeling in the definition of “date of approval.”

On November 25, 2015, Congress enacted IRTNMTA, which addresses concerns that delays in scheduling a newly approved drug may reduce an applicable exclusivity period that commences on the “date of approval.” IRTNMTA provides that the date of approval for an NDA for which FDA intends to recommend controls under the CSA is the later of the date an NDA is approved under section 505(c) of the FD&C Act or the date of issuance of the interim final rule controlling the drug (see section 505(x)(1) and (2) of the FD&C Act). To incorporate IRTNMTA, we are revising the definition of “date of approval” to mean the date on the approval letter from FDA stating that the NDA or ANDA is approved, except that the date of approval for an NDA described in section 505(x)(1) of the FD&C Act is determined as described in section 505(x)(2) of the FD&C Act (see § 314.3(b)).

As reflected in the revised definition, we are currently implementing IRTNMTA directly from the statute and will determine whether additional rulemaking is necessary in the future. However, given the broader relevance of the term “date of approval” to matters covered in part 314, we are making other technical amendments to align with the revised definition and enhance clarity. These technical amendments are described in the following paragraphs.

We are further revising the proposed definition of “listed drug” to establish that a drug product is deemed to be a listed drug on the “date of approval” for the NDA or ANDA for that drug

product, rather than on the “date of the approval letter” (see § 314.3(b)). This technical amendment clarifies the listed drug status of a drug product described in section 505(x)(1) of the FD&C Act, and the corresponding date on which the drug product will be identified in the Orange Book (the list) as a listed drug. We are revising § 314.105(a) to remove the proposed statement that an NDA is approved on the date of the issuance of the approval letter. This statement may be inaccurate with respect to drug products described in section 505(x)(1) of the FD&C Act, and the text is unnecessary in light of the revised definition of “date of approval” (see § 314.3(b)). We also are revising § 314.105(a) to state that a new drug product may not be marketed until the date of approval, rather than the date of the approval letter, for consistency with IRTNMTA. Although section 505(x)(1) of the FD&C Act does not apply to ANDAs, we are making the same revisions to § 314.105(d) for consistency. In addition, we are revising § 314.107(b) to clarify that this provision describes how to determine the first possible date on which a 505(b)(2) application or ANDA can be approved, rather than the “date of approval.” We also are replacing the phrase “the date the patented drug was approved” with “the date of approval” in § 314.107(b)(3)(i)(B) to incorporate the revised definition. Finally, in the paragraph heading for § 314.108(b), we are replacing the phrase “date of approval” with “timing of approval” to more accurately characterize the content of this paragraph.

In the sections of parts 314 and 320 that are the subject of this rulemaking, the references to the “date of approval” are intended to refer to the revised definition in § 314.3(b). For example, we are maintaining the reference to “date of approval” in § 314.53(c)(2)(ii) to ensure that there is no ambiguity post-IRTNMTA about the required timeframe for submission of patent information after approval, given 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 §§ 314.50(i)(4) and 314.94(a)(12)(vi)). Accordingly, for an NDA subject to IRTNMTA, the NDA holder must submit Form FDA 3542 within 30 days of the later of the date on which the NDA is approved under section 505(c) of the FD&C Act or the date of issuance of the interim final rule controlling the drug for the patent information to be considered timely filed.

V.A.4. Definition of “Dosage Form”

We proposed to define “dosage form” to mean the physical manifestation containing the active and inactive ingredients that delivers a dose of the drug product. The physical manifestation 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) design features that affect frequency of dosing (see proposed § 314.3(b)). In the following paragraphs, we discuss a comment on this proposed definition. After considering this comment, we are finalizing the definition without change.

(Comment 5) One comment recommends that FDA broaden the definition of “dosage form” by including an additional factor to describe the physical manifestation of a drug product. The comment requests that FDA establish that a drug product with features that impart properties designed to deter tampering, abuse, or misuse of the drug product does not have the same dosage form as a similar version of the drug product that does not have such properties. The comment suggests that this would clarify that abuse-deterrent formulations and non-abuse-deterrent formulations of a drug product cannot be considered pharmaceutical equivalents or therapeutic equivalents.

(Response 5) FDA declines to adopt the comment's suggestion at this time. FDA may address issues related to the pharmaceutical equivalence and therapeutic equivalence of abuse-deterrent formulations of a drug product through rulemaking or other regulatory mechanisms.

V.A.5. Definitions of “First Applicant” and “Substantially Complete Application”

We proposed to define the terms “first applicant” and “substantially complete application” to incorporate into our regulations the definitions established by the MMA, with minor editorial changes and additional clarifying text (see section 505(j)(5)(B)(iv)(II)(bb) and (cc) of the FD&C Act). We proposed to define “first applicant” 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 (see proposed § 314.3(b)). We proposed to delete the definition of “applicant submitting the first application” in former § 314.107(c)(2) because that definition was superseded by the statutory definition.

We also proposed to define “substantially complete application” to 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 § 314.94 (see proposed § 314.3(b)). We clarified that any information referenced in the ANDA must have been provided to FDA for the ANDA to be substantially complete, and we provided examples of other bases for finding that an ANDA is not substantially complete (see 80 FR 6802 at 6816 to 6817).

In the following paragraphs, we discuss a comment on these proposed definitions. After considering this comment, we are revising the definition of “substantially complete application” for consistency with § 314.101 and making an editorial correction for clarity. We are finalizing the definition of “first applicant” with editorial changes to more clearly incorporate the defined term “substantially complete application.”

(Comment 6) One comment recommends that FDA revise the definitions of “first applicant” and “substantially complete application” to clarify the content required to support a decision that an ANDA is substantially complete “on its face” in order to distinguish deficiencies that may preclude receipt of an ANDA from review issues.

(Response 6) FDA is revising the definition of “substantially complete application” for consistency with other regulations outlining the required content of an ANDA and to enhance clarity. Under existing § 314.101(b), FDA will receive an ANDA if FDA finds that none of the reasons in § 314.101(d) and (e) applies for considering the ANDA not to have been received. The deficiencies described in § 314.101(d) that may result in refusal to receive an ANDA include, but are not limited to, an ANDA that is incomplete “because it does not on its face contain information required” under section 505(j) of the FD&C Act and § 314.94 (see § 314.101(d)(3)).

We are revising the definition of “substantially complete application” to include an express definition of “sufficiently complete” to permit a substantive review that aligns with our standard for receiving an ANDA. As revised, a “substantially complete application” is an ANDA that on its face is sufficiently complete to permit a substantive review. “Sufficiently

complete” to permit a substantive review means that the ANDA contains all the information required under section 505(j)(2)(A)(i) through (viii) of the FD&C Act and does not contain a deficiency described in § 314.101(d) and (e) (see § 314.3(b)). The phrase “on its face” describes FDA's threshold determination that the ANDA includes the information required to make it sufficiently complete to permit a substantive review (

i.e.,

information corresponding to the statutory and regulatory requirements for an ANDA). This evaluation does not involve a substantive review of the data in the ANDA (see § 314.101(b)(1)). As discussed in section V.J.2, we are supplementing § 314.101(d)(3) to more precisely describe the factors that FDA considers in determining whether an ANDA is incomplete on its face.

FDA is revising the definition of “first applicant” to more clearly incorporate the defined term “substantially complete application.” As revised, a first applicant is an ANDA applicant that, on the first day on which a substantially complete application containing a paragraph IV certification is submitted for approval of a drug, submits a substantially complete application that contains, and for which the applicant lawfully maintains, a paragraph IV certification for the drug.

V.A.6. Definition of “Postmark”

We proposed to define the term “postmark” 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 proposed § 314.3(b) and section 505(b)(3)(B)(i) and 505(j)(2)(B)(ii)(I) of the FD&C Act). The purpose of the postmark is to establish a verifiable date from which the 20-day notice period runs. In light of the transition by FDA and regulated industry to electronic communications, FDA proposed to define 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 USPS 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 USPS 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. In the following paragraphs, we discuss two comments on this proposed definition. After considering these comments, we are finalizing the definition without change.

(Comment 7) One comment recommends that FDA provide ANDA applicants with the option to receive a paragraph IV acknowledgment letter by electronic transmission rather than first class mail to help ensure prompt receipt by the ANDA applicant irrespective of location. The comment suggests that this option may reduce the likelihood that an ANDA applicant would fail to send notice of paragraph IV certification within 20 days after the date of the postmark on the paragraph IV acknowledgment letter, and thereby avoid the administrative consequence described in proposed § 314.101(b)(4). Another comment notes that the proposed definition of postmark clarifies the date by which notice of paragraph IV certification must be sent when ANDA applicants receive a paragraph IV acknowledgment letter from FDA both by electronic mail and the USPS.

(Response 7) We agree that electronic transmission of a paragraph IV acknowledgment letter to an ANDA applicant may facilitate timely sending notice of paragraph IV certification. Our definition of “postmark” is intended to accommodate the electronic transmission of paragraph IV acknowledgment letters from FDA to 505(b)(2) and ANDA applicants in the future.

OGD currently sends an ANDA applicant or its authorized representative a paragraph IV acknowledgment letter (or an acknowledgment letter, if appropriate) in an envelope bearing a postmark made by the USPS. If the ANDA applicant or its authorized representative has provided an electronic mail address on Form FDA 356h, which accompanies each submission to the ANDA, OGD also sends a courtesy copy of the paragraph IV acknowledgment letter (or an acknowledgment letter, if appropriate) by electronic mail and subsequently archives the electronic communication. Upon the effective date of this final rule (see section VI), the date of FDA's electronic transmission of a paragraph IV acknowledgment letter to an ANDA applicant also will be the postmark described in section 505(j)(2)(B)(ii)(I) of the FD&C Act. We no longer intend to send a paragraph IV acknowledgment letter to an ANDA applicant by the USPS. Accordingly, we expect few circumstances in which there will be a question about which postmark controls for purposes of determining the date by which notice of paragraph IV certification must be sent. However, if an ANDA applicant (or, in the future, a 505(b)(2) applicant) receives a paragraph IV acknowledgment letter from FDA both by electronic mail and the USPS, the earlier postmark provides the controlling postmark.

Although the comment did not discuss 505(b)(2) applications, we note that FDA is committed to adapting its business practices to evolving technology and anticipates electronically transmitting paragraph IV acknowledgment letters to 505(b)(2) applicants in a manner that meets the requirements of the definition of postmark in the future.

V.A.7. Definition of “Tentative Approval”

We proposed to define “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 a listed drug has unexpired orphan drug exclusivity, 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 § 314.107(b)(1)(iii), (b)(3), or (c) are met, because the listed drug has a period of exclusivity under § 314.108 or section 505A of the FD&C Act, or because a court order under 35 U.S.C. 271(e)(4)(A) orders that the application may be approved no earlier than the date specified (see proposed § 314.3(b) and section 505(j)(5)(B)(iv)(II)(dd)(AA) of the FD&C Act). The proposed definition clarified 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. In the following paragraphs, we discuss a comment on this proposed definition. After considering this comment, we are revising the definition to describe an additional basis for tentative approval and making conforming revisions to §§ 314.101(e)(2), 314.105(a) and (d), and 314.107(b)(4) and (d).

(Comment 8) A comment requests that FDA update proposed § 314.107(d) to reflect that Generating Antibiotic Incentives Now (GAIN) exclusivity may delay approval of a 505(b)(2) application or ANDA, and that FDA make any other

necessary conforming revisions to the regulations.

(Response 8) We agree with the comment. Title VIII of the Food and Drug Administration Safety and Innovation Act (FDASIA) (Pub. L. 112-144), entitled GAIN, provides an exclusivity period extension for certain designated qualified infectious disease products in section 505E of the FD&C Act. We are revising the definition of “tentative approval” to indicate that approval of a 505(b)(2) application or ANDA also may be delayed by a period of exclusivity for the listed drug under section 505E of the FD&C Act. We are making similar revisions to our regulations on approval of an NDA or ANDA (§ 314.105(a) and (d)) and delay due to exclusivity (§ 314.107(d)). We are also revising our regulations on tentative approval to explain that FDA will issue a tentative approval letter when tentative approval is appropriate in accordance with § 314.107 (see § 314.107(b)(4)).

GAIN also extends by 5 years the 4-year period described in section 505(c)(3)(E)(ii) and (j)(5)(F)(ii) of the FD&C Act after which certain 505(b)(2) applications or ANDAs containing a paragraph IV certification may be submitted. Accordingly, we are revising § 314.101(e)(2) to remove the cross-reference to § 314.108(b)(2) and expressly state that FDA will refuse to file an NDA or will consider an ANDA not to have been received if submission of a 505(b)(2) application or an ANDA is not permitted under section 505(c)(3)(E)(ii), 505(j)(5)(F)(ii), or 505E(a) of the FD&C Act. For completeness, we are making a technical amendment to § 314.101(e)(2) to reference pediatric exclusivity under section 505A(b)(1)(A)(i)(I) and (c)(1)(A)(i)(I) of the FD&C Act, which extends by 6 months the 4-year period described in section 505(c)(3)(E)(ii) and (j)(5)(F)(ii) of the FD&C Act.

V.B. Submission of Patent Information (§ 314.53)

V.B.1. General Requirements for Submission of Patent Information (§ 314.53(b) and (c))

Section 314.53(b) of our regulations requires that an applicant submitting an NDA, an amendment to an NDA, or, except as provided in § 314.53(d)(2), a supplement to an approved application, submit the patent information described in § 314.53(c) to its NDA on Forms FDA 3542a and 3542 with the filing or upon and after approval, respectively. The information requested in Form FDA 3542 must be provided for any patent that claims the approved drug substance, approved drug product, or any approved 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. FDA publishes certain information from Form FDA 3542 in the Orange Book after approval of the NDA or the supplement. The following sections describe our proposed revisions to these regulations and our responses to the comments that we received on the proposed rule.

V.B.1.a.

Drug substance (active ingredient) and drug product (formulation or composition) patents.

We proposed to revise § 314.53(c)(1) to omit the reference to “complete” patent information and clarify that FDA will accept a submission of patent information on Forms FDA 3542a or 3542, as appropriate, that omits requested patent information if the omission is permitted under an exception in § 314.53(c)(2). We proposed 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 the requirements for submission of method-of-use patent information, need not identify each basis on which the patent claims the drug (see proposed § 314.53(c)(2)(i)(S) and (c)(2)(ii)(T)). Accordingly, if a patent is eligible for listing as claiming both the drug substance and the drug product, an applicant only would be required to identify one of these two bases for listing. We proposed to clarify that these proposed exceptions to the required submission of patent information do not alter the requirements for submission of method-of-use patent information (see proposed § 314.53(c)(2)(i)(O)(

3

) and (c)(2)(ii)(P)(

4

)).

One comment supports these streamlined requirements for listing patents that claim the drug substance and/or drug product in the Orange Book. In the following paragraphs, we discuss two other comments on these proposed revisions. After considering these comments, we are finalizing these requirements without change. We are making conforming revisions to § 314.53(c)(2)(ii) to replace the phrase “the patent declaration is incomplete” with “the patent declaration does not contain the required information.”

(Comment 9) One comment requests that FDA revise § 314.53(c)(1) to state that FDA will not accept patent information “unless and until” it is submitted on the appropriate form and contains the required information. The comment maintains that this revision would clarify that submission of patent information is considered complete only as of the date on which all required information has been submitted to FDA.

(Response 9) We decline to revise § 314.53(c)(1) as requested. FDA's existing regulations already require that if an NDA holder timely submits the required patent information, but FDA notifies the NDA holder that its Form FDA 3542 is incomplete or shows that the patent is not eligible for listing, the NDA holder must submit an acceptable Form FDA 3542 within 15 days of FDA's notification to be considered timely filed as of the date of the original submission of patent information (see § 314.53(c)(2)(ii)). FDA believes the current procedure is adequate to ensure timely and complete submission of patent information.

(Comment 10) One comment requests that FDA require additional detail regarding drug substance claims, where the drug product's active ingredient may not be self-evident. The comment also suggests that FDA require more detail regarding drug product claims to enable FDA to determine whether a new patent certification is required for a 505(b)(2) or ANDA applicant's change in product formulation and avoid an unwarranted opportunity for a 30-month stay.

(Response 10) The comment does not clearly describe the additional information requested or provide adequate support for any proposed change. FDA previously has explained that “identification of the relevant patent(s), as opposed to the individual patent claims (other than for method-of-use patents), satisfies the [FD&C Act's] explicit requirements [and] provides sufficient information to potential applicants to determine if a more thorough patent search or analysis is warranted” (“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; Final Rule” 68 FR 36676 at 36685, June 18, 2003). (The MMA superseded certain provisions of the 2003 Final Rule related to 30-month stays of approval; 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)).) Moreover, it is unnecessary for an NDA holder to submit more detailed patent information regarding drug product claims for purposes of determining whether a 505(b)(2) or

ANDA applicant must amend a previously submitted patent certification due to a change in the formulation of its proposed product because the 505(b)(2) or ANDA applicant has an independent duty to evaluate whether a previously submitted patent certification continues to be accurate after any change in the formulation of its proposed drug product. We also are adding §§ 314.60(f)(3) and 314.96(d)(3) to expressly describe when a change in product formulation requires an appropriate patent certification or a recertification (see section V.F.1).

V.B.1.b.

Drug substance patents that claim only a polymorph of the active ingredient.

We proposed to revise § 314.53(c)(2)(i)(M)(

2

) and (c)(2)(ii)(N)(

2

) to only require an applicant to provide information on whether the patent claims a polymorph (generally, a different crystalline or amorphous form of the same drug substance) that is the same active ingredient described in the NDA, amendment, or supplement if the only basis on which the patent is eligible for listing is that it claims the polymorph. We proposed conforming revisions to § 314.53(b)(1) and (2), (c)(2)(i)(M)(

3

), and (c)(2)(ii)(N)(

3

) to provide that the applicant's certification regarding test data required by § 314.53(b) applies only to patents that claim only a polymorph.

We received two comments that agreed with the proposed provision. In the following paragraphs, we discuss another comment on this proposed revision. After considering the comment, we are finalizing these revisions without change.

(Comment 11) One comment suggests that FDA require more specific information about the polymorph claimed in the patent that is the same active ingredient in the approved drug product to guide development of proposed products intended for submission in a 505(b)(2) application or ANDA.

(Response 11) The comment does not clearly describe the additional information requested; however, we disagree with the premise of the comment. FDA requires the NDA holder to submit information on Form FDA 3542 to enable the Agency to determine whether the patent or patent information is eligible for listing in the Orange Book based on the criteria in our regulations, to enable the Agency to implement section 505(b)(2)(B) and (j)(2)(A)(viii) of the FD&C Act, and to assist the Agency with its administrative listing responsibilities. The drug substance and drug product designation for listing of a patent in the Orange Book is not intended to define the scope of patent claims that an NDA holder or patent owner may assert in patent infringement litigation against a 505(b)(2) or ANDA applicant (see § 314.53(c)(2)(ii)(T)). Each 505(b)(2) or ANDA applicant is responsible for conducting its own analysis of the scope of relevant patents.

V.B.1.c.

Method-of-use patents.

We proposed to revise § 314.53(b)(1) to further clarify that an NDA applicant or holder may submit a single Form FDA 3542a or Form FDA 3542, as appropriate, for 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) of the patent claim(s) that corresponds to the pending or approved method of use.

We also proposed to revise our regulations to enhance compliance by NDA applicants and holders with the requirements for identifying the specific section(s) of product labeling that corresponds to the method of use claimed by the patent and, upon approval, describing the approved method of use claimed by the patent (the “use code”) required for publication in the Orange Book (see proposed § 314.53(b)(1), (c)(2)(i)(O)(

2

), (c)(2)(ii)(P)(

2

) and (

3

)). To address situations in which the scope of the method of use claimed by the patent is narrower than an indication or other condition of use described in product labeling, we proposed to 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 (see proposed § 314.53(b)(1)). We also proposed 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 (see proposed § 314.53(c)(2)(ii)(P)(

3

)). Finally, we proposed to codify the Agency's longstanding requirement that the NDA holder's use code 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 (see proposed § 314.53(c)(2)(ii)(P)(

3

)).

Several comments support FDA's proposed revisions to the regulations regarding the submission of information on method-of-use patents. In the following paragraphs, we discuss other comments on the submission of information on method-of-use patents. After considering all of these comments, we are making clarifying revisions to § 314.53(b)(1), (c)(2)(i)(O)(

1

) and (

2

), (c)(2)(ii)(P)(

1

) through (

3

), and (e), and conforming revisions to Forms FDA 3542a and 3542.

(Comment 12) One comment suggests that the Agency's proposal regarding the required content of the use code appears to shift to the NDA holder the Agency's burden of determining whether a 505(b)(2) or ANDA applicant is not seeking approval for a protected use. Another comment objects to FDA's requirement that the NDA holder's use code 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. The comment contends that this approach would require NDA holders to speculate about the protected uses that a prospective 505(b)(2) or ANDA applicant may seek to omit from labeling. Moreover, the comment asserts that this proposal is unworkable given that a 240-character use code may not adequately describe a series of patent claims of varying scope. The comment further notes that the use code does not obviate the need for the 505(b)(2) or ANDA applicant to evaluate the scope of the patent.

(Response 12) FDA disagrees with these comments regarding the content requirements for the use code. Given the Agency's ministerial role in patent listing, we require an NDA holder to provide adequate information about the scope of a listed method-of-use patent to assist 505(b)(2) and ANDA applicants in assessing whether the listed patent claims a use for which the 505(b)(2) or ANDA applicant is not seeking approval and to enable FDA to evaluate whether a proposed labeling carve-out is appropriate (see section 505(b)(2)(B) and (j)(2)(A)(viii) of the FD&C Act, respectively; see also

Caraco Pharm. Labs.

v.

Novo Nordisk A/S,

132 S. Ct. 1670, 1684 (2012) (“Use codes are pivotal to the FDA's implementation of the Hatch-Waxman Amendments”)).

We are finalizing the requirement in § 314.53(c)(2)(ii)(P)(

3

) that the NDA holder's description of the patented method of use required for publication 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, with punctuation changes and clarifying revisions to the parenthetical example. We also are

expressly requiring that the NDA holder's description of the patented method of use meets the statutory standard for an NDA holder's submission of patent information (see section 505(b)(1) and (c)(2) of the FD&C Act). As revised, the parenthetical text explains that if the method(s) of use claimed by the patent does not cover an indication or other approved condition of use in its entirety, then the NDA holder must describe only the specific approved method of use claimed by the patent for 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 (see § 314.53(c)(2)(ii)(P)(

3

)). We are making conforming revisions to § 314.53(b)(1). The use code must only describe a patented method of use that is described in FDA-approved product labeling because the scope of the approved conditions of use of a drug product is described in the FDA-approved product labeling. We generally describe this content requirement for the use code as the “specific approved method of use claimed by the patent.” The development of the use code does not require speculation about the protected uses that a prospective 505(b)(2) or ANDA applicant may seek to omit from labeling; rather, it simply requires the NDA holder to describe only the specific approved method(s) of use claimed by the patent. This requirement also does not shift to the NDA holder the Agency's burden of determining whether a 505(b)(2) or ANDA applicant is not seeking approval for a protected use. Based on the use code provided by the NDA holder, FDA determines the specific labeling that describes the protected use and decides whether a 505(b)(2) application can be approved with that information omitted from the labeling or, in the case of an ANDA, whether an ANDA that omits the protected information from the labeling will be rendered less safe or effective for its remaining non-protected conditions of use (see § 314.127(a)(7)).

Given that the majority of use codes listed in the Orange Book do not approach 240 characters, this limitation is not expected to affect the accuracy of the NDA holder's description of the specific approved method(s) of use claimed by the patent. Nevertheless, FDA is expanding the use code character limit to 250 characters because FDA's database system can accommodate this additional text. We agree that the use code is not intended to substitute for the 505(b)(2) or ANDA applicant's review of the patent and the approved labeling in making decisions about whether to challenge a listed patent, request a delay in approval until expiry of the listed patent, or not request approval for a use claimed by the listed patent.

(Comment 13) One comment recommends that FDA clarify the directions on Form FDA 3542 for submitting the use code to avoid potential confusion about whether the NDA holder's use code should be based on language from the approved labeling or from the patent claim(s).

(Response 13) FDA agrees with the recommendation to clarify the instructions on Form FDA 3542 and the related regulations regarding the use code. We are revising § 314.53(b)(1) to clarify the general requirement that the NDA holder's description of the patented method of use required by § 314.53(c)(2)(ii)(P)(

3

) must describe only the approved method(s) of use claimed by the patent (see Response 12 for a discussion of the “specific approved method of use claimed by the patent”). We also are revising § 314.53(c)(2)(i)(O)(

1

) and (c)(2)(ii)(P)(

1

) to remove the phrases “or related indication” and “or indication,” respectively, and supplementing § 314.53(c)(2)(ii)(P)(

3

) to clarify that the use code must describe only the specific approved method of use claimed by the patent. In other words, the scope of the use code must not extend beyond the scope of the patent claim(s) and, within the boundary established by the patent claim(s), the use code must only describe a patented method of use that has been approved by FDA as reflected in approved product labeling (see

Caraco Pharm. Labs.,

132 S. Ct. 1670 at 1683, n.7 (rejecting an argument that the use code may sweep more broadly than the patent based on the requirement to provide a description of each approved method of use

or indication

) (emphasis added)). Consistent with our clarifying revisions to § 314.53(c)(2)(ii)(P)(

3

), we are revising section 4.2b of Form FDA 3542 to state that the NDA holder must submit the description of the specific approved method of use claimed by the patent that is proposed for inclusion as the “use code” in the Orange Book. We also are making conforming revisions to § 314.53(e) to replace the phrase “approved indications or other conditions of use covered by a patent” with the “description of the method of use claimed by the patent as required by § 314.53(c)(2)(ii)(P)(

3

).”

(Comment 14) One comment proposes that FDA standardize use codes rather than relying on the NDA holder's description of the approved method of use claimed by the patent. Another comment recommends that FDA further describe its expectations for the content of use codes by providing hypothetical examples in which the patented method-of-use claim is broader, narrower, or co-extensive with an approved indication or other condition of use or that uses different terminology. The comment also suggests that FDA provide advice on the content of the use code where the method of use claimed by the patent is described in a section of labeling other than Indications and Usage.

(Response 14) We decline to adopt standardized use codes because we do not believe that standardized use codes would accurately capture the nuances of the method-of-use patent claims that NDA holders may submit to FDA for listing. FDA's role in listing patents remains ministerial (see “Abbreviated New Drug Application Regulations; Patent and Exclusivity Provisions; Final Rule,” 59 FR 50338 at 50349, October 3, 1994; see also 68 FR 36676 at 36687), and we continue to believe that there is a need for accurate and detailed information related to the approved methods of use claimed in the patent being submitted for listing (see 68 FR 36676 at 36682). Since 2003, when we began requiring NDA holders to submit the use code for publication in the Orange Book (see 68 FR 36676 at 36683), the Agency has gained significant experience in implementing section 505(b)(2)(B) and (j)(2)(A)(viii) of the FD&C Act based on the NDA holder's use code. Based on our experience, we are clarifying the use code requirements through this rulemaking. We expect that these clarifying revisions to our regulations will improve the accuracy of use codes. As the U.S. Supreme Court noted in

Caraco Pharm. Labs.:

“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). Although we decline to provide hypothetical examples, the following general principles illustrate the clarifying revisions to the regulations regarding the content of use codes.

•

Patented method of use is broader than an indication or other approved condition of use:

The use code must only describe a patented method of use that is described in FDA-approved product labeling. If the method of use claimed by the patent uses different terminology than the approved labeling and/or is broader than an indication or other approved condition of use, then the use code would need to be phrased more narrowly than the patent claim to

only describe the specific patented method of use that is described in FDA-approved product labeling.

•

Patented method of use is co-extensive with an indication or other approved condition of use:

The use code must describe only the specific approved method of use claimed by the patent.

•

Patented method of use is narrower than an indication or other approved condition of use:

If the method of use claimed by the patent does not cover an indication or other approved condition of use in its entirety, then the NDA holder must describe only the specific approved method of use claimed by the patent—not the broader indication or other approved condition of use that may include, but is broader than, the use claimed by the patent.

For example, Prandin (repaglinide) tablets currently are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus, and U.S. Patent No. 6,677,358 (358 patent) was listed in the Orange Book as claiming a method of using Prandin. In

Novo Nordisk A/S

v.

Caraco Pharm. Labs.,

the Federal Circuit explained that claim 4 of the 358 patent “claims `[a] method for treating non-insulin dependent diabetes mellitus (NIDDM) comprising administering to a patient in need of such treatment repaglinide in combination with metformin.' . . . An appropriate use code therefore must be limited to use of `repaglinide in combination with metformin' to treat NIDDM” (688 F.3d 766 at 768 (Fed. Cir. 2012)) (internal citation omitted). A similar approach would apply if the patented method of use is described in a section of labeling other than Indications and Usage. For example, if the patent claims a novel dosing regimen for a particular indication, the use code must specifically describe the protected dosing regimen for that indication and not only the indication to which the dosing regimen relates. Thus, if the method(s) of use claimed by the patent does not cover an indication or other approved condition of use in its entirety, an NDA holder's submission of a use code that describes an entire indication or other approved condition of use would violate FDA's regulations.

FDA requires the NDA holder to submit an accurate description, subject to the verification under penalty of perjury required by § 314.53(c)(2)(ii)(R), of the specific approved method of use claimed by the patent to implement section 505(b)(2)(B) and (j)(2)(A)(viii) of the FD&C Act. An inaccurate description of the approved method of use claimed by the patent (

e.g.,

one that incorrectly describes the entire indication or condition of use to which the patented method of use relates rather than the specific approved method of use claimed by the patent) would impede FDA's ability to make a scientific determination about whether a 505(b)(2) application or ANDA may be approved with labeling that omits the protected information corresponding to the use code.

As described in § 314.53(b)(1), each approved method of use claimed by the patent must be separately identified and thus will require separate listing(s) of method-of-use information in section 4 of Form FDA 3542. We are revising Forms FDA 3542 and 3542a to facilitate separate listings of method-of-use information. We also are revising § 314.53(c)(2)(ii) to clarify the Agency will not list or publish patent information if it is not provided on Form FDA 3542.

(Comment 15) One comment requests that FDA clarify the level of detail with which an NDA applicant must identify 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. Another comment recommends that FDA replace the term “specific sections” with “specific language” and eliminate the parenthetical text in proposed § 314.53(c)(2)(i)(O)(

2

) and (c)(2)(ii)(P)(

2

) to clarify that the protected use may encompass less than the entirety of one of the “sections” of the product labeling. This comment also recommends that FDA replace the phrase “corresponds to the method of use claimed by the patent” with “is claimed by the method of use claimed by the patent” in proposed § 314.53(b)(1), (c)(2)(i)(O)(

2

), and (c)(2)(ii)(P)(

2

) to result in a more accurate identification of the specific labeling that describes a protected method of use.

(Response 15) FDA agrees that the regulations should clearly define the requirement to identify the specific labeling that describes the method of use claimed by the patent. FDA is revising its regulations to clarify that, for approved NDAs, the NDA holder submitting information on the method-of-use patent must identify with specificity the section(s) and subsection(s) of the approved labeling that describe the method(s) of use claimed by the patent submitted (see § 314.53(b)(1)). FDA is making conforming revisions to § 314.53(c)(2)(ii)(P)(

2

) and section 4.2a of Form FDA 3542 with respect to approved labeling, and to § 314.53(c)(2)(i)(O)(

2

) and section 4.2a of Form FDA 3542a with respect to proposed labeling.

Identifying the section(s) and subsection(s) of the approved labeling with specificity means listing on Form FDA 3542 (or, with respect to proposed labeling, Form FDA 3542a) each section and subsection of labeling that contains information describing the patented method of use.

• For prescription drug products with labeling in the “physician labeling rule” (PLR) format (see “Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products,” 71 FR 3922, January 24, 2006), the section(s) and subsection(s) of the approved labeling should be identified by the section and subsection number (see 21 CFR 201.56(d) and 201.57). For example, “section 1, subsection 1” refers to the first indication listed in approved product labeling (see § 201.57(c)(2)).

• For prescription drug products with labeling not in PLR format, the section(s) and subsection(s) of the approved labeling should be identified by the section and subsection title (see §§ 201.56(b) and (e) and 201.80).

• For nonprescription drug products, the section(s) and subsection(s) of the approved labeling should be identified by the section and subsection title (see 21 CFR 201.66).

An NDA holder should evaluate whether FDA-approved revisions to product labeling (

e.g.,

conversion to PLR format) warrant submission of a revised Form FDA 3542 for the purpose of updating section 4.2a.

FDA agrees that the protected use may comprise less than the entirety of a section or subsection of the approved product labeling. However, it is unnecessary to require an NDA holder to identify the specific language in approved product labeling that describes the patented method of use because the use code and identification of the specific section(s) and subsection(s) of labeling that describe the patented method of use are sufficient for FDA to evaluate a 505(b)(2) or ANDA applicant's proposed labeling. Accordingly, FDA declines to replace the term “specific sections” with “specific language” in § 314.53(c)(2)(i)(O)(

2

) and (c)(2)(ii)(P)(

2

). FDA is removing the parenthetical text in proposed § 314.53(c)(2)(i)(O)(

2

) and (c)(2)(ii)(P)(

2

) because it is unnecessary in light of other clarifying revisions to the regulations regarding the use code.

If a 505(b)(2) or ANDA applicant submits a statement under section 505(b)(2)(B) and (j)(2)(A)(viii) of the FD&C Act, FDA evaluates the 505(b)(2) or ANDA applicant's proposed labeling

to determine whether the applicant is not seeking approval for the protected use based on the use code submitted by the NDA holder and with reference to the labeling section(s) and subsection(s) identified by the NDA holder. FDA determines the specific labeling that describes the patented method of use, and decides whether the 505(b)(2) application can be approved with that information omitted from the labeling or, in the case of an ANDA, whether an ANDA that carves out the protected information from the labeling would be rendered less safe or effective than the listed drug for the remaining non-protected conditions of use and preclude approval (see § 314.127(a)(7)). For example, FDA has determined that it can approve ANDAs for broad, general indications that may partially overlap with a protected method of use, as long as any express references to the protected use are omitted from the labeling (see

Hospira, Inc.

v.

Burwell,

2014 WL 4406901 at *17 (D. Md., Sept. 5, 2014) (upholding FDA's interpretation of section 505(j)(2)(A)(viii) of the FD&C Act)). Although identification of the section(s) and subsection(s) of labeling identified by the NDA holder may assist FDA in exercising its scientific judgment to implement section 505(b)(2)(B) and (j)(2)(A)(viii) of the FD&C Act, FDA is not bound by the section(s) and subsection(s) identified by the NDA holder in section 4.2a of Form FDA 3542 in making its determination. FDA will use its independent scientific judgment to determine which section(s) and/or subsection(s) of labeling contain language that must be carved out based on the use code provided.

FDA agrees that the identified section(s) and subsection(s) of labeling should not merely “correspond” to the method of use claimed by the patent because the term “correspond” could be interpreted in an inappropriately broad manner. To enhance accuracy, FDA is revising § 314.53(b)(1), (c)(2)(i)(O)(

2

), and (c)(2)(ii)(P)(

2

) to require that the identified section(s) and subsection(s) of labeling “describe” the method of use claimed by the patent.

(Comment 16) One comment recommends that FDA require NDA holders to resubmit patent information on the updated Form FDA 3542 for all currently listed patents to maintain or revise the Orange Book listing. This comment also suggests that FDA request public comment on revisions to Forms FDA 3542a and 3542 to conform with the changes described in the proposed rule.

(Response 16) We disagree with the recommendation to require NDA holders to resubmit Form FDA 3542 for all currently listed patents to maintain their current Orange Book listings. Given that over 10,000 patent listings appear in the Orange Book, this recommendation would impose a significant burden on NDA holders and the Agency without a commensurate benefit. If a person seeks to confirm the accuracy or relevance of patent information currently listed in the Orange Book in light of the patent listing requirements set forth in § 314.53(b)(1) and (c), the person may submit a patent listing dispute under § 314.53(f)(1) (see section V.B.4.a). NDA applicants and holders will be required to submit patent information on the updated Forms FDA 3542a and 3542 on a prospective basis.

FDA requested public comment on its proposed revisions to the regulations and has made certain changes to the regulations in response to those comments. FDA is revising Forms FDA 3542a and 3542 to conform to the requirements established by this final rule.

V.B.1.d.

Patents previously submitted for listing.

We proposed to revise § 314.53(c)(2)(i)(J) and (c)(2)(ii)(K) to remove the requirement that an applicant provide information on whether the patent has been submitted previously for the NDA or supplement. We received no comments regarding this proposed revision; however, we have decided not to finalize this proposed change. Instead, we have decided to retain the existing requirement to assist the Orange Book staff with updating listed patent information where appropriate (see 68 FR 36676 at 36686 and “Agency Information Collection Activities; Submission for [OMB] Review; Comment Request; Applications for [FDA] Approval to Market a New Drug . . . ,” 72 FR 21266 at 21269, April 30, 2007).

V.B.1.e.

Reissued patents.

We proposed to require an NDA holder to submit additional information on patents that have been reissued by the USPTO under 35 U.S.C. 251. We proposed that an NDA applicant or holder must include information on whether a patent submitted for listing is a reissuance of a patent previously submitted for listing for the NDA or supplement (see proposed § 314.53(c)(2)(i)(J) and (c)(2)(ii)(K)). Our proposal reflected our consideration of 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. In the following paragraphs, we discuss three comments on this proposal (see section V.E.3 for a discussion of comments on patent certification requirements for reissued patents). After considering these comments, we are not finalizing this proposal.

(Comment 17) The first comment recommends that FDA reevaluate its proposed regulations on reissued patents in light of a recent court decision rejecting FDA's “single bundle of patent rights” approach in a case involving the pre-MMA version of the FD&C Act. The second comment suggests that FDA further consider its “single bundle of patent rights” approach given the possibility for issuance of multiple patents based on continuing applications referring to the original patent application. The third comment supports the business certainty provided by FDA's “single bundle of patent rights” approach because the requirement for a 505(b)(2) or ANDA applicant to provide an appropriate patent certification or statement for a reissued patent would be governed by the provisions regarding untimely filed patents if either the original patent or the reissued patent was late-listed as to a pending 505(b)(2) application or ANDA.

(Response 17) FDA agrees that the “single bundle of patent rights” approach reflected in its proposed regulations on reissued patents should not be finalized in light of the recent decision in

Mylan Pharms., Inc.

v.

FDA,

594 Fed. Appx. 791 (4th Cir. Dec. 16, 2014). In

Mylan,

the Court determined that a reissued patent “is a separate grant of rights, even if elements of the reissued patent overlap with those of the original patent” (see 594 Fed. Appx. 791 at 797). The Court held that the statutory reference to “the patent which is the subject of the certification” in the pre-MMA version of section 505(j)(5)(B)(iv) of the FD&C Act means that each patent (original and/or reissued) that is the subject of a paragraph IV certification may be a basis for eligibility for 180-day exclusivity.

Although the

Mylan

decision involved the pre-MMA version of the FD&C Act (in which eligibility for 180-day exclusivity was evaluated on a patent-by-patent basis), the Court's interpretation of “the patent which is the subject of the certification” is relevant to the current version of the FD&C Act when determining eligibility for first applicant status under the MMA's 180-day exclusivity scheme (see

section 505(j)(5)(B)(iii) of the FD&C Act). Accordingly, the Agency now considers reissued patents as separate and distinct from the original patent for purposes of administering the patent certification requirements of the FD&C Act and any 30-month stay of approval or 180-day exclusivity. Given that a reissued patent will be treated no differently than an original patent, it is unnecessary for FDA to require that an NDA holder's submission of patent information include information on whether the patent is a reissued patent of a patent previously submitted for listing, and we are not finalizing proposed § 314.53(c)(2)(i)(J) and (c)(2)(ii)(K).

Upon patent reissuance, the original patent is surrendered and ceases to have legal effect (see 37 CFR 1.178(a)). Thus, an NDA holder is required to withdraw the original patent and request that the original patent be removed from listing in the Orange Book after patent reissuance (see § 314.53(f)(2)). Consistent with our policy for any request to remove a patent from listing in the Orange Book, an original patent that has been reissued would remain listed in the Orange Book until FDA determined that no first applicant is eligible for 180-day exclusivity based on a paragraph IV certification to that patent or after the 180-day exclusivity period of a first applicant based on that patent has expired or has been extinguished.

V.B.2. When and Where To Submit Patent Information (§ 314.53(d))

V.B.2.a.

Submission of patent information for NDA supplements (§ 314.53(d)(2)).

We proposed to revise § 314.53(d)(2) to create two broad categories of supplements for purposes of required submission of patent information. For supplements that seek approval for a change that would result in a new entry in the Orange Book (

e.g.,

a change to the dosage form, route of administration, strength, or prescription drug status), we proposed that an applicant would continue to submit the complete patent information required under § 314.53(c) with submission of the supplement and following approval, respectively. For supplements that seek approval for another type of change (

e.g.,

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 that would not result in a new entry in the Orange Book), we proposed that the patent information submission requirements would depend on whether the existing patent information submitted to FDA for the product approved in the original NDA continued to claim the changed 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 proposed that we would permit an applicant to submit a statement declaring that the patent(s) currently listed for a specific NDA (identified by NDA number and product number as listed in the Orange Book) continue to 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 § 314.53(c)(2)(i)(Q) and (c)(2)(ii)(R) and if patent information required by § 314.53(c)(2)(ii) previously was submitted. If, however, a listed patent no longer claims the product as changed by the supplement, then we proposed that the applicant must submit a request to correct or remove the patent information from the list at the time of approval of the supplement (see proposed § 314.53(f)(2)). Correspondingly, if one or more existing patents claim the product as changed by the supplement and this patent information has not been submitted to FDA, we proposed that the applicant must submit the patent information with the supplement and following approval of the supplement. We proposed a conforming revision to § 314.70(f) to clarify that an applicant that submits a supplement to an NDA also must comply with the patent information requirements under § 314.53.

One comment supports the proposal because it would reduce duplicative submissions of patent information for supplements. We are finalizing proposed § 314.53(d)(2)(i) with an editorial change to clarify that § 314.53(d)(2)(i)(A) and (B) also apply to a supplement that seeks to add (rather than change) a dosage form, route of administration, or strength. To facilitate implementation of this provision, we are revising § 314.53(c)(2)(i)(F) and (c)(2)(ii)(F) to require that the NDA applicant or holder, respectively, identify the dosage form(s), route(s) of administration and whether the drug is proposed or approved for prescription use or over-the-counter (OTC) use in its submission of patent information. We are making conforming revisions to Forms FDA 3542a and 3542.

We are making several clarifying revisions to proposed § 314.53(d)(2)(ii). The proposed rule explained that we would permit an NDA holder to submit a statement declaring that the patent(s) currently listed for a specific NDA continue to claim the drug or method of using the drug for which approval is sought in the NDA supplement (instead of resubmitting the patent information with the NDA supplement), if this statement is accompanied by a signed patent declaration verification (see 80 FR 6802 at 6823). Consistent with the intent of the proposed rule to reduce duplicative submissions of patent information and enhance efficiency, we are not requiring an NDA holder to submit a statement with an NDA supplement if the NDA holder is not required to resubmit patent information pursuant to § 314.53(d)(2)(ii)(A). Accordingly, if an NDA supplement is approved for a change other than one of the changes listed in § 314.53(d)(2)(i) and the NDA holder does not submit Form FDA 3542 or submit a request to withdraw the patent or patent information from the list under § 314.53(f)(2)(iv) (see § 314.53(d)(2)(ii)(B) and (C)), FDA will consider the NDA holder to have affirmed that any currently listed patent(s) continues to claim the drug product as changed by the supplement. We are revising § 314.53(d)(2)(ii)(A) to clarify that patent information already submitted to FDA refers to information required by § 314.53(c). We also are revising § 314.53(d)(2)(ii)(A) to clarify that the requirement to resubmit patent information with a supplement if the description of the patented method of use would change upon approval of the supplement refers to the published description of the patented method of use (

i.e.,

the use code).

We are making a conforming revision to § 314.53(c) to clarify that if the applicant submits a supplement for a change other than one of the changes listed under § 314.53(d)(2)(i), then the patent information submission requirements of § 314.53(d)(2)(ii) apply (see § 314.53(c)(2)(i)(S)(

3

) and (c)(2)(ii)(T)(

3

)).

V.B.2.b.

Untimely filing of patent information (§§ 314.53(d)(3), 314.50(i)(4), and 314.94(a)(12)(vi)).

We proposed to revise our regulations regarding the submission of information on patents issued after the approval of an NDA or supplement to expressly describe our longstanding practice with respect to listing patent information that is not timely filed (see proposed § 314.53(d)(3)). Proposed § 314.53(d)(3) stated that if a patent is issued after approval and 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 §§ 314.50(i)(4) and (6) and 314.94(a)(12)(vi) and (viii). We also proposed to revise §§ 314.50(i)(4) and 314.94(a)(12)(vi) to state that, except as provided in § 314.53(f)(1), an NDA holder's amendment to the description of the approved method(s) of use claimed by the patent (“use code”) 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.

Two comments agreed with this proposal. In the following paragraphs, we discuss two other comments on the proposal for certain amendments to the description of the approved method of use claimed by the patent to be considered untimely filing of patent information. After considering these comments, we are making clarifying revisions to the regulations and describing an additional set of circumstances in which an NDA holder's amendment to the description of the approved method(s) of use claimed by the patent will not be considered untimely filing of patent information.

(Comment 18) One comment recommends that FDA withdraw its proposal, given that changes in patent law or interpretation, developments in patent-specific litigation, and/or proceedings before the USPTO may affect the scope of a patent claim's coverage and necessitate revisions to the use code. The comment notes that these events typically occur more than 30 days after patent issuance and do not involve a corresponding change in product labeling. Another comment recommends that FDA reevaluate its proposal to consider certain changes to the use code as untimely filed patent information in light of the lack of clarity on setting use codes.

(Response 18) We decline to withdraw our proposal given the important role of use codes in enabling a 505(b)(2) or an ANDA applicant to state that it is not seeking approval for the method of use claimed by the patent (see section 505(b)(2)(B) and (j)(2)(D)(viii) of the FD&C Act). However, we agree that revisions to the use code may be appropriate in other limited circumstances, as reflected in our revisions to §§ 314.50(i)(4) and 314.94(a)(12)(vi). Our approach is intended to enhance the accuracy of use codes and ensure that 505(b)(2) and ANDA applicants have timely notice of changes to the asserted patent coverage for a listed drug, while reducing opportunities for manipulation of patent use codes.

As a preliminary matter, we are revising the regulations to more clearly describe the circumstances in which an NDA holder's amendment to the description of the approved method(s) of use claimed by the patent will not be considered untimely filing of patent information (see §§ 314.50(i)(4)(i)(A) and (B) and 314.94(a)(12)(vi)(A)(

1

) and (

2

)). As revised, an NDA holder's amendment to the description of the approved method(s) of use claimed by the patent will be considered timely filed if it is submitted within 30 days of patent issuance or within 30 days of approval of a corresponding change to product labeling. We also are revising the regulations to provide that an NDA holder's amendment to the description of the approved method(s) of use claimed by the patent will be considered timely filed patent information if it is submitted within 30 days of a decision by the USPTO or a Federal court that is specific to the patent and alters the construction of a method-of-use claim(s) of the patent (see §§ 314.50(i)(4)(i)(C) and 314.94(a)(12)(vi)(A)(

3

)). The amendment must contain a copy of the USPTO or court decision, and the accompanying Form FDA 3542 must identify the decision as a change related to the patent in section 1.h of the form (see the following discussion regarding revisions to § 314.53(c)(2)(i)(K) and (c)(2)(ii)(L)).

Our addition of §§ 314.50(i)(4)(i)(C) and 314.94(a)(12)(vi)(A)(

3

) permits NDA holders to make timely revisions to the use code based on a patent-specific decision by the USPTO (

e.g.,

inter partes review, post-grant review, and reexamination) or by a Federal court (

e.g., Markman

hearing) that construes the terms of the patent claim(s). An NDA holder may submit a revised use code based on a patent-specific decision by either a Federal district court, the Court of Appeals for the Federal Circuit, or the U.S. Supreme Court. We decline to broaden the scope of this provision to allow for use code changes to be considered timely filed based solely on changes in patent law or interpretation that are not specific to the patent for which the use code was submitted because we are not experts in patent law and would be unable to evaluate arguments that could effectively remove the limitation for untimely filing of method-of-use patent information.

Our clarifying revisions to the regulations are expected to address concerns about how to set use codes, and there is no need to reevaluate our proposal on this basis.

To facilitate implementation of this provision, FDA is revising § 314.53(c)(2)(i)(K) and (c)(2)(ii)(L) to require that if the patent has been submitted previously for listing, the NDA holder must identify all change(s) from the previously submitted patent information and specify whether the change is related to the patent (

e.g.,

patent term extension or patent-specific decision by the USPTO or a Federal court) or related to an FDA action or procedure (

e.g.,

FDA approval of a supplement that changes the approved conditions of use of the drug). This information will assist the Orange Book staff in updating listed patent information where appropriate and replaces the current requirement that an applicant only identify whether the expiration date is a new expiration date.

We also are making technical amendments in §§ 314.50(i)(4) and 314.94(a)(12)(vi) to explain that a 505(b)(2) or ANDA applicant generally is not required to submit a patent certification

or statement

to address the patent or

patent information

that is late-listed with respect to the pending 505(b)(2) application or ANDA. Although a patent certification or statement generally would not be required in this circumstance, 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, an ANDA applicant may wish to submit a paragraph IV certification to challenge the method-of-use patent with the revised use code if the applicant may be eligible for 180-day exclusivity based on that certification.

V.B.2.c.

Where to send submissions of Forms FDA 3542a and 3542 (§ 314.53(d)(4)).

We proposed to clarify that patent information submitted on Form FDA 3542a with the filing of an NDA, amendment, or supplement must be submitted to the CDER Central Document Room, and should not be submitted to the Orange Book staff (see proposed § 314.53(d)(4)(i); see also §§ 314.50(h) and 314.70(f)). We also proposed to require that patent information submitted 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. Our proposal to designate the OGD Document Room as the official repository for submission of Form FDA 3542 was intended to facilitate prompt listing of patent information in the Orange Book after Form FDA 3542 has been officially

received by the Agency (see proposed § 314.53(d)(4)(ii) and (d)(5)).

In the following paragraphs, we discuss a comment on these proposed revisions. After considering this comment, we are finalizing § 314.53(d)(4)(ii) with revisions to maintain the CDER Central Document Room as the official repository for submission of Form FDA 3542 and we are finalizing § 314.53(d)(4)(i) and (ii) to clarify that Forms FDA 3542a and 3542 can be submitted electronically. We also are finalizing § 314.53(d)(4)(i) and (ii) with an editorial correction to the title of Forms FDA 3542a and 3542, and we are making the same correction in § 314.53(f)(2)(ii) through (iv).

(Comment 19) One comment requests confirmation that NDA holders may submit Form FDA 3542 to the OGD Document Room through the Electronic Submissions Gateway (ESG). The comment also recommends that FDA clarify that Form FDA 3542a must be submitted to the NDA via CDER's Central Document Room.

(Response 19) FDA is revising § 314.53(d) to expressly provide that Form FDA 3542 can be submitted in an electronic format submission that complies with § 314.50(l)(5), which permits submission through the ESG. This revision and the corresponding revision to § 314.53(d)(5) are intended to clarify how submission dates are determined for Form FDA 3542, given the implications of untimely filing of patent information on the patent certification obligations of 505(b)(2) and ANDA applicants that rely upon the listed drug (see §§ 314.50(i)(4) and 314.94(a)(12)(vi)). Beginning in May 2017, Form FDA 3542 and other submissions under section 505(b), (i), and (j) of the FD&C Act must be submitted in the electronic format specified by FDA (see section 745A(a) of the FD&C Act (21 U.S.C. 379k-1(a)) and guidance for industry entitled “Providing Regulatory Submissions in Electronic Form—Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications” (May 2015), available at

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

). Accordingly, we only have specified the method of submission where it is important to describe how receipt dates or submission dates are determined for a particular type of submission.

Based on the transition to electronic submission of Form FDA 3542 and related changes in FDA's administrative processes, we are not finalizing our proposal to change the official repository for submission of Form FDA 3542. Thus, Form FDA 3542 must continue to be submitted to the NDA via the CDER Central Document Room or the ESG. The CDER Central Document Room and the ESG promptly direct submissions of Form FDA 3542 to the Orange Book staff for listing in the Orange Book. To ensure that patents and patent information are listed in the Orange Book only after Form FDA 3542 has been officially received by FDA, the Orange Book staff intends to rely only on submissions of Form FDA 3542 that are received from the Central Document Room and disregard any duplicate copies or courtesy copies of Form FDA 3542 that are submitted through other channels. We are revising § 314.53(d)(4)(ii) to emphasize that Form FDA 3542 should not be submitted to the Orange Book staff.

V.B.2.d.

Submission date of patent information (§ 314.53(d)(5)).

We proposed to revise § 314.53(d)(5) to establish 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 through the ESG (

i.e.,

at the completion of electronic transmission). We proposed that patent information sent to another location at FDA would not be considered received by FDA for purposes of § 314.53(d)(3) on timely filing and a 505(b)(2) or ANDA applicant's patent certification obligations pursuant to § 314.50(i)(4) and (6) or § 314.94(a)(12)(vi) and (viii), respectively, unless it is sent to the official repository identified in the regulation. In the following paragraphs, we discuss two comments on this provision. After considering these comments, we are finalizing § 314.53(d)(5) with revisions unrelated to the comments to conform to the changes made to § 314.53(d)(4)(ii).

(Comment 20) One comment suggests that FDA provide a list of untimely filed patent information to facilitate evaluation of patent certification obligations by 505(b)(2) and ANDA applicants. Another comment recommends that FDA include in the Orange Book the date on which the patent information was submitted to FDA.

(Response 20) FDA agrees that modifying the Orange Book to list the date on which patent information was submitted to FDA as described in § 314.53(d)(5) would enable applicants to determine whether a patent is late-listed as to a pending 505(b)(2) application or ANDA and avoid the need for applicants to contact the Orange Book staff for this information. FDA intends to list the date of submission of patents and patent information in the Orange Book on a prospective basis beginning as soon as practicable after the effective date of this rule. This addition to the Orange Book does not require any modification to the regulations. FDA does not intend to separately publish a list of untimely filed patent information.

V.B.3. Public Disclosure of Patent Information (§ 314.53(e))

We proposed technical corrections to § 314.53(e) to delete the reference to monthly supplements to the Orange Book and clarify that copies of the “submitted patent information” (rather than copies of the “file”) may be requested from FDA's Freedom of Information Staff. We also proposed to expressly state that the submitted patent information, and requests for delisting patents, will be subject to public disclosure (see proposed § 314.53(e)). In the preamble to the proposed rule, we explained that FDA may elect to proactively post on FDA's Web site a copy of the submitted patent information (Form FDA 3542) for listed patents in advance of a request under the Freedom of Information Act (FOIA) based on our anticipation of requests for this information. In the following paragraphs, we discuss a comment on the potential for proactive posting of Form FDA 3542 on FDA's Web site. After considering this comment, we are making an editorial correction to clarify the information that may be subject to public disclosure.

(Comment 21) One comment urges FDA not to proactively post Form FDA 3542 on the FDA Web site based on concerns that the patent information could be misused or lead to misinterpretation of the scope of relevant patent rights in litigation or commercial contexts.

(Response 21) FDA is not persuaded by the comment, given that Form FDA 3542 must contain the verification required by § 314.53(c)(2)(ii)(R) and may be subject to disclosure under FOIA and applicable disclosure regulations. Moreover, FDA has advised prospective 505(b)(2) and ANDA applicants that the use code and other information provided on Form FDA 3542 is not meant to substitute for the applicant's review of the patent. However, at this time, FDA does not intend to proactively post Form FDA 3542 for patent information submitted for listing in the Orange Book because there is an adequate mechanism to obtain a Form FDA 3542 on an individual basis through a FOIA request. We are revising § 314.53(e) to clarify that the submitted

patent information and requests to remove a patent or patent information from the list may be subject to public disclosure.

V.B.4. Correction or Change of Patent Information (§ 314.53(f))

V.B.4.a.

Requests by persons other than the NDA holder (§ 314.53(f)(1)).

We proposed to revise § 314.53(f) to clarify and improve the mechanism for challenging the accuracy or relevance of patent information submitted to the Agency under § 314.53 and listed in the Orange Book (see proposed § 314.53(f)(1)). First, we proposed to establish a 30-day timeframe in which the NDA holder would be required to respond to FDA's request to confirm the correctness or omission of patent information to facilitate timely resolution of the patent listing dispute. Second, we proposed enhanced procedures to govern challenges to the accuracy or relevance of an NDA holder's submission of method-of-use patent information so that the Agency has additional information to implement section 505(b)(2)(B) and (j)(2)(A)(viii) of the FD&C Act in cases where the accuracy or relevance of the use code is disputed (see proposed § 314.53(f)(1)).

For a patent listing dispute regarding method-of-use patent information, we proposed to ask the NDA holder to 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 would enable the Agency to make a determination in accordance with section 505(b)(2)(B) or (j)(2)(A)(viii) of the FD&C Act (see proposed § 314.53(f)(1)). We proposed that if the NDA holder confirms the accuracy of its submitted patent information in response to FDA's request, fails to timely respond to the request, 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, FDA would 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 such a case, we explained that FDA would 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 §§ 314.94(a)(8)(iv) and 314.127(a)(7), as appropriate.

Two comments support FDA's proposed revisions to the patent listing dispute procedure. In the following paragraphs, we discuss several other comments on this proposal. After considering these comments, we are revising § 314.53(f)(1) to describe the rules that will apply to patent listing disputes involving drug substance, drug product, and method-of-use claims. We also are revising § 314.53(c)(2)(ii)(R) to expressly state that the requirement to verify the accuracy and completeness of the submission of patent information applies to a response to a patent listing dispute under § 314.53(f)(1). We intend to take a stepwise approach and evaluate whether FDA's revisions to the regulations on submission of method-of-use patent information (see § 314.53(b)(1) and (c)(2)) and patent listing dispute procedures adequately address the problem of overbroad and ambiguous use codes before we establish a process to review a proposed labeling carve-out with deference to the 505(b)(2) and/or ANDA applicant(s)' interpretation of the scope of the patent. Therefore, at this time, we are not finalizing our proposal to review a proposed labeling carve-out with deference to the applicant(s)' interpretation of the scope of the patent in certain circumstances. We will continue to consider whether there is a need to finalize this proposal in the future.

(Comment 22) Three comments indicate that there are inconsistencies between the text of proposed § 314.53(f) and the process described in the corresponding preamble, and request that FDA clarify the circumstances in which the Agency proposes to review a proposed labeling carve-out for a 505(b)(2) application or ANDA with deference to the 505(b)(2) or ANDA applicant's interpretation of the scope of the patent. Several comments contend that it is inappropriate to defer to the 505(b)(2) or ANDA applicant's interpretation of the scope of the patent where the NDA holder has confirmed the accuracy of the use code. One comment asserts that this approach will encourage 505(b)(2) and ANDA applicants to routinely dispute method-of-use patent information in an attempt to receive deference on a narrow interpretation of the method-of-use patent and submit a statement under section 505(b)(2)(B) or (j)(2)(A)(viii) of the FD&C Act instead of a patent certification. One comment also contends that the Agency's standard for determining that an NDA holder's revision to the use code “does not provide adequate clarity” or determining that there is “insufficient information” to evaluate a proposed labeling carve-out is impermissibly vague.

(Response 22) FDA has made multiple changes to address the issue of overbroad and ambiguous use codes, including revisions to the regulations on submission of patent information and revisions to the patent listing dispute procedures (see sections V.B.1.c and V.B.2.b). We initially intend to evaluate whether these revisions to the regulations adequately address the problem of overbroad and ambiguous use codes. If these revisions to our regulations do not adequately address the problem, we will further consider whether to finalize the proposal to review a proposed labeling carve-out for a 505(b)(2) application or ANDA with deference to the 505(b)(2) and/or ANDA applicant(s)' interpretation of the scope of the patent. If FDA decides to finalize the proposal, FDA would clarify the process and the circumstances in which such deference may be given.

We are revising the regulation to provide a more detailed description of the procedure for patent listing disputes directed to the accuracy or relevance of submitted patent information regarding an approved method of using the drug product (see § 314.53(f)(1) and (f)(1)(i)(B); see also § 314.53(f)(1)(i)(A) (describing patent listing dispute procedures directed to drug substance or drug product claims)). We also are revising § 314.53(c)(2)(ii)(R) to expressly state that the requirement that an NDA holder verify the accuracy and completeness of the submission of patent information applies to a response to a request under § 314.53(f)(1). This regulatory approach is intended to provide the Agency with additional information to facilitate implementation of section 505(b)(2)(B) and (j)(2)(A)(viii) of the FD&C Act (see section 701(a) of the FD&C Act).

For all patent listing disputes, we are requiring that the patent listing dispute communication contain a statement of dispute that describes the specific grounds for disagreement regarding the accuracy or relevance of patent information for FDA to send to the applicable NDA holder. If a person disputes the accuracy or relevance of submitted patent information regarding an approved method of using the drug product, this statement of dispute must be only a narrative description (no more than 250 words) of the person's

interpretation of the scope of the patent with respect to the method of use.

FDA intends to forward the statement of dispute (without review or redaction) to the applicable NDA holder using the electronic mail (email) address or facsimile (fax) number provided by the NDA holder on the most recent Form FDA 356h submitted to the NDA. Therefore, the person submitting the patent listing dispute communication should clearly identify the statement of dispute that he or she intends for FDA to send to the applicable NDA holder, and only include information for which the person consents to disclosure.

• For patent listing disputes directed to drug substance or drug product claims, the NDA holder must confirm the correctness of the patent information and include the signed verification required by § 314.53(c)(2)(ii)(R) or withdraw or amend the patent information in accordance with § 314.53(f)(2) within 30 days of the date on which the Agency sends the statement of dispute. Although proposed § 314.53(f)(1) would have permitted disputes over the omission of patent information, it is unnecessary for FDA to request the NDA holder to confirm the omission of patent information for a listed patent because we no longer require an NDA holder to identify whether a patent claims both the drug substance and the drug product (see § 314.53(c)(2)(ii)(T)). Accordingly, we are making a conforming amendment to remove the phrase “or omission of patent information” from § 314.53(f)(1)(i)(A). Unless the NDA holder withdraws or amends its patent information in response to the patent listing dispute, the Agency will not change the patent information in the Orange Book (see § 314.53(f)(1)(i)(A)).

• For patent listing disputes directed to method-of-use claims, the NDA holder must confirm the correctness of the NDA holder's description of the approved method of use claimed by the patent that has been included as the “use code” in the Orange Book or withdraw or amend the patent information in accordance with § 314.53(f)(2). In either case, the NDA holder must provide a narrative description (no more than 250 words) of the NDA holder's interpretation of the scope of the patent that explains why the existing or amended “use code” describes only the specific approved method of use claimed by the patent for 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 NDA holder must also include the signed verification required by § 314.53(c)(2)(ii)(R) and submit its response within 30 days of the date on which the Agency sends the statement of dispute (see § 314.53(f)(1)(i)(B)). Any response from the NDA holder that is submitted after 30 days will be considered untimely. The narrative description must only contain information for which the NDA holder consents to disclosure because FDA will send the text of the statement to the person who submitted the patent listing dispute without review or redaction to further assist the person (generally a 505(b)(2) or ANDA applicant, a prospective applicant, or its representative) in determining whether a use for which an applicant may seek approval is a protected use.

We are revising the regulation to clarify that if the NDA holder timely responds to the patent listing dispute with a confirmation of the correctness of the patent information, the narrative description required by § 314.53(f)(1)(i)(B), and the signed verification required by § 314.53(c)(2)(ii)(R), the Agency will not change the patent information in the Orange Book (see § 314.53(f)(1)(i)(B)(

1

)). We are also revising the regulation to more clearly state that if the NDA holder timely responds to FDA's request with revised patent information, the narrative description required by § 314.53(f)(1)(i)(B), and the signed verification required by § 314.53(c)(2)(ii)(R), FDA will update the Orange Book to reflect the revised patent information (see § 314.53(f)(1)(i)(B)(

2

) and Response 26). This approach provides additional clarity, and establishes a mechanism for a person (including a 505(b)(2) or ANDA applicant) to request that an NDA holder confirm compliance with the updated requirements for submission of patent information described in § 314.53(b) and (c).

A 505(b)(2) application or ANDA must contain an appropriate certification or statement for each listed patent, including the disputed patent, during and after the patent listing dispute (see § 314.53(f)(1)(ii)). A disputed method-of-use patent may continue to be the subject of a paragraph IV certification. We do not believe that an ongoing patent listing dispute process will have an impact on the timing of approval of a 505(b)(2) application or ANDA that is otherwise eligible for approval and relies on the listed drug for which the disputed patent is listed in the Orange Book. FDA may consider the narrative description from the NDA holder required by § 314.53(f)(1)(i)(B), as appropriate, to assist FDA in exercising its scientific judgment to implement section 505(b)(2)(B) and (j)(2)(A)(viii) of the FD&C Act.

To advise prospective and pending 505(b)(2) or ANDA applicants of a patent listing dispute involving a method-of-use patent, FDA will promptly post information about the patent listing dispute on a Web page linked to the Orange Book. FDA intends to provide information such as the relevant drug product, NDA number, NDA holder, U.S. Patent Number, relevant use code(s), and whether the NDA holder has timely responded to the patent listing dispute (see § 314.53(f)(1)(iii)).

(Comment 23) Three comments recommend that FDA withdraw or revise the proposal to review, in certain circumstances, a proposed labeling carve-out for a 505(b)(2) application or ANDA with deference to the 505(b)(2) or ANDA applicant's interpretation of the scope of the patent. One comment contends that there is no basis for FDA's proposed approach because the statutory scheme contemplates that disputes over the scope of a method-of-use patent will be resolved by Federal courts in patent infringement litigation, especially given that the MMA established a counterclaim procedure in which a 505(b)(2) or ANDA applicant may seek an order requiring the NDA holder to correct or delete the submitted patent information. Another comment maintains that it would be legally inappropriate for FDA to defer to the 505(b)(2) or ANDA applicant's view of the scope of a patent that the applicant does not own, especially if the NDA holder has confirmed the accuracy of the use code. Two comments suggest that when patent listing disputes arise, FDA should seek clarification or correction of patent information through other means.

(Response 23) We believe that FDA has the authority to establish a regulation describing the limited circumstances in which the Agency would defer to the 505(b)(2) or ANDA applicant's interpretation of the scope of a patent that it does not own. However, in light of the incremental approach that we are taking to this issue, we are not finalizing this aspect of our proposal at this time. We will continue to consider whether there is a need to finalize this proposal in the future.

The statutory provisions that permit a 505(b)(2) or ANDA applicant to submit a statement that a listed patent does not claim a use for which the applicant is seeking approval complement the patent certification requirements (see section 505(b)(2)(A) and (B) and (j)(2)(A)(vii)

and (viii) of the FD&C Act). FDA's revised regulations are intended to preserve FDA's ministerial role in listing patents (see 59 FR 50338 at 50349 and 68 FR 36676 at 36683 and 36687) and to also address ambiguous or overbroad use codes that could be a barrier to approval of a 505(b)(2) application or ANDA for uses that are not claimed by the listed patent (see § 314.53(b)(1), (c)(2)(ii)(P)(

3

), and (f)(1)). If an NDA holder provides a timely response to a patent listing dispute and a 505(b)(2) or ANDA applicant disagrees with the NDA holder's response to the patent listing dispute (or disagrees with the use code), the 505(b)(2) or ANDA applicant may submit a paragraph IV certification to challenge the method-of-use patent and assert a counterclaim in the context of an infringement action or pursue a declaratory judgment action, as appropriate, to obtain patent certainty (see section 505(c)(3)(D)(i) and (ii) and (j)(5)(C)(i) and (ii) of the FD&C Act).

We disagree, however, that the counterclaim procedure in section 505(c)(3)(D)(ii) and (j)(5)(C)(ii) of the FD&C Act obviates the need for an enhanced patent listing dispute procedure. Nothing in the FD&C Act precludes FDA from developing a procedure for patent listing disputes in light of our broad authority to issue regulations for the efficient enforcement of the FD&C Act. As the U.S. Supreme Court observed in

Caraco Pharm. Labs.,

“the counterclaim cannot restore the smooth working of a statutory scheme thrown off kilter by an overly broad use code. At best, it permits the generic manufacturer to do what the scheme contemplates it should do—file an ANDA with a section viii statement—but only after expensive and time-consuming litigation. A fix is in order, but it must come from Congress or FDA” (132 S.Ct. 1670 at 1689).

Finally, we note that comments recommending that FDA seek clarification or correction of patent information through other means do not describe an alternative to the approach we proposed. We believe that the modifications that we have made to the patent listing dispute procedure, discussed in Response 22, and our stepwise approach to evaluating whether FDA's revisions to this procedure and the regulations on submission of method-of-use patent information address the problem of overbroad and ambiguous use codes, adequately address the comments received on our proposal.

(Comment 24) Three comments assert that FDA's proposed deference to the 505(b)(2) or ANDA applicant's interpretation of the scope of the patent would be inconsistent with the Agency's longstanding ministerial role in patent-related matters. These comments suggest that FDA lacks the expertise to assess the adequacy of use codes and determine whether deference to the 505(b)(2) or ANDA applicant's interpretation of the scope of the patent is justified. A fourth comment suggests that FDA provide an administrative appeals process and Administrative Law Judge review where FDA reviews a proposed labeling carve-out for a 505(b)(2) application or ANDA with deference to the 505(b)(2) or ANDA applicant's interpretation of the scope of the patent. This comment also suggests that FDA avoid a “mere ministerial approach.”

(Response 24) As noted in Response 23, we are not finalizing this proposal at this time. Accordingly, we do not need to address comments regarding specific aspects of implementation of this proposal in this final rule.

(Comment 25) One comment recommends that FDA require an NDA holder to respond to a request to confirm the accuracy or relevance of patent information in 15 days, rather than 30 days. The comment maintains that a 15-day timeframe is consistent with the regulatory timeframe to make corrections to an incomplete or otherwise inadequate submission of patent information (see § 314.53(c)(2)(ii)).

(Response 25) We decline to modify the regulation as requested. We believe that a period of 30 days from the date on which FDA sends the statement of dispute to the NDA holder provides an appropriate opportunity for the NDA holder to consider the statement of dispute and submit a response that addresses the requirements of § 314.53(f)(1)(i).

(Comment 26) Two comments recommend that FDA clarify that an NDA holder's amendment to the use code in response to a patent listing dispute will not be considered untimely filed patent information under §§ 314.50(i)(4) and 314.94(a)(12)(vi). One comment expresses concern that whether and how an NDA holder responds to a method-of-use patent listing dispute may affect the availability of a 30-month stay should the NDA holder subsequently file a patent infringement action in response to notice of a paragraph IV certification to the patent.

(Response 26) We agree that an NDA holder's amendment to its use code or related information on Form FDA 3542 in response to a patent listing dispute should not be considered untimely filed patent information if it is submitted within 30 days of FDA's request under § 314.53(f)(1)(i)(B) and contains the information required under § 314.53(f)(1)(i)(B)(

1

) or (

2

) (see §§ 314.50(i)(4)(i) and 314.94(a)(12)(vi)(A) (describing untimely filing of patent information “except as provided in § 314.53(f)(1)”)). We note, however, that if an NDA holder responds to the patent listing dispute with an amendment to its use code more than 30 days after the date on which FDA sends the statement of dispute to the NDA holder, FDA will consider the amendment to be untimely filing of patent information because the submission does not comply with the requirements of § 314.53(f)(1).

The patent listing dispute procedure would not have an impact on the availability of a 30-month stay if other statutory and regulatory criteria are met (see section 505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act and § 314.107).

V.B.4.b.

Requests by NDA holder (§ 314.53(f)(2)).

We proposed to expressly require that if an 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 must promptly notify FDA to withdraw the patent or patent information and request that the patent or patent information be removed from the list (see proposed § 314.53(f)(2)(i) and section 505(b)(1) and (c)(2) of the FD&C Act). If an NDA holder is required by court order to amend patent information or withdraw a patent from the list, we proposed to require the NDA holder to submit a copy of the court order to the Orange Book Staff within 14 calendar days of the date on which the order was entered. We also proposed to codify our current practice of removing a patent or patent information 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 (see proposed § 314.53(f)(2)(i)). In addition, we proposed that if the term of the patent is extended under the patent term restoration provisions of 35 U.S.C. 156, the NDA holder must submit a correction to the patent expiration date on Form FDA 3542 within 30 calendar days of receipt of a certificate of extension or documentation of an extension of the term of the patent (see proposed § 314.53(f)(2)(ii) and 35 U.S.C. 156(e)(1) and (2)).

We proposed to require that corrections or changes to previously submitted patent information must be submitted on Form FDA 3542a or 3542,

as appropriate (see proposed § 314.53(f)(2)(iii)). However, we proposed to clarify that an NDA holder's withdrawal of a patent and request to remove a patent from the list is not required to be submitted on Form FDA 3542, but the request must specify the patent number, the application number, and each product(s) approved in the application to which the request applies (see proposed § 314.53(f)(2)(iv)).

In the following paragraphs, we discuss two comments on these proposed provisions. After considering these comments, we are making clarifying revisions to the description of the required amendment or supplement and the address to which the amendment or supplement must be submitted, and technical amendments described in sections V.B.2.c and V.P.3 We are also revising proposed § 314.53(f)(2)(i) to more precisely describe our practice of removing a patent or patent information from the list in response to an NDA holder's request if there is no first applicant eligible for 180-day exclusivity based on a paragraph IV certification to that patent or after the 180-day exclusivity period of a first applicant based on that patent has expired or has been extinguished.

(Comment 27) Two comments request that FDA clarify the implications of failing to timely amend patent information or withdraw a patent. One of the comments requests that FDA clarify the meaning of “promptly notify FDA” in proposed § 314.53(f)(2)(i), and explain whether the timeframe may differ based on the circumstances (

e.g.,

delay withdrawal of an original patent held invalid until the reissued patent has issued). The other comment suggests that if the NDA holder fails to timely notify FDA of a patent term extension or of a court order to amend patent information or withdraw a patent from the list, the patent should be considered untimely filed.

(Response 27) FDA is establishing regulatory timeframes for withdrawal or amendment of patent information and withdrawal of a patent to promote the NDA holder's timely compliance with obligations under the FD&C Act and applicable regulations. 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 or patent information or amend the patent information to ensure that pending 505(b)(2) applications or ANDAs that contain a patent certification to the amended or withdrawn patent or patent information are not inappropriately delayed if they are otherwise eligible for approval. An NDA holder's withdrawal or amendment of patent information or withdrawal of the patent within 14 days of the date on which the NDA holder determines that the patent or patent claim no longer meets the requirements for listing under section 505(b)(1) or (c)(2) of the FD&C Act would be considered “prompt.” If a court enters a final decision from which no appeal has been or can be taken that a patent is invalid, the NDA holder must promptly notify FDA to withdraw the patent and request that the patent be removed from the list irrespective of whether the NDA holder or patent owner is separately requesting a reissue of the patent.

We decline to modify the regulation to consider a patent untimely filed if the NDA holder fails to notify FDA of a court order to amend or withdraw patent information within 14 days because a court can enforce a failure to comply with its order. We also decline to modify the regulation to consider a patent untimely filed if the NDA holder fails to notify FDA of a patent term extension within 30 days because NDA holders have adequate incentive to inform FDA of any patent term extension. We require NDA holders to submit on Form FDA 3542 a correction to the expiration date of the listed patent if the term is extended under 35 U.S.C. 156(e) to ensure that prospective 505(b)(2) and ANDA applicants have timely notice of changes to the asserted patent coverage for a listed drug.

(Commen

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