6802 Federal Register / Vol. 80, No. 25 / Friday, February 6, 2015 / Proposed Rules 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Parts 314 and 320 

[Docket No. FDA–2011–N–0830] 

RIN 0910–AF97 

Abbreviated New Drug Applications 

and 505(b)(2) Applications 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Proposed rule. 

SUMMARY: The Food and Drug 

Administration (FDA) is proposing 

regulations to implement Title XI of the 

Medicare Prescription Drug, 

Improvement, and Modernization Act of 

2003 (MMA), which amended 

provisions of the Federal Food, Drug, 

and Cosmetic Act (the FD&C Act) that 

govern the approval of 505(b)(2) 

applications and abbreviated new drug 

applications (ANDAs). This proposed 

rule would implement portions of Title 

XI of the MMA that pertain to provision 

of notice to each patent owner and the 

new drug application (NDA) holder of 

certain patent certifications made by 

applicants submitting 505(b)(2) 

applications or ANDAs; the availability 

of 30-month stays of approval on 

505(b)(2) applications and ANDAs that 

are otherwise ready to be approved; 

submission of amendments and 

supplements to 505(b)(2) applications 

and ANDAs; and the types of 

bioavailability and bioequivalence data 

that can be used to support these 

applications. This proposed rule also 

would amend certain regulations 

regarding 505(b)(2) applications and 

ANDAs to facilitate compliance with 

and efficient enforcement of the FD&C 

Act. 

DATES: Submit either electronic or 

written comments on the proposed rule 

by May 7, 2015. Submit comments on 

information collection issues under the 

Paperwork Reduction Act of 1995 by 

March 9, 2015 (see the ‘‘Paperwork 

Reduction Act of 1995’’ section of this 

document). See section VII of this 

document for the proposed effective 

date of a final rule based on this 

document. 

ADDRESSES: You may submit comments 

by any of the following methods, except 

that comments on information 

collection issues under the Paperwork 

Reduction Act of 1995 must be 

submitted to the Office of Regulatory 

Affairs, Office of Management and 

Budget (OMB) (see the ‘‘Paperwork 

Reduction Act of 1995’’ section of this 

document). 

Electronic Submissions 

Submit electronic comments in the 

following way: 

• Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the 

instructions for submitting comments. 

Written Submissions 

Submit written submissions in the 

following way: 

• Mail/Hand delivery/Courier (For 

paper, disk, or CD–ROM submissions): 

Division of Dockets Management (HFA– 

305), Food and Drug Administration, 

5630 Fishers Lane, Rm. 1061, Rockville, 

MD 20852. 

Instructions: All submissions received 

must include Docket No. FDA–2011–N– 

0830 for this rulemaking. All comments 

received may be posted without change 

to http://www.regulations.gov, including 

any personal information provided. For 

additional information on submitting 

comments, see the ‘‘Comments’’ heading 

of the SUPPLEMENTARY INFORMATION

section of this document. 

Docket: For access to the docket to 

read background documents or 

comments received, go to http://

www.regulations.gov and insert the 

docket number, found in brackets in the 

heading of this document, into the 

‘‘Search’’ box and follow the prompts 

and/or go to the Division of Dockets 

Management, 5630 Fishers Lane, Rm. 

1061, Rockville, MD 20852. 

FOR FURTHER INFORMATION CONTACT: 

Janice L. Weiner, Center for Drug 

Evaluation and Research, Food and 

Drug Administration, 10903 New 

Hampshire Ave., Bldg. 51, Rm. 6268, 

Silver Spring, MD 20993–0002, 301– 

796–3601. 

SUPPLEMENTARY INFORMATION: 

Table of Contents 

Executive Summary 

I. Background 

A. Hatch-Waxman Amendments 

B. Requirements for Patent Certification or 

Statement 

C. Patent Listing Requirements 

D. MMA 

II. Description of the Proposed Rule 

A. Definitions 

1. Overview of New, Revised, and 

Relocated Definitions 

2. Proposed Amendments to Definitions in 

§ 314.3 

3. Proposed Amendments to Definitions in 

Current § 314.108 

4. Definitions in Current § 320.1 

B. Submission of Patent Information 

(Proposed § 314.53) 

1. General Requirements for Submission of 

Patent Information (Proposed § 314.53(b) 

and (c)) 

2. When and Where To Submit Patent 

Information (Proposed § 314.53(d)) 

3. Public Disclosure of Patent Information 

(Proposed § 314.53(e)) 

4. Correction or Change of Patent 

Information (Proposed § 314.53(f)) 

C. Patent Certification (Proposed 

§§ 314.50(i) and 314.94(a)(12)) 

1. Method-of-Use Patents (Proposed 

§§ 314.50(i)(1)(iii) and 314.94(a)(12)(iii)) 

2. Method-of-Manufacturing Patents 

(Proposed Deletion of §§ 314.50(i)(2) and 

314.94(a)(12)(iv)) 

3. Licensing Agreement (Proposed 

§ 314.50(i)(3)) 

D. Notice of Paragraph IV Certification 

(Proposed §§ 314.52 and 314.95) 

1. Timing of Notice 

2. Notice Required for All Paragraph IV 

Certifications 

3. Contents of Notice 

4. Documentation of Timely Sending and 

Receipt of Notice 

5. Administrative Consequence for Late 

Notice 

E. Amended Patent Certifications 

(Proposed §§ 314.50(i)(6) and 

314.94(a)(12)(viii)) 

1. Amended Patent Certifications After a 

Finding of Infringement 

2. Amended Certifications After Request by 

the NDA Holder to Remove a Patent or 

Patent Information from the List 

3. Amended Certifications Upon Patent 

Reissuance 

4. Other Amended Certifications 

F. Patent Certification Requirements for 

Amendments and Supplements to 

505(b)(2) Applications and ANDAs 

(Proposed §§ 314.60, 314.70, 314.96, and 

314.97) 

1. Types of Amendments or Supplements 

for Which Patent Certification is 

Required 

2. Requirements for Notice of Paragraph IV 

Certifications and Implications for 180- 

day Exclusivity 

G. Amendments or Supplements to a 

505(b)(2) Application for a Different 

Drug and Amendments or Supplements 

to an ANDA That Reference a Different 

Listed Drug (Proposed §§ 314.60, 314.70, 

314.96, and 314.97) 

1. Amendments to an Unapproved ANDA 

(Proposed § 314.96(c)) 

2. Supplements to an ANDA (Proposed 

§ 314.97(b)) 

3. Amendments to an Unapproved 

505(b)(2) Application (Proposed 

§ 314.60(e)) 

4. Supplements to a 505(b)(2) Application 

(Proposed § 314.70(h)) 

H. Procedure for Submission of an 

Application Requiring Investigations for 

Approval of a New Indication for, or 

Other Change From, a Listed Drug 

(Proposed § 314.54) 

I. Petition to Request a Change From a 

Listed Drug (Proposed § 314.93) 

J. Filing an NDA and Receiving an ANDA 

(Proposed § 314.101) 

1. Notification of Filing of a 505(b)(2) 

Application or Receipt of an ANDA 

2. Other Proposed Revisions 

K. Approval of an NDA and ANDA 

(Proposed § 314.105) 


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L. Refusal to Approve an NDA or ANDA 

(Proposed §§ 314.125 and 314.127 and 

Related Provisions in Proposed §§ 314.90 

and 314.99) 

M. Date of Approval of a 505(b)(2) 

Application or ANDA (Proposed 

§ 314.107) 

1. General (Proposed § 314.107(a)) 

2. Effect of Patent(s) on the Listed Drug 

(Proposed § 314.107(b)) 

3. Subsequent ANDA Submission 

(Proposed § 314.107(c)) 

4. Delay of Approval Due to Exclusivity 

(Proposed § 314.107(d)) 

5. Notification of Court Actions or 

Documented Agreement (Proposed 

§ 314.107(e)) 

6. Computation of the 45-Day Time Clock 

(Proposed § 314.107(f)) 

7. Conversion of Approval to Tentative 

Approval (Proposed § 314.107(g)) 

N. Assessing Bioavailability and 

Bioequivalence for Drugs Not Intended 

To Be Absorbed Into the Bloodstream 

(Proposed § 320.23) 

O. Miscellaneous 

1. Clarifying Revisions and Editorial 

Changes 

2. Effect of Other Rulemaking 

III. Legal Authority 

IV. Analysis of Impacts 

A. Summary of the Benefits and Costs of 

the Proposed Rule 

B. Summary of the Regulatory Flexibility 

Analysis 

V. Paperwork Reduction Act of 1995 

VI. Environmental Impact 

VII. Effective Date 

VIII. Federalism 

IX. Request for Comments 

X. References 

Executive Summary 

Purpose of the Regulatory Action 

This proposed rule would implement 

portions of Title XI of the MMA and 

revise and clarify FDA regulations 

relating to 505(b)(2) applications and 

ANDAs in a manner intended to reduce 

unnecessary litigation, reduce delays in 

the approval of 505(b)(2) applications 

and ANDAs that are otherwise ready to 

be approved, and provide business 

certainty to both brand name and 

generic drug manufacturers. The MMA 

and sections 505, 505A, and 527 of the 

FD&C Act (21 U.S.C. 355, 355a, and 

360cc), in conjunction with our general 

rulemaking authority in section 701(a) 

of the FD&C Act (21 U.S.C. 371(a)), 

serve as our principal legal authority for 

this proposal. 

Title XI of the MMA addressed two 

key concerns identified in a Federal 

Trade Commission (FTC) report on 

anticompetitive strategies that may 

delay access to generic drugs by: (1) 

Limiting the availability of 30-month 

stays of approval on 505(b)(2) 

applications and ANDAs that are 

otherwise ready to be approved and (2) 

establishing conditions under which a 

first applicant would forfeit the 180-day 

exclusivity period such that approval of 

subsequent ANDAs would no longer be 

blocked. FDA has been implementing 

the MMA directly from the statute for 

several years. Based on this experience, 

FDA is proposing to amend its 

regulations to implement portions of the 

MMA that pertain to 30-month stays 

and other matters not related to 180-day 

exclusivity. 

FDA is proposing to amend its 

regulations regarding 505(b)(2) 

applications and ANDAs to facilitate 

compliance with and efficient 

enforcement of the FD&C Act, and to 

clarify and update these regulations 

based on recent court decisions and our 

practical experience implementing 

provisions related to the approval of 

505(b)(2) applications and ANDAs. For 

example, we are proposing to clarify 

requirements for the NDA holder’s 

description of the patented method of 

use (the ‘‘use code’’) required for 

publication in FDA’s ‘‘Approved Drug 

Products With Therapeutic Equivalence 

Evaluations’’ (commonly known as the 

Orange Book) to avoid overbroad use 

codes that may delay approval of 

generic drugs. This is intended to 

facilitate FDA’s implementation of the 

statutory provisions that permit 

505(b)(2) and ANDA applicants to omit 

(‘‘carve out’’) protected conditions of 

use from labeling and obtain approval 

for conditions of use that are not 

covered by unexpired patents or 

exclusivity. As the U.S. Supreme Court 

recently noted in Caraco Pharm. Labs. 

v. Novo Nordisk A/S: ‘‘An overbroad 

use code . . . throws a wrench into the 

FDA’s ability to approve generic drugs 

as the statute contemplates’’ (132 S. Ct. 

1670, at 1684 (2012)). 

Finally, we are proposing to update 

the regulations to codify FDA’s current 

practice and policy and thereby promote 

transparency. 

Summary of the Major Provisions of the 

Regulatory Action 

Submission of Patent Information. 

The proposed rule would revise and 

streamline requirements related to 

submission of patent information on: (1) 

Patents that claim the drug substance 

and/or drug product and meet the 

requirements for patent listing on that 

basis; (2) drug substance patents that 

claim only a polymorph of the active 

ingredient; and (3) certain NDA 

supplements. The proposed rule would 

clarify requirements for the submission 

of information related to patents that 

have been reissued by the Patent and 

Trademark Office (PTO). The proposed 

rule describes our approach to treating 

the original and reissued patents as a 

‘‘single bundle’’ of patent rights, which 

first became relevant to approval of 

505(b)(2) applications and ANDAs with 

the submission of the original patent 

information. 

We are proposing to codify our 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-ofuse patent claims a use for which the 

505(b)(2) or ANDA applicant is not 

seeking approval. To restrain overbroad 

use codes, the proposed rule would 

expressly require that if the scope of the 

method-of-use claim(s) of the patent 

does not cover every approved use of 

the drug, the NDA holder’s use code 

must describe only the specific 

portion(s) of the indication or other 

method of use claimed by the patent. 

Timing of Submission of Patent 

Information. We are proposing to 

expressly describe our current practice 

with respect to listing patent 

information that has not been submitted 

to FDA within 30 days after patent 

issuance. Although we list untimely 

filed patents pursuant to section 

505(c)(2) of the FD&C Act, we generally 

do not require an applicant with a 

pending 505(b)(2) application or ANDA 

to provide a patent certification to the 

untimely filed patent. Thus, the 

untimely filed patent will neither delay 

approval of a pending 505(b)(2) 

application or ANDA until patent 

expiration nor necessitate a carve-out of 

information related to a patented 

method of use. 

We are proposing to expand the 

category of untimely filed patent 

information to include certain 

amendments to the NDA holder’s 

description of the approved method(s) 

of use claimed by the patent, if such 

changes do not relate to a corresponding 

change in approved labeling or are 

submitted more than 30 days after such 

labeling change. This proposed 

regulatory revision is intended to reduce 

delays in approval related to 

manipulation of patent use codes in a 

manner not contemplated by the FD&C 

Act. 

In addition, we are proposing to 

establish that the submission date of 

patent information provided by an NDA 

holder after approval would be the 

earlier of the date on which Form FDA 

3542 is date-stamped by the Office of 

Generic Drugs (OGD) Document Room 

or officially received electronically by 

FDA. These proposed revisions are 

intended to facilitate prompt listing in 

the Orange Book and to remove any 


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ambiguity about the date of submission 

in light of the implications for the 

patent certification obligations of 

505(b)(2) and ANDA applicants that rely 

upon the listed drug. 

Correction or Change of Patent 

Information. We are proposing to 

enhance FDA’s response to challenges 

to the accuracy or relevance of 

submissions of patent use code 

information to the Agency, in certain 

circumstances. If, in response to such a 

challenge, the NDA holder confirms the 

accuracy of the information, fails to 

timely respond, or submits a revision to 

the use code that does not provide 

adequate clarity for FDA to determine 

whether the scope of a proposed 

labeling carve-out would be appropriate 

based on the NDA holder’s use code and 

approved labeling, we are proposing to 

review proposed labeling carve-out(s) 

for the 505(b)(2) application or ANDA 

with deference to the 505(b)(2) or ANDA 

applicant’s interpretation of the scope of 

the patent. In addition, we are 

proposing to expressly require the 

correction or change of patent 

information by the NDA holder if: (1) 

The patent or patent claim no longer 

meets the statutory requirements for 

listing; (2) the NDA holder is required 

by court order to amend patent 

information or withdraw a patent from 

the list; or (3) the term of a listed patent 

is extended under patent term 

restoration provisions. These proposed 

revisions would facilitate 

implementation of the MMA provision 

related to patent withdrawal and 

efficient enforcement of the FD&C Act. 

Notice of Paragraph IV Certification— 

Timing. We are proposing to revise our 

regulations to clearly delineate the two 

limitations on the time frame within 

which notice of a paragraph IV 

certification can be provided to the NDA 

holder and each patent owner: (1) The 

date before which notice may not be 

given (reflecting FDA’s long-standing 

practice) and (2) the date, established by 

MMA, by which notice must be given. 

For an original application, a 

505(b)(2) or ANDA applicant must send 

notice of a paragraph IV certification on 

or after the date on which it receives an 

‘‘acknowledgment letter’’ or a 

‘‘paragraph IV acknowledgment letter’’ 

from FDA stating that the application is 

sufficiently complete to permit a 

substantive review, but not later than 20 

days after the date of the ‘‘postmark’’ (as 

defined in the proposed rule) on such 

letter. 

For an amendment or supplement, a 

505(b)(2) or ANDA applicant must send 

notice of a paragraph IV certification 

contained in an amendment to an 

application (that has been received for 

substantive review) or in a supplement 

to an approved application at the same 

time that the amendment or supplement 

is submitted to FDA. We are proposing 

to establish a date (the first working day 

after the day the patent is published in 

the Orange Book) before which an 

ANDA applicant cannot send valid 

notice of a paragraph IV certification to 

a newly listed patent. This approach is 

intended to promote equity among 

ANDA applicants seeking eligibility for 

180-day exclusivity and to reduce the 

burden on industry and FDA associated 

with serial submissions and multiple 

notices of paragraph IV certifications 

related to a newly issued patent. 

Notice of a paragraph IV certification 

that has been sent prematurely is 

invalid, and will not be considered to 

comply with the FD&C Act’s notice 

requirement. We are proposing 

administrative consequences for ANDA 

applicants who fail to send notice of 

paragraph IV certification within the 

statutory time frame established by the 

MMA. The date the ANDA was 

submitted would be deemed to be 

delayed by the number of days by which 

the time frame was exceeded, which 

may result in the applicant losing 

eligibility for 180-day exclusivity. 

Notice of Paragraph IV Certification— 

Content and Methods. We are proposing 

revisions to the content of notice of a 

paragraph IV certification to incorporate 

requirements added by the MMA and to 

support the efficient enforcement of our 

regulations. We also are proposing to 

expand the acceptable methods of 

sending notice of a paragraph IV 

certification beyond registered or 

certified mail to include ‘‘designated 

delivery services.’’ This would reduce 

the burden on 505(b)(2) and ANDA 

applicants who currently must submit 

requests to send notice by common 

alternate delivery methods. 

Amended Patent Certifications. We 

are proposing to clarify the 

requirements for a 505(b)(2) or ANDA 

applicant to amend a paragraph IV 

certification after a judicial finding of 

patent infringement to reflect statutory 

changes made by the MMA. We also are 

proposing to clarify the circumstances 

and time frame in which a 505(b)(2) or 

ANDA applicant must submit an 

amended patent certification after an 

NDA holder has withdrawn a patent and 

requested removal of the patent from the 

Orange Book. The proposed rule would 

codify our current practice of not 

removing a withdrawn patent from the 

list until FDA has determined that no 

first applicant is eligible for 180-day 

exclusivity or such exclusivity is 

extinguished, and exempting 505(b)(2) 

applicants from providing or 

maintaining a certification to withdrawn 

patents. The proposed rule also clarifies 

an applicant’s current patent 

certification obligations with respect to 

a reissued patent, and proposes 

implications for 180-day exclusivity and 

a 30-month stay. In addition, the 

proposed rule would expressly codify 

the current requirement for a 505(b)(2) 

or ANDA applicant to submit a patent 

certification to a newly issued patent 

that claims the listed drug or an 

approved method of use. 

Amendments or Supplements: Patent 

Certification Requirements. We are 

proposing to clarify and augment the 

patent certification requirements for 

amendments and supplements to 

505(b)(2) applications and ANDAs to 

ensure that changes to the drug product 

that could be protected by patent are 

accompanied by a new patent 

certification. A new patent certification 

currently is required to accompany an 

amendment or supplement to add a new 

indication or other condition of use, or 

to add a new strength or change an 

existing strength. The regulations also 

currently require a patent certification 

to be amended if, at any time before 

approval, the applicant learns that the 

previously submitted patent 

certification is no longer accurate. We 

are proposing to augment this regulation 

by requiring a new patent certification 

with an amendment to make other-thanminor changes in product formulation 

or to change the physical form or 

crystalline structure of the active 

ingredient. 

Limitation on Submission of Certain 

Amendments and Supplements to a 

505(b)(2) Application or ANDA. We are 

proposing to codify our current 

interpretation of the MMA’s prohibition 

on submitting an amendment or a 

supplement to seek approval of: (1) ‘‘[A] 

drug that is a different drug’’ than the 

drug identified in the original 505(b)(2) 

application; or (2) ‘‘a drug referring to a 

different listed drug’’ than the drug 

cited as the basis for ANDA submission. 

We are implementing these parallel 

restrictions on submission of certain 

types of changes in an amendment or a 

supplement to a 505(b)(2) application or 

ANDA in a manner that is consistent 

with the statutory text and preserves a 

meaningful opportunity for a single 30- 

month stay. 

505(b)(2) Applications. We are 

proposing to require a 505(b)(2) 

applicant to identify a pharmaceutically 

equivalent product, if already approved, 

as a listed drug relied upon, and comply 

with applicable regulatory 

requirements. This is intended to help 

ensure that the 505(b)(2) pathway is not 

used to circumvent the statutory patent 


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certification obligations that would have 

applied if the proposed product was not 

ineligible for approval in an ANDA. 

Date of Approval of a 505(b)(2) 

Application or ANDA. The proposed 

rule would describe, in a more 

comprehensive manner, the timing of 

approval of a 505(b)(2) application or 

ANDA based on the patent 

certification(s) or statement(s) submitted 

by the 505(b)(2) or ANDA applicant. We 

are proposing to revise the regulations 

to reflect the MMA’s limitation on 

multiple 30-month stays of approval of 

a 505(b)(2) application or an ANDA 

containing a paragraph IV certification 

to certain patents submitted to FDA on 

or after August 18, 2003. 

We are proposing to clarify that the 

statutory 30-month stay begins on the 

later of the date of receipt of notice of 

paragraph IV certification by any owner 

of the listed patent or by the NDA 

holder who is an exclusive licensee (or 

their representatives). This proposed 

revision codifies our current practice 

and provides an efficient means of 

ensuring that each patent owner or NDA 

holder receives the full statutory 30- 

month stay. 

We are proposing to codify the 

MMA’s amendments that clarify the 

type of Federal district and appellate 

court decisions in patent litigation that 

will terminate a 30-month stay and lead 

to approval of a 505(b)(2) application or 

ANDA that is otherwise eligible for 

approval. We also are proposing to 

address other scenarios in which a stay 

may be terminated, including written 

consent to approval by the patent owner 

or exclusive patent licensee, a court 

order terminating the stay, or a court 

order of dismissal without a finding of 

infringement. This is intended to avoid 

unnecessary delays in approval of 

generic drugs while upholding the 

statutory purpose of the stay (i.e., to 

allow time for patent infringement 

claims to be litigated prior to approval 

of the potentially infringing product). 

Notification of Commercial 

Marketing. We are proposing to update 

the regulations to reflect the MMA 

provisions that modify the types of 

events that can trigger the start of the 

180-day exclusivity period. A first 

applicant would be required to submit 

correspondence to its ANDA notifying 

FDA within 30 days of the date of first 

commercial marketing of the drug 

product. If the first applicant does not 

notify FDA within this time frame, we 

are proposing to deem the date of first 

commercial marketing to be the date of 

the drug product’s approval. This may 

have the effect of shortening the 180-day 

exclusivity period in a similar manner 

to the current regulatory consequence 

for failure to provide ‘‘prompt’’ notice of 

first commercial marketing. 

Notification of Court Actions or 

Documented Agreements. We are 

proposing to expand the scope of 

documentation that an applicant must 

submit to FDA regarding patent-related 

court actions and documented 

agreements to ensure that FDA is 

promptly advised of information that 

may affect the timing of approval of a 

505(b)(2) application or ANDA. 

Costs and Benefits 

FDA is proposing to amend the 

regulations for further implementation 

of and consistency with the MMA and 

to make other changes related to 

505(b)(2) applications and ANDAs. 

These changes would improve 

transparency, facilitate compliance and 

enforcement, and preserve the balance 

struck in the Drug Price Competition 

and Patent Term Restoration Act of 1984 

(Pub. L. 98–417). 

Although many provisions of this 

proposed rule would codify current 

practice, elements of this proposal 

would lead to changes that generate 

additional benefits and costs. The 

estimated annual monetized benefits of 

this proposed rule are $194,314, and 

estimated annual monetized costs are 

$91,371. We have identified, but are 

unable to quantify, impacts from 

proposed changes to submitted patent 

information and the implementation of 

an administrative consequence for 

ANDA applicants who fail to provide 

notice of a paragraph IV certification 

within the time frame required by the 

MMA. 

I. Background 

On December 8, 2003, the MMA (Pub. 

L. 108–173) was signed into law. Title 

XI of the MMA significantly amended 

provisions of the FD&C Act that govern 

the approval of NDAs described by 

section 505(b)(2) of the FD&C Act (21 

U.S.C. 355(b)(2)) (505(b)(2) applications) 

and ANDAs described by section 505(j) 

of the FD&C Act. 

I.A. Hatch-Waxman Amendments 

The 505(b)(2) application and ANDA 

approval pathways were enacted as part 

of the Drug Price Competition and 

Patent Term Restoration Act of 1984 

(Pub. L. 98–417) (Hatch-Waxman 

Amendments). The Hatch-Waxman 

Amendments reflect Congress’s efforts 

to balance the need to ‘‘make available 

more low cost generic drugs by 

establishing a generic drug approval 

procedure for pioneer drugs first 

approved after 1962’’ with new 

incentives for drug development in the 

form of marketing exclusivity and 

patent term extensions (see H. Rept. 98– 

857, part 1, at 14–15 (1984), reprinted in 

1984 U.S. Code Congressional and 

Administrative News 2647 at 2647– 

2648). With passage of the HatchWaxman Amendments, the FD&C Act 

describes different routes for obtaining 

approval of two broad categories of drug 

applications: An NDA, for which the 

requirements are set out in section 

505(b) and (c) of the FD&C Act, and an 

ANDA, for which the requirements are 

set out in section 505(j). These 

categories can be further subdivided 

into a ‘‘stand-alone’’ NDA, a 505(b)(2) 

application, an ANDA, and a petitioned 

ANDA. 

A ‘‘stand-alone NDA’’ is an 

application submitted under section 

505(b)(1) of the FD&C Act that contains 

full reports of investigations of safety 

and effectiveness that were conducted 

by or for the applicant or for which the 

applicant has a right of reference or use. 

A 505(b)(2) application is an NDA 

that contains full reports of 

investigations of safety and 

effectiveness, where at least some of the 

information required for approval comes 

from studies not conducted by or for the 

applicant and for which the applicant 

has not obtained a right of reference or 

use (e.g., published literature or the 

Agency’s finding of safety and/or 

effectiveness for one or more listed 

drugs). 

An ANDA is an application for a 

duplicate of a previously approved drug 

that is submitted under the abbreviated 

approval pathway described in section 

505(j) of the FD&C Act. An ANDA must 

contain information to show that the 

proposed product is the same as a 

previously approved drug (the reference 

listed drug or RLD) with respect to 

active ingredient, dosage form, route of 

administration, strength, labeling, and 

conditions of use, among other 

characteristics. An ANDA applicant also 

must demonstrate that its proposed 

product is bioequivalent to the drug 

product selected by the Agency as the 

reference standard for assessing 

bioequivalence with the RLD (see 

section II.A.2.z). (We note that the drug 

product designated as the RLD may not 

necessarily be the drug product 

identified in the Orange Book as the 

reference standard for bioequivalence 

studies, for example, for drug product 

lines with multiple strengths.) An 

applicant that can meet the 

requirements for approval under section 

505(j) of the FD&C Act may rely upon 

the Agency’s finding of safety and 

effectiveness for the RLD and need not 

repeat the extensive nonclinical and 

clinical investigations required for 

approval of a ‘‘stand-alone’’ NDA 


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submitted under section 505(b)(1) of the 

FD&C Act. 

A ‘‘petitioned ANDA’’ is a type of 

ANDA for a drug that differs from a 

previously approved drug product in 

dosage form, route of administration, 

strength, or active ingredient (in a 

product with more than one active 

ingredient), for which FDA has 

determined, in response to a suitability 

petition submitted under section 

505(j)(2)(C) of the FD&C Act, that 

clinical studies are not necessary to 

demonstrate safety and effectiveness. 

The timing of approval for a 505(b)(2) 

application and an ANDA (including a 

petitioned ANDA) is subject to the 

patent and marketing exclusivity 

protections accorded the listed drug(s) 

relied upon and the RLD, respectively. 

An NDA applicant (including a 

505(b)(2) applicant) is required to ‘‘file 

with the application the patent number 

and the expiration date of any patent 

which claims the drug for which the 

applicant submitted the application or 

which claims a method of using such 

drug and with respect to which a claim 

of patent infringement could reasonably 

be asserted if a person not licensed by 

the owner engaged in the manufacture[,] 

use, or sale of the drug’’ (section 

505(b)(1) of the FD&C Act). Upon 

approval of an application under section 

505(c) of the FD&C Act, we publish the 

patent information provided by the 

applicant in the Orange Book, available 

electronically on FDA’s Web site at 

http://www.fda.gov/cder. 

I.B. Requirements for Patent 

Certification or Statement 

A 505(b)(2) application and ANDA 

must include a patent certification 

described in section 505(b)(2) or 

505(j)(2)(A)(vii) of the FD&C Act, 

respectively, for each timely filed patent 

that claims the listed drug(s) relied 

upon or RLD, respectively, or a method 

of using the drug for which the 

applicant is seeking approval and for 

which information is required to be 

filed under section 505(b) or 505(c) of 

the FD&C Act. For each unexpired 

patent listed in the Orange Book, the 

505(b)(2) or ANDA applicant must 

submit either a paragraph III 

certification (section 505(b)(2)(A)(iii) or 

505(j)(2)(A)(vii)(III) of the FD&C Act) 

(delaying approval until the date on 

which such patent will expire), a 

paragraph IV certification (section 

505(b)(2)(A)(iv) or 505(j)(2)(A)(vii)(IV) of 

the FD&C Act) (certifying that such 

patent is invalid or will not be infringed 

by the manufacture, use, or sale of the 

drug product for which the 505(b)(2) 

application or ANDA is submitted), or, 

with respect to a method-of-use patent, 

a statement that the patent does not 

claim a use for which the applicant is 

seeking approval (section 505(b)(2)(B) or 

505(j)(2)(A)(viii) of the FD&C Act). If the 

patent information has not been filed 

with FDA (i.e., is not listed in the 

Orange Book because the patent 

information has not been submitted or 

is not eligible for listing) or the patent 

has expired, a 505(b)(2) or ANDA 

applicant may submit a paragraph I 

certification or paragraph II 

certification, respectively (see section 

505(b)(2)(A)(i) and (ii) and 

505(j)(2)(A)(vii)(I) and (II) of the FD&C 

Act). If, in the opinion of the 505(b)(2) 

or ANDA applicant and to the best of 

their knowledge, there are no patents 

that claim the listed drug(s) relied upon 

or the RLD, respectively, or that claim 

a use of such drug, the 505(b)(2) or 

ANDA applicant may submit a ‘‘no 

relevant patents’’ certification (see 

§ 314.50(i)(1)(ii) or § 314.94(a)(12)(ii) (21 

CFR 314.50(i)(1)(ii) or 314.94(a)(12)(ii)). 

An applicant submitting a paragraph 

IV certification is required to give notice 

of its paragraph IV certification to the 

holder of the NDA for the listed drug(s) 

relied upon or RLD and each owner of 

the patent that is the subject of the 

certification. Notice of a paragraph IV 

certification subjects the 505(b)(2) or 

ANDA applicant to the risk that it will 

be sued for patent infringement. If the 

NDA holder or patent owner initiates a 

patent infringement action within 45 

days after receiving notice of the 

paragraph IV certification, there 

generally will be a statutory 30-month 

stay of approval of the 505(b)(2) 

application or ANDA while the patent 

infringement litigation is pending (see 

section 505(c)(3)(C) and (j)(5)(B)(ii) of 

the FD&C Act). ANDA applicants have 

a statutory incentive to challenge listed 

patents that may be invalid, 

unenforceable, or not infringed by the 

drug product described in the ANDA. 

The first applicant to submit a 

substantially complete ANDA that 

contains, and for which the applicant 

lawfully maintains, a paragraph IV 

certification may be eligible for a 180- 

day period of marketing exclusivity 

(180-day exclusivity) during which 

approval of subsequent ANDAs 

containing a paragraph IV certification 

to a listed patent for the same drug 

product will not be granted (see section 

505(j)(5)(B)(iv) of the FD&C Act). 

I.C. Patent Listing Requirements 

In July 2002, the FTC published a 

report on ‘‘Generic Drug Entry Prior to 

Patent Expiration: An FTC Study’’ (FTC 

Report) that, among other things, 

identified circumstances in which 

ANDA applicants were delayed in 

entering the market (see http://

www.ftc.gov/sites/default/files/

documents/reports/generic-drug-entryprior-patent-expiration-ftc-study/

genericdrugstudy_0.pdf). These 

circumstances included multiple 30- 

month stays of approval (related to 

paragraph IV certifications for 

additional patents listed after ANDA 

submission) and a delay in ‘‘triggering’’ 

the start of a first applicant’s 180-day 

period of marketing exclusivity thereby 

blocking subsequent ANDA applicants. 

In response to the FTC Report, FDA 

published a proposed rule in October 

2002 to amend its patent listing 

requirements and to permit only a single 

30-month stay of approval for a 

505(b)(2) application or ANDA (see 67 

FR 65448, October 24, 2002) (October 

2002 proposed rule). The final rule on 

‘‘Applications for FDA Approval to 

Market a New Drug: Patent Submission 

and Listing Requirements and 

Application of 30-Month Stays on 

Approval of [ANDAs] Certifying That a 

Patent Claiming a Drug Is Invalid or 

Will Not Be Infringed’’ was published in 

June 2003 (68 FR 36676, June 18, 2003) 

(June 2003 final rule). 

I.D. MMA 

The MMA was enacted on December 

8, 2003, and superseded certain sections 

of the June 2003 final rule regarding the 

application of 30-month stays of 

approval of certain 505(b)(2) 

applications and ANDAs; the 

superseded regulations were 

subsequently revoked by technical 

amendment (see ‘‘Application of 30- 

Month Stays on Approval of [ANDAs] 

and Certain [NDAs] Containing a 

Certification That a Patent Claiming the 

Drug Is Invalid or Will Not Be Infringed; 

Technical Amendment’’ (69 FR 11309, 

March 10, 2004). 

Title XI of the MMA addressed two 

key concerns identified in the FTC 

Report by limiting the availability of 30- 

month stays of approval on 505(b)(2) 

applications and ANDAs that are 

otherwise ready to be approved (30- 

month stays) and by establishing 

conditions under which a first applicant 

would forfeit the 180-day exclusivity 

period such that approval of subsequent 

ANDAs would no longer be blocked. 

Section 1101 of the MMA provides that 

a 30-month stay of approval of a 

505(b)(2) application or ANDA is 

available only if patent infringement 

litigation was initiated within the 45- 

day period after receipt of notice of a 

paragraph IV certification for a patent 

that had been submitted to FDA before 

the date of submission of the 505(b)(2) 

application or ANDA (excluding an 

amendment or supplement to the 


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application). The resulting incentive for 

an applicant to change the listed drug 

relied upon through an amendment of 

or a supplement to a 505(b)(2) 

application or ANDA is addressed by 

the MMA’s prohibition of the 

submission of certain types of changes 

(including those requiring reference to a 

different listed drug) in an amendment 

of or supplement to a 505(b)(2) 

application or ANDA. In addition, 

section 1101 of the MMA amended the 

FD&C Act to specify the types of court 

actions that will terminate a 30-month 

stay of approval. 

Section 1101 of the MMA also created 

new requirements for 505(b)(2) and 

ANDA applicants sending notice of a 

paragraph IV certification, including 

changes to the timing and contents of 

such notice. In addition, the MMA 

established conditions under which a 

505(b)(2) or ANDA applicant may bring 

a declaratory judgment action to obtain 

‘‘patent certainty’’ (i.e., obtain a judicial 

determination of non-infringement, 

invalidity, or unenforceability) with 

respect to a listed patent for which it 

has given notice of a paragraph IV 

certification but has not been sued by 

the NDA holder or patent owner(s) 

within the statutory timeframe. If a 

patent infringement action is initiated 

against the 505(b)(2) or ANDA 

applicant, the MMA provides that the 

applicant may assert a counterclaim 

seeking an order requiring a correction 

or deletion of the patent information 

submitted to FDA for listing by the NDA 

holder or patent owner. 

Section 1102 of the MMA altered the 

conditions under which a 180-day 

period of marketing exclusivity is 

granted by requiring, among other 

things, that a first applicant lawfully 

maintain the paragraph IV certification 

contained in its submission of a 

substantially complete ANDA. In 

addition, section 1102 of the MMA 

established conditions under which a 

first applicant would forfeit the 180-day 

exclusivity period. 

Section 1103 of the MMA clarified the 

types of bioavailability and 

bioequivalence data that can be used to 

support a 505(b)(2) application or 

ANDA for a drug that is not intended to 

be absorbed into the bloodstream. 

On March 3, 2004, we published a 

notice in the Federal Register entitled 

‘‘Generic Drug Issues; Request for 

Comments’’ (69 FR 9982) (Request for 

MMA Comments) which invited public 

comment to further identify issues 

related to the MMA provisions 

regarding 30-month stays, 180-day 

exclusivity, and bioavailability and 

bioequivalence, along with any 

suggestions for how to resolve those 

issues. Comments received in response 

to the Agency’s Request for MMA 

Comments are addressed in this 

document, as appropriate. 

We are currently implementing the 

180-day exclusivity provisions of the 

MMA directly from the statute and will 

determine if additional rulemaking is 

necessary in the future. Where a novel 

issue of interpretation is raised by a 

particular factual scenario regarding 

forfeiture of 180-day exclusivity, we 

may open a public docket or otherwise 

seek comment from affected parties in 

advance of taking action (see, e.g., 

Docket Nos. FDA–2007–N–0445 

(acarbose tablets), FDA–2007–N–0269 

(granisetron hydrochloride injection), 

FDA–2007–N–0035 (ramipril capsules), 

and FDA–2008–N–0483 (dorzolamide 

hydrochloride—timolol maleate 

ophthalmic solution), available at http:// 

www.regulations.gov). 

We invite interested parties to 

comment on any aspect of this proposed 

rule. In addition to requesting general 

comments on this proposal, we have 

identified issues throughout this 

document on which we are specifically 

seeking comments. 

II. Description of the Proposed Rule 

This proposed rule implements 

portions of the MMA that pertain to 30- 

month stays and other matters not 

related to 180-day exclusivity, and 

makes our regulations governing 

505(b)(2) applications and ANDAs 

consistent with amendments made to 

the FD&C Act by the MMA. In addition, 

FDA is proposing to amend its 

regulations regarding 505(b)(2) 

applications and ANDAs to facilitate 

compliance with and efficient 

enforcement of the FD&C Act, and to 

clarify and update these regulations 

based on our practical experience 

implementing the provisions related to 

approval of 505(b)(2) applications and 

ANDAs. 

Table 1 summarizes the proposed 

changes related to FDA’s patent listing, 

patent certification, and 30-month stay 

regulations in part 314 (21 CFR part 

314) and bioavailability and 

bioequivalence regulations in part 320 

(21 CFR part 320): 

TABLE 1—HIGHLIGHTS OF PROPOSED CHANGES TO FDA’S PATENT LISTING, PATENT CERTIFICATION, AND 30-MONTH

STAY REGULATIONS 1

21 CFR Section to which changes 

apply 

Proposed Changes See section of this document 

(identified in parentheses) for more detailed information regarding the proposed change 

314.3 ............................................... Overview of New, Revised, and Relocated Definitions (II.A.1). 

Proposed Amendments to Definitions in § 314.3 (II.A.2). 

Definitions in Current § 314.108 (II.A.3). 

Definitions in Current § 320.1 (II.A.4). 

314.50(i)(1) ...................................... Patent Certification Requirements for Method-of-Use Patents (II.C.1). 

Procedure for Submission of an Application Requiring Investigations for Approval of a New Indication for, 

or Other Change From, a Listed Drug (II.H). 

314.50(i)(2) ...................................... Patent Certification Requirements for Method-of-Manufacturing Patents. 

(II.C.2). 

314.50(i)(3) ...................................... Licensing Agreements (II.C.3). 

314.50(i)(4) ...................................... Untimely Filing of Patent Information (II.B.2). 

314.50(i)(6) ...................................... Amended Patent Certifications, including: 

a. Amended patent certifications after a finding of infringement; 

b. Amended certifications after a request by the NDA holder to remove a patent from the list; 

c. Amended certifications upon patent reissuance; and 

d. Other amended certifications. 

(II.E.1 through II.E.4). 

314.52(b) and (d) ............................ Timing of Notice of Paragraph IV Certification, including: 

a. Date before which notice may not be given; 

b. Date by which notice must be given; and 

c. Certification of provision of notice. 

(II.D.1). 


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TABLE 1—HIGHLIGHTS OF PROPOSED CHANGES TO FDA’S PATENT LISTING, PATENT CERTIFICATION, AND 30-MONTH

STAY REGULATIONS 1—Continued 

21 CFR Section to which changes 

apply 

Proposed Changes See section of this document 

(identified in parentheses) for more detailed information regarding the proposed change 

314.52(c) ......................................... Contents of Notice of Paragraph IV Certification, including: 

a. Statement that any required bioavailability or bioequivalence studies for a 505(b)(2) application 

have been submitted; 

b. Statement confirming receipt of an acknowledgment letter or a paragraph IV acknowledgment letter; 

c. Documentation that paragraph IV certification was submitted and notice was sent only for patents 

listed in the Orange Book; and 

d. Offer of confidential access accompanying notice. 

(II.D.3). 

314.52(d) ......................................... Notice Required for All Paragraph IV Certifications. 

(II.D.2). 

314.52(e) ......................................... Documentation of Timely Sending and Receipt of Notice of Paragraph IV Certification, including: 

a. Acceptable methods of sending notice of paragraph IV certification; and 

b. Amendment documenting timely sending and confirmation of receipt of notice of paragraph IV certification. 

(II.D.4). 

314.53(b) and (c) ............................ General Requirements for Submission of Patent Information, including: 

Revisions to scope of required submission of patent information. 

(II.B.1). 

314.53(d) ......................................... When and Where To Submit Patent Information, including: 

a. Submission of patent information for NDA supplements; 

b. Untimely filing of patent information; 

c. Where to send submissions of Form FDA 3542a and 3542; and 

d. Submission date of patent information. 

(II.B.2). 

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

314.53(f) .......................................... Correction or Change of Patent Information, including: 

a. Patents that claim an approved method of using the drug product (method-of-use patents); and 

b. Requests by NDA holder to remove patent information from the list. 

(II.B.4). 

314.54 ............................................. Procedure for Submission of an Application Requiring Investigations for Approval of a New Indication for, 

or Other Change From, a Listed Drug. 

(II.H). 

314.60(e) ......................................... Amendments to an Unapproved 505(b)(2) Application for A Different Drug, including: 

a. Applications within the scope of section 505(b)(4)(A) of the FD&C Act; 

b. Proposed amendments subject to section 505(b)(4)(A) of the FD&C Act; 

c. Exception for amendments to seek approval of a different strength; and 

(II.G.3). 

314.60(f) .......................................... Patent Certification Requirements for Amendments to 505(b)(2) Applications (II.F). 

314.70(h) ......................................... Supplements to a 505(b)(2) Application for A Different Drug (II.G.4). 

314.70(i) .......................................... Patent Certification Requirements for Supplements to 505(b)(2) Applications (II.F). 

314.90 ............................................. Refusal to Approve an NDA (II.L). 

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

314.94(a)(12)(iii) .............................. Patent Certification Requirements for Method-of-Use Patents (II.C.2). 

314.94(a)(12)(iv) ............................. Patent Certification Requirements for Method-of-Manufacturing Patents (II.C.3). 

314.94(a)(12)(viii) ............................ Amended Patent Certifications, including: 

a. Amended patent certifications after a finding of infringement; 

b. Amended certifications after a request by the NDA holder to remove a patent from the list; 

c. Amended certifications upon patent reissuance; and 

d. Other amended certifications. 

(II.E.1 through II.E.4). 

314.95(b) and (d) ............................ Timing of Notice of Paragraph IV Certification, including: 

a. Date before which notice may not be given; 

b. Date by which notice must be given; and 

c. Certification of provision of notice. 

(II.D.1). 

314.95(c) ......................................... Contents of Notice of Paragraph IV Certification, including: 

a. Statement confirming receipt of an acknowledgment letter or a paragraph IV acknowledgment letter; 

b. Clarification that paragraph IV certifications may be submitted only for patents listed in the Orange 

Book; and 

c. Offer of confidential access accompanying notice. 

(II.D.3). 

314.95(d) ......................................... Notice Required for All Paragraph IV Certifications (II.D.2). 

314.95(e) ......................................... Documentation of Timely Sending and Receipt of Notice of Paragraph IV. 

Certification, including: 

a. Acceptable methods of sending notice of paragraph IV certification; and 

b. Amendment documenting timely sending and confirmation of receipt of notice of paragraph IV certification. 

(II.D.4). 


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TABLE 1—HIGHLIGHTS OF PROPOSED CHANGES TO FDA’S PATENT LISTING, PATENT CERTIFICATION, AND 30-MONTH

STAY REGULATIONS 1—Continued 

21 CFR Section to which changes 

apply 

Proposed Changes See section of this document 

(identified in parentheses) for more detailed information regarding the proposed change 

314.96(c) ......................................... Amendments to an Unapproved ANDA That Reference a Different Listed Drug, including: 

a. Approval of a pharmaceutically equivalent RLD in an NDA; 

b. Changes to the proposed drug product would result in pharmaceutical equivalence to a different 

RLD; 

c. Exception for amendments to seek approval of a different strength; and 

d. Procedure for submission of a new ANDA that identifies a different RLD. 

(II.G.1). 

314.96(d) ......................................... Patent Certification Requirements for Amendments to ANDAs (II.F). 

314.97(b) ......................................... Supplements to an ANDA That Reference a Different Listed Drug. 

a. Changes to the proposed drug product would result in pharmaceutical equivalence to a different 

RLD; 

b. Exception for supplements to seek approval of a different strength; and 

c. Procedure for submission of a new ANDA that identifies a different RLD. 

(II.G.2). 

314.97(c) ......................................... Patent Certification Requirements for Supplements to ANDAs (II.F). 

314.99 ............................................. Refusal to Approve an ANDA (II.L). 

314.101 ........................................... Notification of Filing of a 505(b)(2) Application or Receipt of an ANDA and 

Other Proposed Revisions (II.J.1 through II.J.2). 

Administrative Consequence for Late Notice of Paragraph IV Certification (II.D.5). 

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

314.107(a) ....................................... Date of Approval of a 505(b)(2) Application or ANDA (II.M.1). 

314.107(b) ....................................... Effect of Patent(s) on the Listed Drug, including: 

a. Timing of approval based on patent certification or statement; 

b. Patent information filed after submission of 505(b)(2) application or ANDA; 

c. Disposition of patent litigation; and 

d. Tentative approval. 

(II.M.2). 

314.107(c) ....................................... Subsequent ANDA Submission (II.M.3). 

314.107(d) ....................................... Delay of Approval Due to Exclusivity (II.M.4). 

314.107(e) ....................................... Notification of Court Actions or Documented Agreement (II.M.5). 

314.107(f) ........................................ Computation of the 45-day time clock (II.M.6). 

314.107(g) ....................................... Conversion of Approval to Tentative Approval (II.M.7). 

314.108 ........................................... Definitions in Current § 314.108 (II.A.3). 

314.125 ........................................... Refusal to Approve an NDA (II.L). 

314.127 ........................................... Refusal to Approve an ANDA (II.L). 

320.1 ............................................... Definitions in Current § 320.1 (II.A.4). 

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

(II.N). 

1These highlights reference important proposed revisions to our regulations, but should not be relied upon in place of the proposed regulation. 

II.A. Definitions 

II.A.1. Overview of New, Revised, and 

Relocated Definitions 

We are proposing to amend § 314.3(b) 

to define terms relevant to amendments 

to the FD&C Act made by the MMA and 

to add definitions of terms that have 

been used by the Agency for several 

years in the context of implementing 

section 505(b) and (j) of the FD&C Act. 

We also are proposing amendments to 

§ 314.3(b) and elsewhere to conform 

with other changes that we are 

proposing in this regulation and to 

incorporate new definitions. Although 

some of these revisions are not required 

for implementation of the MMA, these 

proposed changes are intended to 

enhance the clarity of our regulations in 

part 314 and promote consistency 

throughout our regulations. 

Several definitions that we are 

proposing to add to § 314.3(b) involve 

terms that are defined specifically by 

the MMA (see definitions of ‘‘180-day 

exclusivity,’’ ‘‘first applicant,’’ 

‘‘substantially complete application,’’ 

and ‘‘tentative approval’’ in section 

II.A.2. Our proposed definitions of these 

terms closely track the statutory 

language with only minor editorial 

changes (see section 505(j)(5)(B)(iv)(I) 

and (j)(5)(B)(iv)(II) of the FD&C Act). We 

also are proposing to add definitions of 

a ‘‘paragraph IV acknowledgment letter’’ 

and an ‘‘acknowledgment letter’’ to 

§ 314.3(b), as the term ‘‘paragraph IV 

acknowledgment letter’’ is relevant to 

amendments made to section 

505(b)(3)(B)(i) and (j)(2)(B)(ii)(I) of the 

FD&C Act regarding timing 

requirements for notices of paragraph IV 

certifications (see section II.A.2). 

We are proposing to add definitions of 

terms that have been commonly used by 

the Agency over the years in the context 

of implementing section 505(b) and (j) 

of the FD&C Act and part 314, but that 

have not been expressly defined in 

§ 314.3(b) (see definitions of 

‘‘abbreviated new drug application,’’ 

‘‘ANDA,’’ ‘‘dosage form,’’ ‘‘new drug 

application,’’ ‘‘NDA,’’ ‘‘ANDA holder,’’ 

‘‘NDA holder,’’ ‘‘patent owner,’’ 

‘‘reference standard,’’ ‘‘strength,’’ and 

‘‘therapeutic equivalents’’ in section 

II.A.2). These proposed definitions are 

intended to codify our longstanding use 

of these terms, rather than substantively 

change the meaning. 

We are proposing to revise the 

definitions of certain existing terms in 

§ 314.3(b) (see definitions of ‘‘listed 

drug’’ and ‘‘the list’’ in section II.A.2) to 

conform with other changes we are 

proposing in this regulation and to 

clarify the distinction between 

approvals and tentative approvals (see 

section II.K). We also are proposing to 

revise the definitions of ‘‘abbreviated 

application’’ and ‘‘applicant’’ in 

§ 314.3(b) to reflect statutory changes 

made by the Food and Drug 

Administration Modernization Act of 


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1997 (Public Law 105–115) (FDAMA) 

that eliminated the previous need to 

distinguish between ANDAs and 

abbreviated antibiotic applications. We 

are proposing amendments to § 314.3(b) 

and elsewhere to incorporate terms used 

by the Agency into existing definitions 

(see proposed amendments to definition 

of ‘‘applicant’’ to use terms ‘‘NDA’’ and 

‘‘ANDA’’ in lieu of ‘‘application’’ and 

‘‘abbreviated application,’’ respectively, 

in section II.A.2). 

For clarity and ease of reference, we 

are proposing to add definitions of 

‘‘paragraph IV certification’’ and 

‘‘commercial marketing’’ to § 314.3(b) 

based on the current use of these terms 

in other sections of part 314. As 

discussed in section II.A.2.v, a 

paragraph IV certification is defined by 

section 505(b)(2)(A)(iv) and 

(j)(2)(A)(vii)(IV) of the FD&C Act and 

currently described in implementing 

regulations in part 314. Commercial 

marketing of certain drug products is a 

statutory trigger for beginning the period 

of 180-day exclusivity and is described 

in current and proposed regulations (see 

sections II.A.2.l and II.M.3). We also are 

proposing to move the definitions of the 

terms ‘‘active moiety’’ and ‘‘date of 

approval’’ in current § 314.108(a) to 

§ 314.3(b). These definitions are relevant 

to matters covered in other sections of 

part 314 and thus appropriate for 

inclusion in the general definition 

section for this part. 

We also are proposing to add 

definitions of ‘‘active ingredient,’’ 

‘‘inactive ingredient,’’ and the related 

term ‘‘component’’ to § 314.3(b) based 

on the current definitions in § 210.3(b) 

(21 CFR 210.3(b)). These definitions 

reflect the current use of these terms in 

other sections of part 314. 

Finally, we are proposing to move the 

definitions that currently are in 

§ 320.1(a) through (g) to § 314.3(b) for 

ease of reference and organizational 

convenience. The terms currently 

defined in § 320.1 (‘‘bioavailability,’’ 

‘‘drug product,’’ ‘‘pharmaceutical 

equivalents,’’ ‘‘pharmaceutical 

alternatives,’’ ‘‘bioequivalence,’’ 

‘‘bioequivalence requirement,’’ and 

‘‘same drug product formulation’’) are 

relevant to matters covered in part 314 

in addition to matters in part 320, and 

certain of these terms are already used 

in part 314. (As noted elsewhere in this 

document, our proposed amendments to 

part 320 (discussed in section II.N) 

would make clear that proposed terms 

defined in § 314.3 will be applicable to 

part 320 when those terms are used in 

part 320.) With three exceptions (the 

definitions of ‘‘bioavailability,’’ 

‘‘bioequivalence,’’ and ‘‘drug product,’’ 

discussed in section II.A.2), we are 

proposing to move the definitions in 

existing § 320.1(a) through (g) to 

§ 314.3(b) without changes. We are 

proposing to modify the definition of 

bioavailability in current § 320.1(a) to 

reflect a statutory change made by the 

MMA. We are proposing conforming 

revisions to the definition of 

bioequivalence. It is not necessary to 

move the definition of drug product in 

§ 320.1(b) to § 314.3 because this section 

already includes a definition of drug 

product that we believe is functionally 

identical. 

II.A.2. Proposed Amendments to 

Definitions in § 314.3 

II.A.2.a. 180-day exclusivity period. 

The MMA defines the term ‘‘180-day 

exclusivity period’’ for purposes of 

section 505(j)(5) of the FD&C Act to 

mean ‘‘the 180-day period ending on the 

day before the date on which an 

application submitted by an applicant 

other than a first applicant could 

become effective under this clause’’ (see 

section 505(j)(5)(B)(iv)(II)(aa) of the 

FD&C Act). We are proposing to 

supplement this definition for ANDAs 

subject to the MMA to incorporate the 

statutory trigger for 180-day exclusivity, 

as described in section 505(j)(5)(B)(iv)(I) 

of the FD&C Act, and make minor 

editorial changes. In proposed 

§ 314.3(b), the term ‘‘180-day exclusivity 

period’’ is defined as the 180-day period 

beginning on the date of the first 

commercial marketing of the drug 

(including the commercial marketing of 

the RLD) by any first applicant of an 

ANDA (see discussion of ‘‘commercial 

marketing’’ and ‘‘first applicant’’ in 

sections II.A.2.l and II.A.2.q). The 180- 

day period ends on the day before the 

date on which an ANDA submitted by 

an applicant other than a first applicant 

could be approved (see section 

505(j)(5)(B)(iv)(I) through 

(j)(5)(B)(iv)(II)(aa) of the FD&C Act). As 

reflected in the parenthetical reference 

to commercial marketing of the RLD, the 

180-day exclusivity period may be 

triggered by the commercial marketing 

of an ‘‘authorized generic drug,’’ as that 

term is currently defined in § 314.3(b). 

FDA interprets the 180-day 

exclusivity provisions added by the 

MMA to apply only to ANDAs referring 

to an RLD for which the first ANDA was 

submitted after December 8, 2003, 

whether or not that ANDA contained a 

paragraph IV certification at the time of 

submission (see section 1102(b)(1) of the 

MMA (Effective Date provision)). If one 

or more ANDAs were submitted before 

December 8, 2003, but the first 

paragraph IV certification was 

submitted in an ANDA after that date, 

all ANDAs would be governed by the 

pre-MMA 180-day exclusivity 

provisions in order to impose the same 

statutory exclusivity scheme on all 

ANDAs referencing a specific RLD and 

avoid a possible disparate effect on 

ANDA applicants simultaneously 

undertaking the same patent challenge 

(see FDA’s letter to ANDA applicants for 

topiramate sprinkle capsules dated 

April 15, 2009, available on FDA’s Web 

site at http://www.fda.gov). 

II.A.2.b. Abbreviated application, 

abbreviated new drug application, or 

ANDA. We are proposing to revise the 

definition of ‘‘abbreviated application’’ 

to include the alternate terms 

‘‘abbreviated new drug application’’ and 

‘‘ANDA’’ for clarity and administrative 

efficiency. Conforming revisions have 

been proposed throughout the sections 

of parts 314 and 320 in this rulemaking 

to incorporate the commonly used 

acronym ‘‘ANDA’’ in place of references 

to ‘‘abbreviated application’’ and 

‘‘abbreviated new drug application.’’ 

In addition, we are proposing to 

delete the text in § 314.3(b) that explains 

that the term ’’ ‘[a]bbreviated 

application’ applies to both an 

abbreviated new drug application and 

an abbreviated antibiotic application’’ to 

reflect statutory changes made by 

FDAMA. Section 125 of FDAMA 

repealed section 507 of the FD&C Act 

under which marketing applications, 

including ANDAs, for antibiotics had 

been approved. FDAMA provided that 

ANDAs for antibiotics previously 

approved under section 507 of the FD&C 

Act would be deemed approved under 

section 505(j) of the FD&C Act. We note 

that there have been subsequent 

amendments to the FD&C Act involving 

applications for antibiotic drugs (see QI 

Program Supplemental Funding Act of 

2008, Public Law 110–379 (2008)); 

however, these amendments are not 

specifically addressed in this proposed 

rulemaking. 

II.A.2.c. Acknowledgment letter. We 

are proposing to define the term 

‘‘acknowledgment letter’’ as a 

counterpart to the term ‘‘paragraph IV 

acknowledgment letter,’’ which is 

proposed for inclusion in § 314.3(b) to 

facilitate implementation of the MMA’s 

requirements for the timing of notice of 

a paragraph IV certification (see sections 

II.A.2.u and II.D.1). We propose to 

define ‘‘acknowledgment letter’’ as a 

written, postmarked communication 

from FDA to an applicant stating that 

the Agency has determined that a 

505(b)(2) application or ANDA is 

sufficiently complete to permit a 

substantive review. The proposed 

definition states that an 

acknowledgment letter indicates that 

the 505(b)(2) application is regarded as 


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filed or the ANDA is regarded as 

received. An acknowledgment letter is 

used for 505(b)(2) applications and 

ANDAs that contain a patent 

certification or statement other than a 

paragraph IV certification for the listed 

drug(s) relied upon or RLD, respectively 

(compare definition of ‘‘paragraph IV 

acknowledgment letter’’ discussed in 

section II.A.2.u). 

Although the term ‘‘acknowledgment 

letter’’ applies to both 505(b)(2) 

applications and ANDAs that contain a 

patent certification or statement other 

than a paragraph IV certification, there 

are important practical differences 

between the letters for each type of 

application. In FDA’s Center for Drug 

Evaluation and Research (CDER), the 

Office of Generic Drugs (OGD) reviews 

ANDAs after submission to determine 

whether the ANDA may be received for 

substantive review under 

§ 314.101(b)(1). OGD will send an 

acknowledgment letter (or a paragraph 

IV acknowledgment letter, if 

appropriate) to the applicant after a 

determination has been made that the 

ANDA is sufficiently complete to permit 

a substantive review. 

For NDAs, including 505(b)(2) 

applications, a determination regarding 

whether the application may be filed is 

made within 60 days after FDA is in 

receipt of the application as provided in 

§ 314.101(a)(1). In the absence of a 

refusal to file letter sent to the NDA 

applicant on or before day 60, the NDA 

is deemed filed. In the context of a 

505(b)(2) application, our proposed 

definition of ‘‘acknowledgment letter’’ 

reflects the current practice by CDER’s 

Office of New Drugs (OND) with respect 

to its notification of issues identified 

during the filing review (filing 

communication) to the applicant 

generally not later than 14 calendar days 

after the 60-day filing date. This filing 

communication is informally known as 

a ‘‘74-day letter’’ (see Manual of Policies 

and Procedures (MAPP) 6010.5, ‘‘NDAs: 

Filing Review Issues’’ (effective May 8, 

2003) (available on FDA’s Web site at 

http://www.fda.gov). Under our 

proposed definition, the filing 

communication sent by the OND review 

division to the 505(b)(2) applicant is the 

‘‘acknowledgment letter’’ from FDA 

stating that the 505(b)(2) application is 

sufficiently complete to permit a 

substantive review. 

It should be noted that if an original 

ANDA contains a patent certification or 

statement other than a paragraph IV 

certification, and the applicant submits 

an amendment containing a paragraph 

IV certification before the ANDA has 

been received for substantive review, 

the applicant may receive, for 

administrative reasons, an 

acknowledgment letter, rather than a 

paragraph IV acknowledgment letter. 

This contingency is addressed in 

proposed § 314.95 by the use of both 

terms. 

II.A.2.d. Act. We are proposing to 

modify the definition of ‘‘act’’ in 

§ 314.3(b) so that the citation to the U.S. 

Code reflects sections added to the 

FD&C Act by FDAMA, the Food and 

Drug Administration Amendments Act 

of 2007 (FDAAA), the Food and Drug 

Administration Safety and Innovation 

Act (FDASIA), and other legislation. 

II.A.2.e. Active ingredient. We are 

proposing to add the definition of 

‘‘active ingredient’’ currently in 

§ 210.3(b)(7) to § 314.3(b) without 

changes. The term ‘‘active ingredient’’ is 

relevant to matters covered in part 314 

in addition to matters in part 210 and 

thus appropriate for inclusion in the 

general definition section for this part. 

II.A.2.f. Active moiety. We are 

proposing to move the definition of the 

term ‘‘active moiety’’ in current 

§ 314.108(a) to § 314.3(b) without 

changes. This definition is relevant to 

matters covered in other sections of part 

314 and thus appropriate for inclusion 

in the general definition section for this 

part. 

II.A.2.g. ANDA holder and NDA 

holder. We are proposing to define the 

terms ‘‘ANDA holder’’ and ‘‘NDA 

holder’’ to mean the applicant that owns 

an approved ANDA or NDA, 

respectively. These terms have been 

commonly used by the Agency over the 

years in the context of implementing 

section 505(b) and (j) of the FD&C Act 

and part 314, but have not been 

expressly defined in § 314.3(b). 

II.A.2.h. Applicant. We are proposing 

to revise the definition of ‘‘applicant’’ to 

conform with other changes that we are 

proposing in this regulation and 

incorporate the commonly used 

acronyms ‘‘NDA’’ and ‘‘ANDA.’’ In 

addition, we are proposing to delete the 

reference to ‘‘an antibiotic drug’’ in the 

current definition of ‘‘applicant’’ to 

reflect statutory changes made by 

FDAMA that eliminated the previous 

need to distinguish between a new drug 

and an antibiotic drug. 

II.A.2.i. Application, new drug 

application, or NDA. We are proposing 

to revise the definition of ‘‘application’’ 

to include the alternate terms ‘‘new drug 

application’’ and ‘‘NDA’’ for clarity and 

administrative efficiency. Conforming 

revisions have been proposed 

throughout the sections of parts 314 and 

320 in this rulemaking to incorporate 

the commonly used acronym ‘‘NDA’’ in 

place of references to ‘‘application’’ and 

‘‘new drug application.’’ In addition, we 

are proposing to expressly state that the 

terms ‘‘application, new drug 

application, or NDA’’ refer to ‘‘standalone’’ applications submitted under 

section 505(b)(1) of the FD&C Act and 

to 505(b)(2) applications. Although 

certain regulations in part 314 refer 

specifically to 505(b)(2) applications, 

505(b)(2) applications also are subject to 

any applicable regulations governing 

new drug applications. 

We considered replacing the term 

‘‘application’’ with ‘‘new drug 

application or NDA,’’ rather than 

including ‘‘new drug application’’ or 

‘‘NDA’’ as alternate terms, because the 

term ‘‘application’’ is sometimes used to 

generally refer to any application (e.g., 

a ‘‘stand-alone’’ NDA, 505(b)(2) 

application, or ANDA) in a concise 

manner. However, such a proposal 

would have necessitated additional 

conforming revisions throughout part 

314 that are beyond the scope of this 

rulemaking. We are proposing to replace 

the term ‘‘application’’ with ‘‘NDA or 

ANDA’’ in certain sections of part 314 

to clarify the text and reflect FDA’s 

longstanding interpretation of the 

provision (see, e.g., the definition of 

‘‘specification’’ in proposed § 314.3(b)). 

II.A.2.j. Bioavailability, 

bioequivalence. The MMA amended the 

definitions of ‘‘bioavailability’’ and 

‘‘bioequivalence’’ in section 505(j)(8)(A) 

and (j)(8)(C) of the FD&C Act to confirm 

that, for drugs not intended to be 

absorbed into the bloodstream, FDA 

may ‘‘assess bioavailability by 

scientifically valid measurements 

intended to reflect the rate and extent to 

which the active ingredient or 

therapeutic ingredient becomes 

available at the site of drug action’’ 

(emphasis added). For such drugs, the 

MMA provides that FDA may establish 

‘‘alternative scientifically valid methods 

to show bioequivalence . . .’’ (see 

section 505(j)(8)(C) of the FD&C Act 

(emphasis added)). Section 1103(b) of 

the MMA expressly states that the 

amendments to section 505(j)(8)(A) and 

(j)(8)(C) of the FD&C Act ‘‘do[] not alter 

the standards for approval of drugs 

under section 505(j)’’ of the FD&C Act. 

The amendments to section 

505(j)(8)(A) and (C) of the FD&C Act 

codify FDA’s current practice, based on 

its existing regulations in §§ 320.1(a) 

and (e), 320.23(a)(1), and 320.24 and 

implementation of those regulations, 

regarding assessment of bioavailability 

and demonstration of bioequivalence for 

drugs not intended to be absorbed into 

the bloodstream (see Schering Corp. v. 

FDA, 51 F.3d 390 (3d Cir. 1995), cert. 

denied, 516 U.S. 907 (1995) (holding 

that FDA’s regulatory standard in 

§ 320.1(e) for bioequivalence of nonVerDate Sep<11>2014 19:42 Feb 05, 2015 Jkt 235001 PO 00000 Frm 00011 Fmt 4701 Sfmt 4702 E:\FR\FM\06FEP2.SGM 06FEP2

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systemically effective drugs is a 

permissible construction of the statute); 

see also section II.N). 

We are proposing to revise the 

definitions of bioavailability and 

bioequivalence in § 320.1(a) and (e) to 

incorporate the textual revisions made 

in section 505(j)(8)(A) of the FD&C Act 

and move the revised definitions to 

§ 314.3(b) in light of their relevance to 

matters covered in part 314 in addition 

to matters in part 320. The proposed 

definitions include a statement that for 

drug products that are not intended to 

be absorbed into the bloodstream, 

bioavailability and bioequivalence may 

be assessed by scientifically valid 

measurements intended to reflect the 

rate and extent to which the active 

ingredient or active moiety becomes 

available at the site of action (emphasis 

added). FDA will evaluate the scientific 

appropriateness of methodologies to 

assess the bioavailability or demonstrate 

the bioequivalence of non-systemically 

absorbed drugs based on the best 

available scientific evidence. We do not 

interpret section 505(j)(8)(A) and 

(j)(8)(C) of the FD&C Act to require full 

analytical method validation (which 

may have the effect of altering the 

standards for approval of ANDAs, 

contrary to section 1103(b) of the 

MMA), but rather methods that FDA 

considers to be scientifically valid or 

appropriate (see Docket No. FDA–2004– 

N–0062–0013 (comment submitted by 

the Biotechnology Industry 

Organization (BIO)) at 2 to 3, available 

at http://www.regulations.gov (BIO 

MMA Comment). 

To clarify our interpretation of 

‘‘bioavailability’’ and conform the 

definition with terminology used to 

define bioequivalence, we are proposing 

to revise the reference to ‘‘site of action’’ 

in current § 320.1(a) to ‘‘site of drug 

action’’ (see § 320.1(e)). For locallyacting drug products that are not 

systemically absorbed or have low 

systemic bioavailability, a 

pharmacokinetic comparison of drug 

and/or metabolite concentrations in 

plasma would not always reflect the rate 

and extent to which the active 

ingredient or active moiety becomes 

available at the site of drug action (e.g., 

gastrointestinal tract or lungs). This is 

consistent with our historical 

interpretation and application of this 

term and the express language of section 

505(j)(8)(A) of the FD&C Act. 

In addition, we are proposing to 

substitute the term ‘‘active moiety’’ for 

the statutory term ‘‘therapeutic 

ingredient’’ in the definitions of 

‘‘bioavailability’’ and ‘‘bioequivalence.’’ 

This approach reflects our longstanding 

judgment that the term ‘‘active moiety’’ 

is more appropriate than the term 

‘‘therapeutic ingredient’’ in the context 

of section 505(j)(8)(A) of the FD&C Act 

(see, e.g., ‘‘Abbreviated New Drug 

Application Regulations’’; final rule, 57 

FR 17950 at 17972, April 28, 1992) 

(1992 final rule) (‘‘Congress clearly 

intended a meaning different from 

‘active ingredient’ by the term 

‘therapeutic ingredient’ or it would not 

have used both terms [in what is now 

section 505(j)(8) of the FD&C Act]. The 

term ‘active moiety’ refers to the 

molecule or ion in an active ingredient, 

excluding those appended portions of 

the molecule that cause the ingredient 

to be an ester, or a salt or other 

noncovalent derivative that is 

responsible for the physiological or 

pharmacological action of the 

ingredient.’’) 

We also are proposing clarifying 

revisions in § 314.94(a)(7)(iii) relevant to 

bioequivalence studies. Proposed 

§ 314.94(a)(7)(iii) would state that the 

requirements for submission of a 

description of the analytical and 

statistical methods used in each 

bioequivalence study applies to in vitro 

bioequivalence studies as well as in 

vivo bioequivalence studies. An in vitro 

study used to establish or support 

bioequivalence may include, for 

example, an in vitro kinetic binding 

study, an in vitro equilibrium binding 

study, a permeability study, and a study 

of plume geometry, spray pattern, or 

droplet or particle size distribution for 

nasal spray products. 

II.A.2.k. Bioequivalence requirement. 

We are proposing to move the definition 

of ‘‘bioequivalence requirement’’ 

currently in § 320.1(f) to § 314.3(b), with 

a minor grammatical correction, for ease 

of reference and organizational 

convenience. The term ‘‘bioequivalence 

requirement’’ is relevant to matters 

covered in part 314 in addition to 

matters in part 320 and thus appropriate 

for inclusion in the general definition 

section for this part. 

II.A.2.l. Commercial marketing. We 

are proposing to define ‘‘commercial 

marketing’’ to mean the introduction or 

delivery for introduction into interstate 

commerce of a drug product described 

in an approved ANDA, outside the 

control of the ANDA holder, except for 

investigational use under part 312 of 

this chapter, but does not include 

transfer of the drug product for reasons 

other than sale to parties identified in 

the approved ANDA. 

This proposed definition is based on 

the use of this term in current 

§ 314.107(c)(4); however, we are 

proposing to alter the scope of the 

exclusion for transfer of the drug 

product for reasons other than sale. 

Section 314.107(c)(4) currently provides 

that commercial marketing ‘‘does not 

include transfer of the drug product for 

reasons other than sale within the 

control of the manufacturer or 

application holder’’ (emphasis added). 

Our proposed definition is intended to 

clarify that the ANDA holder’s shipment 

of a drug product described in an 

approved ANDA to any party named in 

the ANDA for purposes described in the 

ANDA (e.g., contract packaging) is not 

‘‘commercial marketing’’ of the drug 

product even though such transfer 

arguably places the drug products 

outside of the control of the 

manufacturer for some period of time. 

However, shipment of the drug product 

to any other party or for any other 

purpose would not fall within this 

exception and would be considered 

‘‘commercial marketing’’ (i.e., an 

introduction or delivery for introduction 

into interstate commerce of a drug 

product described in an approved 

ANDA outside the ANDA holder’s 

control). For example, if the ANDA 

holder ships the drug product to a 

wholesaler, a repackager not identified 

in the ANDA, or directly to a pharmacy, 

hospital, health maintenance 

organization, or other like entity, the 

ANDA holder will have commercially 

marketed the product as of the date of 

its shipment (if the ANDA holder 

complies with the notification 

requirement described in proposed 

§ 314.107(c)(2)). 

The first commercial marketing of a 

drug is discussed in section II.A.2.a 

(definition of the 180-day exclusivity 

period). 

II.A.2.m. Component. We are 

proposing to add the definition of 

‘‘component’’ currently in § 210.3(b)(3) 

to § 314.3(b) without changes. The term 

‘‘component’’ is used within the defined 

term ‘‘active ingredient’’ and thus is 

appropriate for inclusion in the general 

definition section for this part (see 

section II.A.2.e). 

II.A.2.n. Date of approval. We are 

proposing to move the definition of 

‘‘date of approval’’ currently in 

§ 314.108(a) to § 314.3(b) with several 

revisions. These proposed revisions to 

the definition of ‘‘date of approval’’ are 

not intended to alter our interpretation 

of § 314.108. 

Our proposed revisions to the 

definition of ‘‘date of approval’’ 

incorporate use of the term ‘‘approval 

letter,’’ which also is defined in 

§ 314.3(b), and broaden the definition to 

include the date of approval for an 

ANDA. In addition, we are proposing to 

remove from the definition of ‘‘date of 

approval’’ the caveat that the date of 

approval is the date on the approval 


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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’’ (§ 314.108(a)). This 

qualification is inapplicable to the date 

of approval of an ANDA because final 

printed labeling is required as a 

condition of approval (see 

§§ 314.94(a)(8) and 314.127(a)(7)). With 

respect to NDAs (including 505(b)(2) 

applications), § 314.105(b) specifically 

addresses the circumstances under 

which FDA will approve an NDA and 

issue the applicant an approval letter on 

the basis of draft labeling, and it is 

unnecessary to summarize this 

approach in the definition of ‘‘date of 

approval.’’ 

As proposed for revision, the ‘‘date of 

approval’’ is the date on the approval 

letter from FDA stating that the NDA or 

ANDA is approved. The date of 

approval refers only to a final approval 

and not to a tentative approval. We note 

that the date on the approval letter 

generally appears on the last page 

containing the electronic signature 

(endorsement). 

II.A.2.o. Dosage form. We are 

proposing to define ‘‘dosage form’’ to 

mean the physical manifestation 

containing the active and inactive 

ingredients that delivers a dose of the 

drug product. This includes such factors 

as (i) the physical appearance of the 

drug product, (ii) the physical form of 

the drug product prior to dispensing to 

the patient, (iii) the way the product is 

administered, and (iv) design features 

that affect frequency of dosing. This 

term has been commonly used by the 

Agency over the years in the context of 

implementing section 505(j) of the 

FD&C Act and part 314. However, 

except for the examples of dosage forms 

used in the definition of ‘‘drug 

product,’’ the term ‘‘dosage form’’ not 

been expressly defined in § 314.3(b). 

The dosage form is generally 

determined based on the form of the 

product before dispensing to the patient 

(see Abbott Laboratories v. Young, 691 

F. Supp. 462, 464 n. 1 (D.D.C. 1988) 

(‘‘The final dosage form of a drug is the 

form in which it appears prior to 

administration to the patient’’), 

remanded on other grounds, 920 F.2d 

984 (D.C. Cir. 1990), cert. denied, 502 

U.S. 819 (1991)). This is consistent with 

other factors such as physical 

recognition, dosing, and manner of 

administration that contribute to the 

determination of dosage form. Appendix 

C to the Orange Book lists the dosage 

form categories for currently marketed 

products. 

II.A.2.p. Drug product. A ‘‘drug 

product’’ is a finished dosage form (for 

example, a tablet, capsule, or solution) 

that contains a drug substance, 

generally, but not necessarily, in 

association with one or more other 

ingredients. We are proposing to delete 

a similar definition of ‘‘drug product’’ in 

current § 320.1(b) when we move the 

definitions in § 320.1 to § 314.3(b), to 

reflect the fact that § 314.3(b) already 

includes a definition of drug product. 

Although the two definitions of ‘‘drug 

product’’ differ slightly in wording, we 

believe that they are functionally 

identical, so that this proposed revision 

is intended to eliminate redundancy but 

not result in any substantive change in 

our interpretation of part 320. 

II.A.2.q. First applicant. The MMA 

defines the term ‘‘first applicant’’ for 

purposes of section 505(j)(5) of the 

FD&C Act (see section 

505(j)(5)(B)(iv)(II)(bb) of the FD&C Act). 

We are proposing to add the statutory 

definition, with minor editorial changes 

and additional clarifying text, to 

§ 314.3(b) to facilitate our continuing 

implementation of the 180-day 

exclusivity provisions of the FD&C Act. 

We are proposing to define ‘‘first 

applicant’’ in § 314.3(b) to mean an 

applicant that, on the first day on which 

a substantially complete ANDA 

containing a paragraph IV certification 

is submitted for approval of a drug, 

submits a substantially complete ANDA 

that contains, and for which the 

applicant lawfully maintains, a 

paragraph IV certification for the drug. 

We are proposing to delete the 

definition of ‘‘applicant submitting the 

first application’’ in current 

§ 314.107(c)(2) because it is superseded 

by the statutory definition (see section 

II.M.3). We note that an applicant may 

be a ‘‘first applicant’’ based on the 

submission of a paragraph IV 

certification in an amendment to an 

ANDA if other criteria are met. 

We interpret the term ‘‘drug’’ in the 

statutory definition of ‘‘first applicant’’ 

to mean ‘‘drug product’’ as currently 

defined in § 314.3(b) (see section 

505(j)(5)(B)(iv)(II)(bb) of the FD&C Act). 

Consistent with our longstanding 

practice, we note that different strengths 

of a drug product constitute different 

drug products. For example, different 

ANDA applicants seeking approval for 

different strengths of a drug product 

approved in a single NDA may each be 

first applicants with respect to a 

different strength of the drug product, if 

other applicable statutory and 

regulatory requirements are met (see 

Apotex, Inc. v. Shalala, 53 F. Supp. 2d 

454 (D.D.C.), aff’d, 1999 U.S. App. 

LEXIS 29571 (D.C. Cir. 1999)). In 

addition, there may be multiple first 

applicants for a single drug product if 

more than one ANDA applicant first 

submitted a substantially complete 

ANDA that contains, and for which the 

applicant lawfully maintains, a 

paragraph IV certification on the same 

day. 

We have interpreted the statutory 

requirement for a first applicant to 

‘‘lawfully maintain’’ a paragraph IV 

certification to mean that the ANDA 

applicant must, as a condition of 

retaining first applicant status, continue 

to lawfully assert that a relevant listed 

patent (i.e., at least one of the patents for 

which a paragraph IV certification 

qualified the ANDA applicant for first 

applicant status) is invalid, 

unenforceable, or will not be infringed 

by the manufacture, use, or sale of the 

drug for which the ANDA is submitted 

(see Letter from G. Buehler, Director, 

Office of Generic Drugs, to ANDA 

Applicant regarding 180-day exclusivity 

for dorzolamide/timolol ophthalmic 

solution, Docket No. FDA–2008–N– 

0483–0017 at 5–6, available at http://

www.regulations.gov) (Dorzolamide/

Timolol Letter). This approach comports 

with comments that we received on the 

interpretation of the phrase ‘‘lawfully 

maintained’’ in response to the Request 

for MMA Comments (see Docket No. 

FDA–2004–N–0062–0006 (comment 

submitted by the Pharmaceutical 

Research and Manufacturers of America 

(PhRMA)) at 3–5, available at http://

www.regulations.gov (PhRMA MMA 

Comment); see also Docket No. FDA– 

2004–N–0062–0009 (comment 

submitted by Eli Lilly and Company) at 

1–2, available at http://

www.regulations.gov (Lilly MMA 

Comment)). 

For example, if an ANDA applicant is 

sued for infringement of a patent that 

qualified the applicant for first 

applicant status and a court enters a 

final decision from which no appeal has 

been or can be taken that the patent is 

infringed (or signs a settlement order or 

consent decree in the action that 

includes a finding of infringement and 

does not permit market entry before 

patent expiration), the ANDA applicant 

can no longer lawfully maintain a 

paragraph IV certification with respect 

to the infringed patent (see 

Dorzolamide/Timolol Letter at 6). As 

discussed in section II.E.1, the ANDA 

applicant is required to submit an 

amended patent certification under 

§ 314.94(a)(12)(i)(A)(3) (paragraph III 

certification) in these circumstances. In 

addition, an ANDA applicant can no 

longer lawfully maintain a paragraph IV 

certification when the patent expires or 

if an ANDA applicant changes its 

certification from a paragraph IV 

certification to a 505(j)(2)(A)(viii) 


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statement (see proposed 

§ 314.94(a)(12)(viii)(C) and (D); see also 

Dorzolamide/Timolol Letter at 6, note 

5). 

It should be noted that an amendment 

to a substantially complete ANDA does 

not mean that the ANDA is no longer 

substantially complete or that a first 

applicant has not lawfully maintained 

its paragraph IV certification (unless the 

amendment requires a new patent 

certification and the amended patent 

certification is not a paragraph IV 

certification). However, if a first 

applicant submits several major 

amendments to its ANDA, there is a risk 

that the applicant may not be able to 

obtain tentative approval within 30 

months after the date on which the 

ANDA is filed, thereby forfeiting its 

eligibility for any 180-day exclusivity 

period (see section 505(j)(5)(D)(i)(IV) of 

the FD&C Act). 

We note that certain definitions, such 

as the definition of ‘‘first applicant,’’ 

may be revised or supplemented in the 

future as we continue to implement the 

180-day exclusivity provisions of the 

MMA. 

II.A.2.r. Inactive ingredient. We are 

proposing to add the definition of 

‘‘inactive ingredient’’ currently in 

§ 210.3(b)(8) to § 314.3(b) without 

changes. The term ‘‘inactive ingredient’’ 

is relevant to matters covered in part 

314 in addition to matters in part 210 

and thus appropriate for inclusion in 

the general definition section for this 

part. 

II.A.2.s. Listed drug. We are proposing 

to revise the definition of ‘‘listed drug’’ 

to clarify that a listed drug includes a 

drug product that is listed in the 

discontinued section of the Orange Book 

and that has not been withdrawn or 

suspended under section 505(e)(1) 

through (e)(5) or 505(j)(6) of the FD&C 

Act or withdrawn from sale (irrespective 

of whether the NDA has been 

withdrawn) for what FDA has 

determined are reasons of safety or 

effectiveness. Accordingly, the proposed 

definition in § 314.3(b) would state that 

a listed drug is a new drug product that 

‘‘has been approved’’ instead of one that 

‘‘has an effective approval.’’ With 

respect to the exceptions to listed drug 

status, we are correcting the paragraph 

number in the reference to the statutory 

provision under which an ANDA may 

be withdrawn or suspended for reasons 

of safety or effectiveness (see section 

505(j)(6) of the FD&C Act). 

In addition, we are proposing 

conforming revisions to incorporate 

other changes we are proposing in this 

rulemaking regarding the distinction 

between approvals and tentative 

approvals (see section II.K) and reliance 

upon the electronic version of the 

Orange Book (see section II.A.2.ee). 

Listed drug status is evidenced by the 

drug product’s identification in the 

current FDA’s ‘‘Approved Drug 

Products With Therapeutic Equivalence 

Evaluations’’ (the list) as an approved 

drug. However, we note that a drug 

product is deemed to be a listed drug on 

the date of the approval letter for the 

NDA or ANDA for that drug product, 

rather than the date on which the 

product is listed in the Orange Book. 

II.A.2.t. Original application, original 

NDA. We are proposing to revise the 

definition of ‘‘original application’’ to 

include the alternate term ‘‘original 

NDA’’ for clarity and administrative 

efficiency. In addition, we are proposing 

to replace references to ‘‘application’’ 

with ‘‘NDA’’ for consistency with other 

changes in this proposed rulemaking. 

These minor revisions are not intended 

to substantively change the meaning of 

the term ‘‘original application.’’ 

II.A.2.u. Paragraph IV 

acknowledgment letter. We are 

proposing to define ‘‘paragraph IV 

acknowledgment letter’’ to mean a 

written, postmarked communication 

from the FDA to an applicant stating 

that the Agency has determined that a 

505(b)(2) application or ANDA 

containing a paragraph IV certification 

is sufficiently complete to permit a 

substantive review (compare definition 

of ‘‘acknowledgment letter’’ discussed 

in section II.A.2.c). An acknowledgment 

letter or paragraph IV acknowledgment 

letter indicates that the 505(b)(2) 

application is regarded as filed or the 

ANDA is regarded as received. 

The proposed definition of 

‘‘paragraph IV acknowledgment letter’’ 

is intended to facilitate implementation 

of the MMA’s timing requirements for 

notice to the NDA holder and each 

patent owner of a paragraph IV 

certification. A 505(b)(2) or ANDA 

applicant is required to send notice of 

its paragraph IV certification within 20 

days after the date of the postmark on 

the paragraph IV acknowledgment letter 

(see section 505(b)(3)(B)(i) and 

(j)(2)(B)(ii)(I) of the FD&C Act and 

section II.D.1). 

In response to the Request for MMA 

Comments, the Generic Pharmaceutical 

Association (GPhA) requested that FDA 

amend § 314.101(b)(2) to state that FDA 

will notify the applicant ‘‘in writing via 

a postmarked notice’’ that the ANDA 

has been received in light of the MMA’s 

timing requirements for notice of 

paragraph IV certification (see Docket 

No. FDA–2004–N–0062–0012 (comment 

submitted by GPhA) at 4–5, available at 

http://www.regulations.gov) (GPhA 

MMA Comment). Incorporation of the 

term ‘‘paragraph IV acknowledgment 

letter’’ in proposed § 314.101(b)(2) 

would address this concern with respect 

to ANDAs (see section II.J). In addition, 

although OGD currently sends a 

paragraph IV acknowledgment letter in 

an envelope bearing a postmark made 

by the U.S. Postal Service, we are 

proposing to broaden the definition the 

‘‘postmark’’ to accommodate electronic 

transmissions in the future (see section 

II.A.2.y). 

For ANDAs, OGD currently sends a 

‘‘paragraph IV acknowledgment letter’’ 

to confirm the date on which the ANDA 

was received and to establish the 

timeframe within which an ANDA 

applicant must send notice of a 

paragraph IV certification contained in 

the original ANDA (see section II.D.1). 

The letter also provides ANDA 

applicants with an overview of the 

notice requirements associated with 

submission of a paragraph IV 

certification to a listed patent for the 

RLD. 

For 505(b)(2) applications that rely on 

the Agency’s finding of safety and/or 

effectiveness for a listed drug and 

include a paragraph IV certification for 

a listed patent, the Notification of Issues 

Identified during the Filing Review 

(filing communication), sometimes 

referred to as the ‘‘74-day letter,’’ would 

constitute the ‘‘paragraph IV 

acknowledgment letter’’ defined in 

§ 314.3. Unlike the paragraph IV 

acknowledgment letter for ANDAs, the 

OND filing communication is typically 

sent in a franked envelope that may not 

bear a postmark made by the U.S. Postal 

Service. For purposes of § 314.52(b) and 

(c) (21 CFR 314.52(b) and (c)) only, the 

‘‘date of the postmark’’ on the 

‘‘paragraph IV acknowledgment letter’’ 

will be considered to be 4 calendar days 

after the date on which the filing 

communication is signed by the 

signatory authority (generally the 

Division Director or designee in the 

OND review division), which generally 

reflects the date on which the document 

is received by the U.S. Postal Service 

(see definition of ‘‘postmark’’ in 

proposed § 314.3). For example, if the 

filing communication is electronically 

signed by the Division Director or 

designee on Thursday, April 7th, the 

date of the postmark on the paragraph 

IV acknowledgment letter for the 

505(b)(2) application, for purposes of 

§ 314.52(b), would be Monday, April 

11th. If OND sends the filing 

communication via electronic 

transmission in the future, then our 

proposed definition of ‘‘postmark’’ in 

§ 314.3(b) would apply. 

As noted previously, the paragraph IV 

acknowledgment letter triggers the 


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requirements in proposed §§ 314.52(b) 

and 314.95(b) for sending notice of the 

paragraph IV certification. The proposed 

difference in interpreting the term 

‘‘postmark’’ as applied to paragraph IV 

acknowledgment letters for 505(b)(2) 

applications reflects current OND 

practice regarding the mailing of filing 

communications, which should occur 

no later than 74 days after the date of 

submission of the 505(b)(2) application. 

In addition, although an indisputable 

date of mailing is needed for competing 

ANDAs that may be eligible for a period 

of 180-day exclusivity, a 505(b)(2) 

application does not raise these 

concerns. We invite comment on this 

proposed approach or whether an 

alternative approach should be 

considered. 

II.A.2.v. Paragraph IV certification. 

We are proposing to define ‘‘paragraph 

IV certification’’ in § 314.3(b) to mean a 

patent certification of invalidity, 

unenforceability, or noninfringement 

described in § 314.50(i)(1)(i)(A)(4) or 

§ 314.94(a)(12)(i)(A)(4) for 505(b)(2) 

applications and ANDAs, respectively. 

This term is routinely used by the 

Agency and applicants to refer to this 

type of patent certification. The addition 

of the term ‘‘paragraph IV certification’’ 

to § 314.3(b) would provide a 

convenient means of clearly referencing 

the patent certification described in the 

section 505(b)(2)(A)(iv) and 

(j)(2)(A)(vii)(IV) of the FD&C Act and 

implementing regulations. 

II.A.2.w. Patent owner. We are 

proposing to define ‘‘patent owner’’ as 

the owner of the patent for which 

information is submitted for an NDA. A 

patent may be owned by more than one 

person. If a patent owner seeks to have 

its designated representative receive 

notice of a paragraph IV certification by 

a 505(b)(2) or ANDA applicant that 

relies upon a listed drug claimed by the 

patent, the patent owner should ensure 

that current information regarding the 

correspondence address, in accordance 

with 37 CFR 1.33(d), is submitted to the 

PTO. 

II.A.2.x. Pharmaceutical alternatives 

and pharmaceutical equivalents. We are 

proposing to revise the definition of 

‘‘pharmaceutical equivalents’’ to clarify 

that this term is intended to refer to 

drug products in identical dosage forms 

and route(s) of administration that 

contain identical amounts of the 

identical active ingredient. The 

requirement for pharmaceutically 

equivalent products to have the same 

route(s) of administration is consistent 

with FDA’s current practice, as 

described in section 1.2 of the preface 

to the Orange Book (33rd Edition, 2013, 

at vii). We are not proposing any 

changes to the definition of 

‘‘pharmaceutical alternatives.’’ 

We are proposing to move the 

definitions of ‘‘pharmaceutical 

alternatives’’ and ‘‘pharmaceutical 

equivalents’’ currently in § 320.1(c) and 

(d) to § 314.3(b), for ease of reference 

and organizational convenience. The 

concepts of ‘‘pharmaceutical 

alternatives’’ and ‘‘pharmaceutical 

equivalents’’ are relevant to matters 

covered in part 314 (including but not 

limited to § 314.94 and proposed 

§§ 314.50(i)(1)(i)(C), 314.93(f), 314.96(c), 

and 314.97(b), discussed in section 

II.G.1–2, II.H, and II.I) in addition to 

matters in part 320 (21 CFR part 320). 

II.A.2.y. Postmark. We are proposing 

to define the term ‘‘postmark’’ in 

§ 314.3(b) to address the MMA’s 

requirement that a 505(b)(2) or ANDA 

applicant send notice of its paragraph IV 

certification within ‘‘20 days after the 

date of the postmark on the notice [i.e., 

the paragraph IV acknowledgment 

letter] with which [FDA] informs the 

applicant that the application has been 

filed’’ (see section 505(b)(3)(B)(i) and 

505(j)(2)(B)(ii)(I) of the FD&C Act). The 

term ‘‘postmark’’ is not used elsewhere 

in section 505 of the FD&C Act or in our 

current regulations in part 314. In light 

of the transition by FDA and regulated 

industry to electronic communications, 

an interpretation of the term ‘‘postmark’’ 

to mean a postmark made by the U.S. 

Postal Service (‘‘U.S. postmark’’) could 

quickly become outdated. The purpose 

of the postmark in section 505(b)(3)(B)(i) 

and (j)(2)(B)(ii)(I) of the FD&C Act is to 

establish a verifiable date from which 

the 20-day notice period runs. 

Accordingly, we are proposing a broader 

definition of a ‘‘postmark’’ to mean ‘‘an 

independently verifiable evidentiary 

record of the date on which a document 

is transmitted, in an unmodifiable 

format, to another party. For postmarks 

made by the U.S. Postal Service or a 

designated delivery service, the date of 

transmission is the date on which the 

document is received by the domestic 

mail service of the U.S. Postal Service 

or by a designated delivery service. For 

postmarks documenting an electronic 

event, the date of transmission is the 

date (in a particular time zone) that FDA 

sends the electronic transmission on its 

host system as evidenced by a verifiable 

record. If the sender and the intended 

recipient are located in different time 

zones, it is the sender’s time zone that 

provides the controlling date of 

electronic transmission.’’ This proposed 

definition of ‘‘postmark’’ is adapted 

from the definition of ‘‘electronic 

postmark’’ in regulations issued by the 

Internal Revenue Service (IRS) with 

respect to electronic filing of documents 

required under 26 U.S. C. 7502 (see 26 

CFR 301.7502–1(d)(3)(ii)). 

We invite comment on our proposed 

interpretation of the term ‘‘postmark’’ in 

the context of a paragraph IV 

acknowledgment letter from FDA to an 

applicant for a 505(b)(2) application or 

ANDA, and whether our regulations 

should be amended to define differently 

the specific date from which the 20-day 

notice period runs. 

II.A.2.z. Reference standard. We are 

proposing to define ‘‘reference 

standard’’ as the drug product selected 

by FDA that an applicant seeking 

approval of an ANDA must use in 

conducting an in vivo bioequivalence 

study required for approval. This 

proposed definition reflects the 

Agency’s longstanding use of this term, 

as described in the preamble to our 1992 

final rule implementing the HatchWaxman Amendments (‘‘FDA intends 

the reference listed drug to be the same 

drug product selected by the agency as 

the reference standard for 

bioequivalence determinations’’ (57 FR 

17950 at 17954). By generally 

designating a single drug product as the 

standard to which generic versions must 

be shown to be bioequivalent, FDA 

seeks to avoid possible significant 

variations among generic drugs, which 

could result if such drugs were 

compared to different drug products. 

The reference standard is identified in 

the Orange Book by the word ‘‘yes’’ in 

the ‘‘RLD’’ column. In certain 

circumstances, a drug product approved 

in an ANDA (including a petitioned 

ANDA) may be designated as the 

reference standard for bioequivalence 

studies intended to support approval of 

an ANDA. For example, if the RLD is a 

drug product approved in an NDA that 

has been withdrawn from marketing (for 

reasons other than safety or 

effectiveness), a therapeutically 

equivalent drug product approved in an 

ANDA may be designated as the 

reference standard. 

We recognize that the term ‘‘reference 

standard’’ has other meanings, 

including in the context of part 314 (see 

§ 314.50(e)(1)(C)) regarding submission 

of representative samples of reference 

standards used in analytical studies, 

excluding pharmacopoeial reference 

standards). The proposed definition of 

‘‘reference standard’’ applies solely to 

the product used in conducting an in 

vivo bioequivalence study required for 

approval. 

II.A.2.aa. Same drug product 

formulation. We are proposing to move 

the definition of ‘‘same drug product 

formulation’’ currently in § 320.1(g) to 

§ 314.3(b), without changes, for ease of 

reference and organizational 


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convenience. The term ‘‘same drug 

product formulation’’ is relevant to 

matters covered in part 314 (including 

but not limited to §§ 314.94 and 314.96) 

in addition to matters in part 320. 

II.A.2.bb. Strength. We are proposing 

to define the term ‘‘strength’’ in 

§ 314.3(b) to mean the amount of drug 

substance contained in, delivered, or 

deliverable from a drug product. The 

amount of drug substance contained in, 

delivered, or deliverable from a drug 

product includes: (i)(A) The total 

quantity of drug substance in mass or 

units of activity in a dosage unit or 

container closure (e.g., weight/unit 

dose, weight/volume or weight/weight 

in a container closure, or units/volume 

or units/weight in a container closure) 

and/or, as applicable (i)(B) the 

concentration of the drug substance in 

mass or units of activity per unit volume 

or mass (e.g., weight/weight, weight/

volume, or units/volume). If these 

weights and measures are not applicable 

to a type of drug product or dosage 

form, then the strength of the drug 

product may be described by such other 

criteria the Agency establishes for 

determining the amount of drug 

substance contained in, delivered, or 

deliverable from the drug product. For 

example, the strength of certain drugdevice combination products (such as a 

transdermal delivery system) may be 

expressed as the amount of drug 

substance delivered per unit time. 

This proposed definition is intended 

to codify FDA’s interpretation of the 

term ‘‘strength’’ in the context of section 

505(j)(2)(A)(iii) of the FD&C Act. This 

proposed definition also will facilitate 

implementation of certain statutory 

provisions added by the MMA regarding 

amendments and supplements that seek 

approval of a ‘‘different strength’’ (see 

section 505(b)(4)(B) and (j)(2)(D)(ii) of 

the FD&C Act). Different strengths of a 

drug product constitute different drug 

products. 

The amount of the drug substance 

‘‘delivered’’ from a drug product is 

intended to describe the mass of drug 

substance delivered to the patient either 

per unit time (e.g., as in transdermal 

delivery system) or per actuation (e.g., 

as in metered dose inhalers) and 

excludes excess drug substance that 

although not available for labeled use, is 

necessary to allow for the specified total 

delivery (e.g., a specified number of 

hours for a transdermal delivery system 

or a specified number of actuations for 

a metered dose inhaler). 

The amount of drug substance 

‘‘deliverable from’’ a drug product is 

intended to exclude the excess volume 

allowed by the U.S. Pharmacopeia 

(USP) (to permit withdrawal and 

administration of the labeled volume of 

an injectable product) from the 

description of the ‘‘strength’’ of the drug 

product (see 21 CFR 201.51(g)). 

FDA has a longstanding history of 

considering a difference in the total 

quantity of drug substance of a 

parenteral product (e.g., a single or 

multiple dose vial) or a difference in the 

concentration of a parenteral product to 

be a difference in the ‘‘strength’’ of the 

product for purposes of section 

505(j)(2)(A)(iii) of the FD&C Act. FDA 

considers it important to review 

proposed differences in the total drug 

content or the concentration of a 

parenteral product because such 

changes can result in medication errors 

and incorrect dosing of patients. 

Accordingly, the strength of a parenteral 

drug product is determined by both 

criteria in paragraph (i) of the proposed 

definition—i.e., the total quantity of 

drug substance in a container closure 

and the concentration of the drug 

substance. 

For other dosage forms, the strength of 

the drug product is determined based 

only on the criteria in paragraph (i)(A) 

or (i)(B) of the proposed definition. For 

example, the strength of a solid oral 

dosage form is determined only by the 

total quantity of drug substance in a 

dosage unit (e.g., a 25-milligram (mg) 

tablet). In contrast, the strength of a 

semisolid dosage form is typically 

determined by the concentration of the 

drug substance. For example, the 

strength of a cream is generally 

expressed by the concentration as a 

weight/weight percentage reflecting the 

mass of the drug substance per unit 

mass of the drug product. 

We recognize that the weights and 

measures described in paragraph (i) of 

the proposed definition may not be 

applicable to all types of drug product 

or dosage forms. Accordingly, paragraph 

(ii) of the proposed definition provides 

that the strength of the drug product 

may be described by such other criteria 

as the Agency establishes for 

determining the amount of drug 

substance contained in, delivered, or 

deliverable from the drug product. 

It should be emphasized that the 

proposed definition of strength refers to 

the amount of the drug substance (active 

ingredient), and not the amount of the 

active moiety, in the drug product. 

However, we recognize that approved 

drug products formulated with a salt of 

an acid or a base (commonly referred to 

as ‘‘salt drug products’’) may use the 

active moiety in the name rather than 

the drug substance to conform with a 

drug product naming policy established 

by the USP. Although the USP naming 

policy describes the ‘‘strength’’ of a drug 

product as the amount of active moiety 

present in the product, the strength of 

the drug product for purposes of section 

505(j)(2)(A)(iii) of the FD&C Act is the 

amount of the drug substance. These 

approaches to describing the strength of 

the drug product do not conflict because 

if two drug products containing the 

same drug substance are demonstrated 

to have the same ‘‘strength’’ in terms of 

active moiety, they will always have the 

same strength in terms of drug 

substance. For example, a tablet drug 

product that contains 125 mg of the 

drug substance ‘‘novelpril maleate’’ 

equivalent to 100 mg of the active 

moiety ‘‘novelpril’’ would be expressed 

as ‘‘novelpril tablet 100 mg.’’ Based on 

the proposed definition in § 314.3(b), 

the strength of the drug product is 125 

mg of the drug substance ‘‘novelpril 

maleate.’’ The label for this product 

would describe both the ‘‘strength’’ 

expressed in terms of active moiety and 

the strength expressed in terms of drug 

substance. The Agency recognizes that 

this naming policy will result in 

situations in which the ‘‘strength’’ that 

directly follows the drug product name 

for such products will be expressed in 

terms of active moiety and not in terms 

of drug substance, and that this might be 

confusing. FDA seeks comment on this 

approach to the proposed definition of 

strength in light of these considerations. 

We also generally invite comment on 

whether this proposed definition 

adequately encompasses the broad range 

of dosage forms and drug products to 

which a proposed definition of 

‘‘strength’’ in § 314.3(b) would apply. 

II.A.2.cc. Substantially complete 

application. The MMA defines the term 

‘‘substantially complete application’’ for 

purposes of section 505(j)(5) of the 

FD&C Act (see section 

505(j)(5)(B)(iv)(II)(cc) of the FD&C Act). 

We are proposing to define 

‘‘substantially complete application’’ in 

§ 314.3(b) to incorporate this statutory 

definition with minor editorial 

revisions. As proposed, a ‘‘substantially 

complete application’’ would mean an 

ANDA that on its face is sufficiently 

complete to permit a substantive review 

and contains all the information 

required under section 505(j)(2)(A) of 

the FD&C Act and § 314.94. For an 

application to be substantially complete, 

any information referenced in the 

application must have been provided to 

the Agency. For example, FDA will 

refuse to receive an ANDA for which a 

referenced Drug Master File has not 

been submitted or that omitted relevant 

stability or bioequivalence data as of the 

date of submission of the ANDA. There 

may be other bases for finding that an 

application is not substantially 


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complete—for example, electronic 

submissions that are not readable or do 

not follow FDA’s recommendations for 

electronic application format may be 

determined to be not substantially 

complete and refused for receipt. 

In addition, we are proposing 

conforming revisions to § 314.101(b) to 

clarify that receipt of an ANDA means 

that FDA has made a threshold 

determination that the ANDA is 

substantially complete (see section II.J). 

Our proposed replacement of the 

current criterion ‘‘sufficiently complete 

to permit a substantive review’’ with the 

synonymous term ‘‘substantially 

complete application’’ is not intended to 

alter the meaning. Rather, we are 

seeking to use defined terms 

consistently throughout our regulations. 

II.A.2.dd. Tentative approval. The 

MMA defines the term ‘‘tentative 

approval’’ for purposes of section 

505(j)(5) of the FD&C Act to mean 

‘‘notification to an applicant by the 

Secretary that an [ANDA] meets the 

requirements of [section 505(j)(2)(A)], 

but cannot receive effective approval 

because the application does not meet 

the requirements of [section 

505(j)(5)(B)], there is a period of 

exclusivity for the listed drug under 

[section 505(j)(5)(F)] or section 505A, or 

there is a 7-year period of exclusivity for 

the listed drug under section 527’’ 

(section 505(j)(5)(B)(iv)(II)(dd)(AA) of 

the FD&C Act). We are proposing to 

define ‘‘tentative approval’’ in § 314.3(b) 

to incorporate the statutory text and 

extend this general definition, with 

appropriate conforming revisions, to 

include tentative approval of an NDA 

(including a 505(b)(2) application). 

Proposed § 314.3(b) defines ‘‘tentative 

approval’’ to mean the notification that 

an NDA (including a 505(b)(2) 

application) or ANDA otherwise meets 

the requirements for approval under the 

FD&C Act, but cannot be approved 

because there is unexpired orphan drug 

exclusivity for a listed drug, or that a 

505(b)(2) application or ANDA 

otherwise meets the requirements for 

approval under the FD&C Act, but 

cannot be approved until the conditions 

in § 314.107(b)(1)(iii), (b)(3), or (c) are 

met, because there is a period of 

exclusivity for the listed drug under 

§ 314.108 or section 505A of the FD&C 

Act (21 U.S. C. 355a), or because a court 

order pursuant to 35 U.S. C. 271(e)(4)(A) 

orders that the application may be 

approved no earlier than the date 

specified. Proposed § 314.107(b)(4) 

describes the circumstances in which 

FDA will issue a tentative approval 

letter (see section II.M.2.d). 

The proposed definition of ‘‘tentative 

approval’’ clarifies that a drug product 

that is granted tentative approval is not 

an approved drug and will not be 

approved until FDA issues an approval 

letter after any necessary additional 

review of the NDA or ANDA (compare 

section 505(j)(5)(B)(iv)(II)(dd)(BB) of the 

FD&C Act). We have proposed minor 

editorial revisions to the limitation 

described in the statute to replace 

references to ‘‘effective approval’’ of an 

NDA or ANDA with language reflecting 

our current practice. As discussed in 

section II.K, the Agency does not issue 

approval letters with delayed effective 

dates. 

II.A.2.ee. The list. We are proposing to 

revise the definition of ‘‘the list’’ to 

mean the list of approved drug products 

published in FDA’s current ‘‘Approved 

Drug Products With Therapeutic 

Equivalence Evaluations,’’ available 

electronically on FDA’s Web site (http:// 

www.fda.gov/cder). These clarifying 

revisions reflect our longstanding 

practice of relying upon the electronic 

version of the Orange Book (currently 

available at http://

www.accessdata.fda.gov/scripts/cder/

ob/default.cfm), which is updated on a 

regular basis and can be accessed from 

FDA’s Web site. We are proposing to 

delete the words ‘‘current edition,’’ ‘‘any 

current supplement,’’ and ‘‘publication’’ 

from the definition as these phrases 

imply reference to a printed version. As 

discussed in section II.B.3, the Agency 

no longer arranges for publication of an 

annual printed edition or monthly 

printed supplements to the Orange 

Book. 

Although the format of the electronic 

version of the Orange Book may change 

with advances in technology, FDA 

intends to maintain a publicly available 

version of the list that includes, among 

other things: Approved NDAs and 

ANDAs; therapeutic equivalence 

evaluations (as applicable); exclusivity 

granted to a listed drug; patents 

submitted for listing by the NDA holder; 

use codes for method-of-use patents; 

requests to remove a patent from the 

list; and, upon request on a prospective 

basis, the date on which patents are 

received by FDA for listing. 

II.A.2.ff. Therapeutic equivalents. We 

are proposing to define ‘‘therapeutic 

equivalents’’ as approved drug products 

that are pharmaceutical equivalents and 

for which bioequivalence has been 

demonstrated. Therapeutic equivalents 

can be expected to have the same 

clinical effect and safety profile when 

administered to patients under the 

conditions of use specified in the 

labeling. This proposed definition 

reflects the Agency’s longstanding 

interpretation of this term as set forth in 

section 1.2 of the preface to the Orange 

Book (33rd Edition, 2013, at vii). 

II.A.3. Proposed Amendments to 

Definitions in Current § 314.108 

As discussed in sections II.A.1, 

II.A.2.f, and II.A.2.n, we are proposing 

to move the definitions of the terms 

‘‘active moiety’’ and ‘‘date of approval’’ 

from § 314.108(a) to § 314.3(b). We are 

proposing to amend § 314.108 to state 

that the definitions in § 314.3 (in 

addition to other definitions in 

§ 314.108) apply to § 314.108. 

We also are proposing to add a 

definition of ‘‘bioavailability study’’ to 

§ 314.108(a) to clarify the scope of this 

term as used in section 505(c)(3)(E)(iii), 

(c)(3)(E)(iv), (j)(5)(F)(iii), and (j)(5)(F)(iv) 

of the FD&C Act and § 314.108(b)(4) and 

(b)(5) regarding certain exclusivity 

determinations. The FD&C Act provides 

that a ‘‘bioavailability study’’ is not a 

type of ‘‘new clinical investigations . . . 

essential to the approval of the 

application [or supplement] and 

conducted or sponsored by the 

applicant’’ eligible for a 3-year period of 

exclusivity during which a 505(b)(2) 

application or ANDA may not be 

approved for the same conditions of 

approval (see section 505(c)(3)(E)(iii), 

(c)(3)(E)(iv), (j)(5)(F)(iii), and (j)(5)(f)(iv) 

of the FD&C Act; see also § 314.108(b)(4) 

and (b)(5)). 

The proposed definition of 

‘‘bioavailability study’’ means a study to 

determine the bioavailability or the 

pharmacokinetics of a drug. This 

definition incorporates by reference the 

revised definition of ‘‘bioavailability’’ 

proposed in § 314.3. This proposed 

revision is intended to clarify that a 

pharmacokinetic study, which generally 

is conducted in the same manner as a 

bioavailability study, also is not eligible 

for 3-year exclusivity. Although not 

specifically defined in part 314, the 

term ‘‘pharmacokinetics’’ is generally 

understood to refer to the way a drug is 

handled by the body, which is described 

by pharmacokinetic measures (such as 

area under the curve and concentration 

at the maximum) and other derived 

measures (such as clearance, half-life, 

and volume of distribution). The values 

of these measures reflect the absorption 

(A), distribution (D), and elimination (E) 

of a drug from the body. A drug can be 

eliminated by both metabolism (M) to 

one or more active and inactive 

metabolites and excretion of the 

unchanged drug. The overall set of 

processes is often referred to as ADME, 

which ultimately controls systemic 

exposure to a drug and its metabolites 

after drug administration. 


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II.A.4. Definitions in Current § 320.1 

We are proposing to move the 

definitions in current § 320.1(a) through 

(g) to § 314.3(b). We are proposing this 

change for ease of reference because 

certain terms defined in current § 320.1 

already are set forth in other parts of our 

regulations (e.g., ‘‘bioequivalence’’). 

Proposed § 320.1 would simply state 

that the definitions in § 314.3(b) apply 

to part 320. 

II.B. Submission of Patent Information 

(Proposed § 314.53) 

II.B.1. General Requirements for 

Submission of Patent Information 

(Proposed § 314.53(b) and (c)) 

Section 314.53(b) of our regulations 

requires that an applicant submitting an 

NDA (including a 505(b)(2) application), 

an amendment to an NDA, or, except as 

provided in § 314.53(d)(2), a 

supplement to an approved application, 

submit the patent information described 

in § 314.53(c) on Forms FDA 3542a and 

3542 with the filing or upon and after 

approval, respectively. The information 

provided in Form FDA 3542 for any 

patent which claims the drug or a 

method of using the drug and with 

respect to which a claim of patent 

infringement could reasonably be 

asserted if a person not licensed by the 

owner engaged in the manufacture, use, 

or sale of the drug is published in the 

Orange Book after approval of the NDA 

or the supplement. 

In the Federal Register of April 30, 

2007 (72 FR 21266), we responded to 

comments submitted to FDA regarding 

FDA’s request for an extension of 

approval of the collection of information 

related to patent submission and listing 

requirements involving Forms FDA 

3542a and 3542 (April 2007 notice). At 

that time, we made certain revisions to 

Forms FDA 3542a and 3542 and the 

instructions for completing those forms 

to clarify acceptable practices in 

accordance with our existing 

regulations. Other proposed changes to 

Forms FDA 3542a and 3542 would have 

required revisions to the regulations 

upon which the requirements in Forms 

FDA 3542a and 3542 are based. In 

sections II.B.1.a and II.B.2.a, we propose 

certain revisions to the content of patent 

information submitted to FDA and the 

circumstances under which submission 

of patent information is required. These 

changes to the required submission of 

patent information are intended to 

clarify the basis for requiring certain 

information, revise and streamline our 

requirements, and describe acceptable 

approaches to compliance with 

applicable regulations. 

Table 2 summarizes the proposed 

changes related to reporting 

requirements for submission of patent 

information: 

TABLE 2—HIGHLIGHTS OF PROPOSED CHANGES REGARDING PATENT REPORTING REQUIREMENTS 1

Current regulations Proposed revisions to regulations 

General Requirements (§ 314.53(c)(1)) General Requirements (§ 314.53(c)(1)) 

Patent information will not be accepted unless it is complete and submitted on the appropriate forms (Form FDA 3542a or 3542). • Patent information will not be accepted unless it is submitted on the 

appropriate forms (Form FDA 3542a or 3542) and contains the information required in § 314.53(c)(2). 

Reporting Requirements (§ 314.53(c)(2)) Reporting Requirements (§ 314.53(c)(2)) 

The required information and verification in § 314.53(c)(2)(i) and 

(c)(2)(ii) includes: 

The required information and verification in § 314.53(c)(2)(i) and 

(c)(2)(ii) includes: 

• Information on whether the patent has been submitted previously for the NDA. 

• Information on whether the patent is a re-issued patent of a patent submitted previously for listing for the NDA or supplement. 

• Information on whether the drug substance patent claims a polymorph that is the same active ingredient that is described in the 

pending NDA or supplement, and, if so, has test data described 

in § 314.53(b)(2). 

• Information on whether the drug substance patent claims only a 

polymorph that is the same active ingredient that is described in 

the pending NDA or supplement, and, if so, has test data described in § 314.53(b)(2). 

Method-of-Use Patents (§ 314.53(c)(2)(i)(O) and (c)(2)(ii)(P)) Method-of-Use Patents (§ 314.53(c)(2)(i)(O) and (c)(2)(ii)(P)) 

The required information and verification in § 314.53(c)(2)(i) and 

(c)(2)(ii) includes: 

The required information and verification in § 314.53(c)(2)(i) and 

(c)(2)(ii) includes: 

• Information on each method-of-use patent including the following: • Information on each method-of-use patent including the following: 

(2) Identification of the specific section of the proposed labeling for the drug product that corresponds to the method of 

use claimed by the patent submitted 

(3) The description of the patented method of use as required 

for publication. 

(2) Identification of the specific section(s) of the proposed labeling for the drug product that corresponds to the method 

of use claimed by the patent submitted (if the scope of the 

method-of-use claim(s) of the patent does not cover every 

use of the drug, the applicant must identify only the specific 

portion(s) of the indication or other condition of use claimed 

by the patent); 

(3) The description of the patented method of use as required 

for publication (which must contain adequate information to 

assist 505(b)(2) and ANDA applicants in determining whether a listed method-of-use patent claims a use for which the 

505(b)(2) or ANDA applicant is not seeking approval). 

[No corresponding regulation] Exceptions to Required Submission of Patent Information 

(§ 314.53(c)(2)(i)(S) and 314.53(c)(2)(ii)(T)) 

• If the applicant submits information for a patent that claims the drug 

substance (active ingredient) and meets the requirements for listing 

on that basis, then the applicant is not required to provide information on whether that patent also claims the drug product (composition/formulation). 

• If the applicant submits information for a patent that claims the drug 

product (composition/formulation) and meets the requirements for 

listing on that basis, then the applicant is not required to provide information on whether that patent also claims the drug substance (active ingredient). 


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TABLE 2—HIGHLIGHTS OF PROPOSED CHANGES REGARDING PATENT REPORTING REQUIREMENTS 1—Continued 

Current regulations Proposed revisions to regulations 

• However, an applicant that submits information for a method-of-use 

patent must also submit information regarding whether that patent 

also claims either the drug substance or the drug product. 

1These highlights describe important proposed revisions to our regulations, but should not be relied upon in place of the proposed regulation. 

II.B.1.a. Drug substance (active 

ingredient) and drug product 

(formulation or composition) patents. 

We are proposing to revise § 314.53(c)(1) 

to clarify that FDA accepts patent 

information submitted on Form FDA 

3542a or 3542, as appropriate, as long as 

the form contains the information 

required in § 314.53(c). The statement in 

our current regulations that FDA ‘‘will 

not accept the patent information unless 

it is complete . . .’’ has generated 

confusion in some cases, particularly 

where a portion of the specific 

information requested in a section on 

FDA Form FDA 3542a or 3542 was not 

applicable to the patent for which the 

form was submitted. By proposing to 

revise § 314.53(c)(1) to state that we will 

not accept the patent information unless 

it ‘‘contains the information required in 

paragraph (c)(2) of this section,’’ we are 

clarifying that FDA will accept a 

submission of patent information on 

Form FDA 3542a or 3542, as 

appropriate, that omits patent 

information requested on the form 

where that omission is permitted under 

an exception in § 314.53(c)(2). 

We are proposing to add 

§ 314.53(c)(2)(i)(S) and (c)(2)(ii)(T) to 

describe exceptions to the required 

submission of patent information. 

Proposed § 314.53(c)(2)(i)(S)(1) and 

(c)(2)(ii)(T)(1) state that if a patent 

claims the drug substance that is the 

active ingredient in the drug product for 

which approval is sought or has been 

granted, respectively, and is eligible for 

listing in the Orange Book, it is not 

necessary for an applicant to provide 

information on whether the patent also 

claims the drug product. Similarly, we 

are proposing to add 

§ 314.53(c)(2)(i)(S)(2) and (c)(2)(ii)(T)(2) 

to provide that if a patent claims the 

drug product for which approval is 

sought or has been granted, respectively, 

and is eligible for listing in the Orange 

Book, it is not necessary for an applicant 

to provide information on whether the 

patent also claims the drug substance 

that is the active ingredient in the drug 

product. These proposed revisions to 

our regulations provide that an 

applicant need only satisfy the 

requirements for patent listing set forth 

in section 505(b)(1) and (c)(2) of the 

FD&C Act and, subject to 

§ 314.53(c)(2)(i)(O)(3) and (c)(2)(ii)(P)(4), 

discussed in this section of the 

document, need not identify each basis 

on which the patent claims the drug. 

The designation of a patent as claiming 

the drug substance and/or drug product 

for purposes of listing in the Orange 

Book is not intended to define the scope 

of the patent claims that an NDA holder 

or patent owner may assert against a 

505(b)(2) or ANDA applicant based on 

a listed patent. 

Whether or not the applicant provides 

information stating that the patent 

claims the drug substance or the drug 

product, an applicant must submit 

information regarding whether the 

patent claims one or more methods of 

using the drug product for which 

approval is sought or has been granted 

(method-of-use patent). We are 

proposing to add § 314.53(c)(2)(i)(O)(3) 

and (c)(2)(ii)(P)(4) to confirm that the 

proposed exceptions to required 

submission of patent information do not 

alter the requirements for submission of 

method-of-use patent information. The 

information regarding method-of-use 

patents is required for implementation 

of the patent certification and statement 

provisions of the FD&C Act. Section 

505(b)(2)(B) and (j)(2)(A)(viii) of the 

FD&C Act provide that a 505(b)(2) and 

ANDA applicant, respectively, may 

submit a statement for a method-of-use 

patent which does not claim a use for 

which the applicant is seeking approval, 

instead of a patent certification under 

section 505(b)(2)(A)(iii) or 

505(j)(2)(A)(vii)(III) of the FD&C Act 

(paragraph III certification) or a 

paragraph IV certification to the listed 

patent. Information on whether a patent 

claims the drug substance or drug 

product in addition to whether the 

patent claims one or more methods of 

use is required because a 505(b)(2) or 

ANDA applicant that avails itself of the 

statutory provision that permits it to not 

seek approval of a method of use 

claimed by the patent (and carve out 

from product labeling the method-of-use 

information claimed by the patent) 

would still be required to submit a 

patent certification with respect to any 

drug substance or drug product claims 

covered by the same listed patent (see 

Letter from Janet Woodcock, M.D., 

Director, CDER, to Rosemarie R. WilkOrescan, Novo Nordisk Inc., and James 

F. Hurst, Winston & Strawn LLP, dated 

December 4, 2008, regarding Docket 

Nos. FDA–2008–P–0343–0009 and 

FDA–2008–P–0411–0006, available at 

http://www.regulations.gov) 

(Repaglinide Citizen Petition Response). 

For example, a 505(b)(2) or ANDA 

applicant may submit a statement under 

section 505(b)(2)(B) or 505(j)(2)(A)(viii), 

respectively, of the FD&C Act for a 

method-of-use patent that does not 

claim a use for which the applicant is 

seeking approval and a paragraph IV 

certification for any remaining drug 

substance, drug product, or other 

method-of-use claims covered by the 

same patent. This approach is 

sometimes described as a ‘‘split 

certification’’ to the patent. 

We note that a 505(b)(2) or ANDA 

applicant that submitted a paragraph IV 

certification in addition to a statement 

under section 505(b)(2)(B) or 

505(j)(2)(A)(viii) of the FD&C Act must 

comply with the notice requirements for 

a paragraph IV certification and may be 

subject to a 30-month stay of approval 

if patent infringement litigation is 

initiated within the statutory timeframe. 

An ANDA applicant that submitted a 

paragraph IV certification and a 

statement pursuant to section 

505(j)(2)(A)(viii) of the FD&C Act to a 

listed patent also may be eligible for 

180-day exclusivity based on its 

paragraph IV certification if the 

applicant is a ‘‘first applicant’’ and 

meets other statutory and regulatory 

requirements. 

II.B.1.b. Drug substance patents that 

claim only a polymorph of the active 

ingredient. Section 314.53(c)(2)(i)(M)(2) 

and (c)(2)(ii)(N)(2) currently require 

submission of information on whether 

the patent claims a polymorph 

(generally, a drug substance with a 

different crystalline (including solvates 

and hydrates) or amorphous form of the 

same drug substance) that is the same 

active ingredient as that described in the 

pending NDA, amendment, or 

supplement. We explained in the 

preamble to the June 2003 final rule that 

‘‘it would be consistent to interpret 

‘drug substance’ for patent submission 

and listing purposes as including 

certain drug substances having different 

physical forms if they would be 


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considered the same active ingredient 

for ANDA approval purposes’’ (68 FR 

36676 at 36678). 

We are proposing to revise these 

regulations to state that an applicant is 

only required to provide information on 

whether the patent claims a polymorph 

that is the same active ingredient 

described in the pending NDA, 

amendment, or supplement if the only 

basis on which the patent is eligible for 

listing is that it claims the polymorph. 

Based on comments received from 

industry on this issue (see April 2007 

notice) and inquiries from applicants 

regarding completion of Forms FDA 

3542a and 3542, we have tentatively 

concluded that our regulations need to 

be modified. With respect to a patent 

that claims the drug substance or drug 

product described in the pending NDA, 

amendment, or supplement and one or 

more polymorphic forms of the drug 

substance, an applicant is not required 

to provide information on whether the 

patent claims a polymorph if the patent 

otherwise meets the statutory 

requirements for submission of patent 

information regarding the drug 

substance or drug product. 

Similarly, we are proposing to make 

conforming revisions to § 314.53(b)(1), 

(b)(2), (c)(2)(i)(M)(3), and (c)(2)(ii)(N)(3) 

to provide that the applicant 

certification regarding test data required 

by § 314.53(b) applies only to patents 

that claim only a polymorph. This 

provision also had generated confusion, 

and we are proposing revisions for 

clarification. 

II.B.1.c. Method-of-use patents. 

Section 314.53(b)(1) currently states that 

an applicant ‘‘shall separately identify 

each pending or approved method of 

use and related patent claim.’’ This text 

has been subject to differing 

interpretations by applicants as to 

whether our regulations require 

submission of patent information (and 

completion of Forms FDA 3542a and 

3542) on a claim-by-claim basis. In the 

June 2003 final rule, we explained that 

we require identification of individual 

patent claims for method-of-use patents 

to assist 505(b)(2) and ANDA applicants 

in determining whether a listed methodof-use patent claims a use for which the 

505(b)(2) or ANDA applicant is not 

seeking approval (see 68 FR 36676 at 

36682 and 36685). In the April 2007 

notice, we clarified that ‘‘consistent 

with our regulations at § 314.53(b)(1), 

. . . an applicant may list together 

multiple patent claims for each pending 

or approved method of use. However, 

each pending or approved method of 

use must be separately identified and 

therefore will require separate listing(s) 

of method-of-use information in section 

4 of Forms FDA 3542a and 3542. 

Therefore, if a patent claims one or more 

methods of use that apply to a pending 

application or approved product, each 

pending or approved method of use 

would need to be listed separately along 

with the patent claim number(s) for the 

patent claim(s) for the pending or 

approved method of use. A single Form 

FDA 3542a or Form FDA 3542, as 

appropriate, may be used to list a patent 

claiming more than one method of use, 

provided that each method of use is 

listed separately along with the patent 

claim number(s) for the patent claim(s) 

for the pending or approved method of 

use. This regulatory approach 

accomplishes the statutory objective of 

providing adequate information to 

permit ANDA and 505(b)(2) applicants 

to file statements which assert that the 

method-of-use patent does not claim a 

use for which the applicant is seeking 

approval’’ (72 FR 21266 at 21268). 

We are proposing to revise 

§ 314.53(b)(1) by replacing the word 

‘‘claim’’ with ‘‘claim(s)’’ in the phrase 

‘‘shall separately identify each pending 

or approved method of use and related 

patent claim.’’ This proposed revision is 

intended to further clarify that an 

applicant may list together multiple 

patent claims for a pending or approved 

method of use on Forms FDA 3542a and 

3542, respectively. However, each 

pending or approved method of use 

must be separately identified and 

therefore will require separate listing(s) 

of method-of-use information in section 

4 of Forms FDA 3542a and 3542. 

We also are proposing to revise 

§ 314.53(b)(1), (c)(2)(i)(O)(2), 

(c)(2)(ii)(P)(2) and (c)(2)(ii)(P)(3) to 

enhance compliance by NDA applicants 

with the requirements for identifying 

the specific section(s) of product 

labeling that correspond to the method 

of use claimed by the patent and, upon 

approval, describing the approved 

method of use claimed by the patent, as 

required for publication in the Orange 

Book. Proposed § 314.53(b)(1) would 

expressly require that if the scope of the 

method-of-use claim(s) of a patent does 

not cover every use of the drug, the 

applicant must identify only the specific 

sections of product labeling that 

correspond to the specific portion(s) of 

the indication or other condition of use 

claimed by the patent. The specific 

product labeling that corresponds to the 

protected use may appear in sections of 

the labeling other than ‘‘Indications and 

Usage.’’ This proposed revision and 

conforming revisions to proposed 

§ 314.53(c)(2)(i)(O)(2) and (c)(2)(ii)(P)(2) 

would address situations in which the 

scope of the method of use claimed by 

the patent is narrower than the 

indication or other condition of use 

described in product labeling. In such 

cases, the NDA applicant must identify 

only the specific sections of product 

labeling that correspond to the 

portion(s) of the indication or other 

condition of use claimed by the patent 

and not the broader indication or other 

condition of use in the product labeling 

which may include, but not be limited 

to, the use claimed by the patent. 

Accurate identification of the specific 

sections of product labeling that 

correspond to the use claimed by the 

patent is necessary to enable FDA to 

implement section 505(b)(2)(B) and 

(j)(2)(A)(viii) of the FD&C Act, which 

permit 505(b)(2) and ANDA applicants 

to omit protected conditions of use from 

labeling. This information regarding 

product labeling also is necessary for 

FDA to evaluate whether the omission 

of aspects of the listed drug’s labeling 

protected by patent would render the 

proposed drug product less safe or 

effective than the listed drug for all 

remaining non-protected conditions of 

use and preclude approval (see 

§ 314.127(a)(7); see also 

§ 314.94(a)(8)(iv)). 

Proposed § 314.53(c)(2)(ii)(P)(3) 

would codify our longstanding 

requirement that the NDA applicant’s 

description of the patented method of 

use (the ‘‘use code’’) required for 

publication in the Orange Book must 

contain adequate information to assist 

FDA and 505(b)(2) and ANDA 

applicants in determining whether a 

listed method-of-use patent claims a use 

for which the 505(b)(2) or ANDA 

applicant is not seeking approval. If the 

scope of the method-of-use claim(s) of 

the patent does not cover every 

approved use of the drug, the NDA 

holder’s ‘‘use code’’ must contain only 

the specific portion(s) of the indication 

or other method of use claimed by the 

patent. This requirement is necessary to 

effectively implement the statutory 

provisions that permit 505(b)(2) and 

ANDA applicants to submit a statement 

that the applicant is not seeking 

approval for the use claimed in the 

listed patent instead of a patent 

certification to the listed patent with 

respect to the method of use claim(s) 

(see section 505(b)(2)(B) and 

(j)(2)(C)(viii) of the FD&C Act, 

respectively). We require the NDA 

holder to submit an accurate 

description, subject to the verification 

requirements in § 314.53(c)(2)(ii)(R), of 

the method of use within the scope of 

the patent that claims an approved use 

of the drug to implement these statutory 

provisions. As the U.S. Supreme Court 

noted in Caraco Pharm. Labs. v. Novo 


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Nordisk A/S: ‘‘An overbroad use code 

. . . throws a wrench into the FDA’s 

ability to approve generic drugs as the 

statute contemplates’’ (132 S. Ct. 1670, 

at 1684 (2012)). 

II.B.1.d. Patents previously submitted 

for listing. We are proposing to revise 

§§ 314.53(c)(2)(i)(J) and (c)(2)(ii)(K) to 

remove the requirement that an 

applicant provide information regarding 

whether the patent has been submitted 

previously for the NDA or supplement. 

This requirement was intended to assist 

the Orange Book staff with their 

administrative listing responsibilities 

(see 68 FR 36676 at 36686). In response 

to a request for clarification of the 

purpose of this inquiry (see 72 FR 21266 

at 21269) and to streamline the patent 

information submission requirements, 

we are proposing to revise 

§§ 314.53(c)(2)(i)(J) and (c)(2)(ii)(K) to 

request information on whether the 

patent is a reissuance of a patent 

submitted previously for listing in the 

Orange Book for the NDA or 

supplement, including the original 

patent number of the listed patent (see 

section II.B.1.e). 

If a patent has been submitted 

previously for listing in the Orange 

Book, we currently request information 

on whether the expiration date is a new 

expiration date (§ 314.53(c)(2)(i)(K) and 

(c)(2)(ii)(L)). For example, a patent 

expiration date may be extended after 

NDA approval in response to a request 

for patent term restoration pursuant to 

35 U.S.C. 156 (see proposed 

§ 314.53(f)(2)(ii), discussed in section 

II.B.4.b). We are continuing to request 

this information. 

We note that our proposed revisions 

to the patent information submission 

requirements for supplements to an 

approved NDA (see section II.B.2.a) are 

designed to identify, among other 

things, whether patents previously 

submitted for listing for the underlying 

NDA continue to claim the changed 

product as approved in the supplement. 

II.B.1.e. Reissued patents. We are 

proposing certain revisions to our 

regulations to describe our requirements 

regarding submission of information 

related to patents that have been 

reissued by the PTO. Generally, a patent 

may be reissued to correct certain errors 

in the scope of claims or defects in a 

specification or drawing that otherwise 

would have invalidated, in whole or in 

part, the patent (see 35 U.S.C. 251). 

Accordingly, a reissued patent may 

affect both the patent certification or 

statement submitted by a 505(b)(2) or 

ANDA applicant and the infringement 

claims that could be asserted by the 

patent owner or NDA holder. 

Although we recognize that the 

original patent is surrendered upon 

patent reissuance (see 37 CFR 1.178(a)), 

we are proposing to treat the original 

patent and the reissued patent as a 

‘‘single bundle’’ of patent rights, albeit 

patent rights that may have changed 

with reissuance, for purposes of 

administering the patent certification 

requirements of the FD&C Act and any 

30-month stay of approval or 180-day 

exclusivity that relates to a paragraph IV 

certification to the original patent (see 

discussion in section II.E.4). FDA’s role 

in listing patents remains ministerial 

(see 59 FR 50338 at 50349, October 3, 

1994 (1994 final rule); 68 FR 36676 at 

36687 (June 2003 final rule)); however, 

we are mindful of the implications of 

reissued patents in fulfilling our 

statutory obligations regarding 

implementation of the patent 

certification and statement, 30-month 

stay, 180-day exclusivity, and tentative 

approval provisions of the FD&C Act. 

We are proposing these revisions to 

describe the responsibilities of an NDA 

applicant associated with listing a 

reissued patent. The requirements for a 

505(b)(2) or ANDA applicant to provide 

an appropriate patent certification or 

statement to a reissued patent are 

discussed in section II.E.4). 

We currently receive submissions of 

patent information for reissued patents 

and list those patents that are eligible 

for listing in the Orange Book. Reissued 

patents are identified by the PTO with 

the letters ‘‘RE’’ preceding the patent 

number and, because a patent is 

reissued for the unexpired part of the 

term of the original patent, have the 

same expiration date as the original 

patent. If the scope of claims was 

narrowed or broadened upon 

reissuance, the NDA applicant or holder 

may submit a reissued patent for listing 

in the Orange Book with a revised 

designation of whether the patent 

claims the drug substance, drug 

product, and/or a method or use, or 

with a revised use code. 

Proposed § 314.53(c)(2)(i)(J) and 

(c)(2)(ii)(K) would provide that an NDA 

applicant or holder is required to 

include information on whether a patent 

submitted for listing is a reissuance of 

a patent previously submitted for listing 

for the NDA or supplement. Submission 

of patent information for reissued 

patents is subject to the 30-day 

timeframe for timely filed patent 

information set forth in section 505(c)(2) 

of the FD&C Act. As discussed further 

in section II.B.2.b, the timely filing of 

patent information for a reissued patent 

(including a reissued patent with a 

broadened scope of claims) does not 

alter the patent certification obligations 

of a 505(b)(2) or ANDA applicant whose 

application was pending when the 

original patent was filed by the holder 

of an approved application for listing 

more than 30 days after patent issuance 

(‘‘late listed’’). In other words, if a 

505(b)(2) or ANDA applicant is not 

required to provide a patent certification 

or statement to the original patent 

pursuant to § 314.50(i)(4) or 

§ 314.94(a)(12)(vi) because the patent 

was late listed, the 505(b)(2) or ANDA 

applicant would not be required to 

provide a patent certification or 

statement to the reissued patent even if 

timely filed following reissuance. This 

approach recognizes that the original 

and reissued patents comprise a ‘‘single 

bundle’’ of patent rights, which first 

became relevant to approval of 505(b)(2) 

applications and ANDAs with the 

submission of the patent information 

prior to reissuance. As described in 

section II.E.3, the date of submission of 

the original patent information also 

determines the availability of a 30- 

month stay arising from patent 

infringement litigation resulting from 

notice of a paragraph IV certification to 

the original or reissued patent (see 

section 505(c)(3)(C) and (j)(5)(B)(iii) of 

the FD&C Act). 

An original patent that has been 

reissued would remain listed in the 

Orange Book until FDA determined that 

any first ANDA applicant is no longer 

eligible for 180-day exclusivity or the 

180-day exclusivity period has expired 

(see section II.E.4). We intend to 

designate original patents that have 

been reissued and remain listed in the 

Orange Book for this reason with the 

suffix ‘‘*RE’’ based on information 

submitted by the NDA applicant or 

holder in accordance with 

§ 314.53(c)(2)(ii)(K). In the absence of 

this designation, an applicant that 

submits an ANDA after a reissued 

patent is listed in the Orange Book may 

not provide a patent certification or 

statement with respect to the original 

patent. Instead, the ANDA applicant 

must provide a patent certification or 

statement to the reissued patent. 


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Should the scope of a reissued patent 

be narrowed such that it is no longer 

eligible for listing under section 

505(b)(1) or 505(c)(2) of the FD&C Act, 

the NDA holder is required to request 

that the patent or patent information be 

removed from listing in the Orange 

Book (‘‘patent delisting’’), subject to the 

exceptions set forth in proposed 

§ 314.53(f)(2) (see discussion in section 

II.B.4.b). 

II.B.2. When and Where To Submit 

Patent Information (Proposed 

§ 314.53(d)) 

Table 3 summarizes the proposed 

changes regarding when and where to 

submit patent information: 

TABLE 3—HIGHLIGHTS OF PROPOSED CHANGES REGARDING SUBMISSION OF PATENT INFORMATION 1

Current regulations Proposed revisions to regulations 

Supplements (§ 314.53(d)(2)(i)) ................................................................ Supplements (§ 314.53(d)(2)(i)). 

• Applicant must submit patent information required under § 314.53(c) 

for a patent that claims the drug, drug product, or method of use for 

which approval is sought in a supplement: 

(A) to change the formulation; ..........................................................

(B) to add a new indication or other condition of use; .....................

(C) to change the strength; ...............................................................

(D) to make any other patented change regarding the drug, drug 

product, or method of use..

• Applicant must submit patent information required under § 314.53(c) 

for a patent that claims the drug substance, drug product, or method 

of use for which approval is sought in a supplement: 

(A) to change the dosage form or route of administration; 

(B) to change the strength; or 

(C) to change the drug product from prescription to OTC use. 

Supplements (§ 314.53(d)(2)(ii)) ...............................................................

If an applicant submits a supplement for a change described in 

§ 314.53(d)(2)(i), the following patent information submission requirements apply: 

Supplements (§ 314.53(d)(2)(ii)). 

If an applicant submits a supplement for a change other than one described in § 314.53(d)(2)(i), the following patent information submission requirements apply: 

• If previously submitted patent information claims the changed 

product, the applicant must submit a certification with the supplement identifying the patents that claim the changed product. 

• If previously submitted patent information claims the changed product, the applicant is not required to resubmit this patent information 

unless the description of the patented method of use would change 

upon approval of the supplement, and FDA will continue to list this 

patent information for the product; 

• If no patents, including previously submitted patents, claim the 

changed product, it must so certify. 

• If previously submitted patent information no longer claims the 

changed product, the applicant must submit a request to remove that 

patent information from the list at the time of approval of the supplement; 

• If one or more existing drug substance, drug product, or method-ofuse patents claim the changed drug product for which approval is 

sought in the supplement and such patent information has not been 

submitted to FDA, the applicant must submit the patent information 

required under § 314.53(c). 

Patent information deadline (§ 314.53(d)(3)) ............................................ Newly issued patents (§ 314.53(d)(3)). 

• If a patent is issued for a drug, drug product, or method of use 

after an application is approved, the applicant must submit to 

FDA the required patent information within 30 days of the date 

of patent issuance. 

• If a patent is issued for a drug substance, drug product, or method of 

use after an NDA is approved, the applicant must submit to FDA the 

required patent information within 30 days of the date of patent 

issuance. 

• If the required patent information is not submitted within 30 days of 

patent issuance, FDA will list the patent, but patent certifications will 

be governed by the provisions regarding untimely filed patents at 

§§ 314.50(i)(4) and (i)(6) and 314.94(a)(12)(vi) and (a)(12)(viii). 

Late submission of patent information (§§ 314.50(i)(4) and 

314.94(a)(12)(vi)).

Untimely filing of patent information (§§ 314.50(i)(4) and 

314.94(a)(12)(vi)). 

• [Provision directed to submission of required patent information 

in general.].

• 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 will be considered untimely filing of patent information if: 

—the amendment is submitted more than 30 days after patent 

issuance and it is not related to a corresponding change in approved product labeling; or 

—the amendment is submitted more than 30 days after a corresponding change in approved product labeling. 

Copies (§ 314.53(d)(4)) ............................................................................. Submission of Forms FDA 3542a and 3542 (§ 314.53(d)(4)). 

• Applicant must submit an archival copy and a copy for the 

chemistry, manufacturing, and controls (CMC) section of the review copy to the CDER Central Document Room.

• Applicant must submit patent information required by § 314.53(c)(1) 

and (c)(2)(i), § 314.50(h), or § 314.70(f) on Form FDA 3542a to the 

CDER Central Document Room at the address identified on FDA’s 

Web site. 

Æ Form FDA 3542a should not be submitted to the Orange Book Staff 

in the Office of Generic Drugs. 

• Applicant must submit patent information by letter separate from, 

but at the same time as, submission of the supplement.

• Applicant must submit patent information required by § 314.53(c)(1) 

and (c)(2)(ii) on Form FDA 3542 to the Office of Generic Drugs, Document Room, Attention: Orange Book Staff. 

Submission date (§ 314.53(d)(5)) ............................................................. Submission date (§ 314.53(d)(5)). 

• Patent information will be considered submitted to FDA as of the 

date the information is received by the Central Document Room. 

• Patent information will be considered submitted to FDA for purposes 

of § 314.53(d)(3) as of the earlier of the date the information submitted on Form FDA 3542 is date-stamped by the Office of Generic 

Drugs, Document Room, or officially received electronically by FDA 

through the Electronic Submissions Gateway. 

1These highlights describe important proposed revisions to our regulations, but should not be relied upon in place of the proposed regulation. 


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II.B.2.a. Submission of patent 

information for NDA supplements 

(proposed § 314.53(d)(2)). We are 

proposing to revise the requirements for 

submission of patent information for 

NDA supplements to reduce duplicative 

submissions of patent information and 

enhance efficiency. 

Section 314.53(c) requires submission 

of patent information for certain types of 

supplements that relate to the drug 

product or a method of using the drug 

product, namely those supplements that 

seek approval to change the 

formulation, add a new indication or 

other condition of use, change the 

strength, or make any other patented 

change regarding the drug, drug 

product, or any method of use (see 

§ 314.53(d)(2)(i)(A) through (d)(2)(i)(D)). 

This approach avoided unnecessary 

resubmission of patent information with 

supplements that did not involve a 

change to the drug product or a method 

of using the product or involved a 

change that could not be patented (see 

54 FR 28872 at 28910, July 10, 1989; 

and 59 FR 50338 at 50344). We are 

proposing to eliminate certain of these 

patent information submission 

requirements for supplements that seek 

approval for a change to an approved 

product and for which existing patents 

listed in the Orange Book for the 

specific drug product that is the subject 

of the supplement continue to claim the 

changed product (see proposed 

§ 314.53(d)(2)(ii)(A)). These proposed 

revisions to our regulations also address 

a comment submitted by an association 

representing research-based 

pharmaceutical and biotechnology 

companies that ‘‘submission of Forms 

FDA 3542a and 3542 with submission 

and upon approval, respectively, of an 

NDA supplement is redundant where 

the information has not changed since 

the form last was filed, imposes a 

burden on sponsors, and serves no 

statutory purpose’’ (72 FR 21266 at 

21270). 

Our proposed revisions to 

§ 314.53(d)(2) would create two broad 

categories of supplements for purposes 

of patent information submission based 

on whether the supplement is a type for 

which approval would result in a new 

entry in the Orange Book. For 

supplements that seek approval for a 

change that will result in a new entry in 

the Orange Book (e.g., a change to the 

dosage form, route of administration, 

strength (including changes to 

concentration or total drug content), or 

prescription drug status (i.e., change the 

drug product from prescription use to 

over-the-counter (OTC) use)), an 

applicant must continue to submit 

patent information required under 

§ 314.53(c) with submission of the 

supplement and following approval, 

respectively. Although these types of 

changes may not necessarily result in a 

submission of different patent 

information, by requiring an NDA 

holder to submit complete patent 

information for a supplement that, if 

approved, would result in a new entry 

in the Orange Book, we ensure that 

patent information listed for the new 

entry clearly expresses the NDA 

holder’s view regarding which patent(s) 

claim the drug or a method of using the 

drug as approved in the supplement. 

For example, different strengths of a 

drug product may have different patent 

coverage with respect to method-of-use 

patents that claim a dosing regimen or 

indication. In such a case, patent 

information would be required to be 

submitted with the filing of the NDA 

supplement and would be required to be 

submitted upon approval of the NDA 

supplement. This submission of patent 

information on Forms FDA 3542a and 

3542 would, among other things, 

identify with specificity the new 

method of use claimed by the patent 

with reference to the proposed or 

approved labeling, respectively, for the 

drug product. If the patents listed for the 

approved NDA also claim the drug or 

method of using the drug for which 

approval is sought in the NDA 

supplement, we will permit an 

applicant to submit a statement 

declaring that the patents currently 

listed for a specific NDA (identified by 

NDA number and product number as 

listed in the Orange Book) also claim the 

drug or method of using the drug for 

which approval is sought in the NDA 

supplement, if this statement is 

accompanied by the signed patent 

declaration verification required by 

§ 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 (see June 2003 final rule (68 

FR 36676 at 36681)). This proposed 

approach fulfills the statutory 

requirements for patent listing set forth 

in section 505(b)(1) and (c)(2) of the 

FD&C Act and ensures that patents 

listed for separate entries for drug 

products in the Orange Book are 

supported by an unambiguous 

submission of applicable patent 

information. 

It should be noted that proposed 

§ 314.53(d)(2)(i)(A) is intended to 

encompass only the types of changes in 

dosage form or route of administration 

that may be submitted as an NDA 

supplement and does not apply to 

proposed changes in dosage form or 

route of administration that should be 

submitted as a separate application (see 

guidance for industry entitled 

‘‘Submitting Separate Marketing 

Applications and Clinical Data for 

Purposes of Assessing User Fees’’ 

(December 2004), available at http:// 

www.fda.gov/downloads/Drugs/

GuidanceComplianceRegulatory

Information/Guidances/UCM079

320.pdf) (Separate Marketing 

Application Guidance). Similarly, we 

note that proposed § 314.53(d)(2)(i)(C) 

describes supplements to change the 

drug product from prescription use to 

OTC status for all conditions of use, 

because a separate marketing 

application would be required for a 

change to OTC status for fewer than all 

conditions of use. 

Our proposal would eliminate the 

automatic requirement for submission of 

patent information with a supplement 

seeking approval for a change in 

formulation or new indication or other 

condition of use (except for those 

conditions of use described in 

§ 314.53(d)(2)(i)). However, new 

submission of patent information would 

still be required if the patent(s) that 

claim the product as changed by the 

supplement differ from the patent(s) 

currently listed for the drug product. 

For supplements that seek approval for 

a change to a listed product that would 

not result in a new entry in the Orange 

Book (i.e., a change other than one of the 

changes described in proposed 

§ 314.53(d)(2)(i)), an applicant needs to 

evaluate whether each patent for which 

information is currently listed in the 

Orange Book for the drug product 

continues to claim the changed product. 

If existing patents listed for the product 

approved in the original application 

claim the product as changed by the 

supplement, the applicant is not 

required to resubmit this patent 

information unless the description of 

the method of use claimed by a patent 

would change upon approval of the 

supplement (see proposed 

§ 314.53(d)(2)(ii)(A)). (In this regard, we 

note that an untimely filed patent that 

claims the product approved in the 

original application cannot be 

transformed into a timely filed patent 

with submission of a supplement.) 

If, however, a listed patent no longer 

claims the product as changed by the 

supplement (e.g., a new formulation is 

no longer claimed by a patent listed for 

the original formulation of the drug 

product), then the applicant must 

submit a request to correct or remove 

the patent information from the list in 

accordance with proposed § 314.53(f)(2) 

at the time of approval of the 

supplement. Correspondingly, if one or 

more existing patents claim the product 


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as changed by the supplement (e.g., a 

supplement seeking approval for a new 

indication) and this patent information 

has not been submitted to FDA, the 

applicant must submit the patent 

information with the supplement and 

following approval. The requirement in 

proposed § 314.53(d)(2)(ii)(C) also 

would apply to submission of patent 

information for a patent currently listed 

for the drug as approved in the original 

application that claims the drug 

approved in the supplement in a new 

way (e.g., a new or additional method of 

use) and for which the patent 

information would be required to be 

submitted under § 314.53(c). In this 

case, the applicant would be required to 

comply with § 314.53(c) and submit 

patent information describing the new 

or additional method of use claimed by 

the patent with the supplement and 

following approval. 

As noted previously in this section of 

the document, the Agency has received 

comments criticizing as redundant the 

requirement for submission of Forms 

FDA 3542a and 3542 with submission 

and upon approval, respectively, of an 

NDA supplement where the information 

has not changed since the form last was 

filed (see April 2007 notice). Section 

505(b)(1) of the FD&C Act requires the 

submission of patent information with 

the filing of a supplement to an NDA. 

To the extent that patents currently 

listed for the drug product continue to 

claim the product as changed by the 

supplement, we interpret the statute to 

not require resubmission of duplicative 

patent information. In circumstances 

other than those described in proposed 

§ 314.53(d)(2)(ii)(A), an applicant or 

sponsor must submit required patent 

information with submission and upon 

approval of a supplement. This 

requirement facilitates the prompt 

listing of patent information 

postapproval by requiring applicants to 

complete their initial assessment of 

relevant patents with submission of 

their application and during the 

pendency of its review. 

We are proposing a conforming 

revision to § 314.70(f) to clarify that an 

applicant that submits a supplement to 

an NDA (including a 505(b)(2) 

application) also must comply with the 

patent information requirements under 

§ 314.53. 

II.B.2.b. Untimely filing of patent 

information (proposed §§ 314.53(d)(3), 

314.50(i)(4), and 314.94(a)(12)(vi)). We 

are proposing to supplement 

§ 314.53(d)(3) to expressly describe our 

longstanding practice with respect to 

listing untimely filed patents. Proposed 

§ 314.53(d)(3) states that if the required 

patent information is not submitted 

within 30 days of the issuance of the 

patent, FDA will list the patent, but 

patent certifications will be governed by 

the provisions regarding untimely filed 

patents in §§ 314.50(i)(4) and (i)(6) and 

314.94(a)(12)(vi) and (a)(12)(viii) of this 

part. We also are proposing to revise 

§§ 314.50(i)(4) and 314.94(a)(12)(vi) to 

include certain amendments to the 

description of the approved method(s) 

of use claimed by the patent within the 

category of untimely filed patent 

information. 

Section 505(c)(2) of the FD&C Act 

requires an NDA holder to file patent 

information for a patent issued after the 

date of approval of the application 

within 30 days of patent issuance. (As 

clarified in proposed § 314.53(c)(2)(ii), 

this statutory requirement for timely 

filing does not apply to patent 

information submitted prior to approval 

of an NDA or supplement, even if the 

patent information is submitted to FDA 

more than 30 days after the patent is 

issued by the PTO.) 

Section 505(c)(2) of the FD&C Act 

further directs the Agency to publish 

information on the newly-issued patent 

upon its submission, and we have 

interpreted this statutory provision to 

require listing in the Orange Book 

irrespective of whether the patent 

information has been timely filed. 

Although we list untimely filed patents 

pursuant to section 505(c)(2) of the 

FD&C Act, we generally do not require 

an applicant with a pending 505(b)(2) 

application or ANDA to provide a 

patent certification to a patent for which 

the NDA holder failed to comply with 

the statutory timeframe for submission 

of patent information after approval. 

Accordingly, the untimely filed patent 

will neither delay approval of a pending 

505(b)(2) application or ANDA until 

patent expiration nor necessitate a 

carve-out of information related to a 

patented method of use. 

Although an applicant with a pending 

505(b)(2) application or ANDA that 

references the drug product generally 

would not be required to submit a 

patent certification to an untimely filed 

patent that was late-listed as to the 

pending 505(b)(2) application or ANDA, 

we would permit an applicant to submit 

and maintain a patent certification 

(including a paragraph IV certification) 

or a statement pursuant to section 

505(b)(2)(B) or 505(j)(2)(B)(viii) of the 

FD&C Act, if desired. For example, a 

505(b)(2) or ANDA applicant may wish 

to submit a paragraph IV certification to 

challenge the late-listed patent and 

obtain patent certainty (i.e., determine 

whether the NDA holder or patent 

owner will initiate a patent 

infringement action against the 

applicant) instead of possibly marketing 

at risk. 

We also are proposing to revise 

§§ 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 will be considered untimely 

filing of patent information if: 

• The amendment is submitted more 

than 30 days after patent issuance and 

it is not related to a corresponding 

change in approved product labeling or 

• the amendment is submitted more 

than 30 days after a corresponding 

change in approved product labeling. 

This proposed revision is consistent 

with the objective of ensuring that 

prospective 505(b)(2) and ANDA 

applicants have timely notice of changes 

to the asserted patent coverage for a 

listed drug. In addition, proposed 

§§ 314.50(i)(4) and 314.94(a)(12)(vi) 

would complement proposed revisions 

to § 314.53 that are intended to enhance 

NDA holders’ compliance with the 

requirement to accurately identify the 

specific sections of product labeling that 

correspond to the use claimed by the 

patent (see section II.B.1.c). If an 

amendment to change the patent use 

code is not related to a corresponding 

change in approved product labeling 

and is submitted more than 30 days 

after patent issuance (or patent 

reissuance), then the patent information 

is properly considered untimely filed. In 

accordance with §§ 314.50(i)(4) and 

314.94(a)(12)(vi), an untimely filed 

method-of-use patent does not require a 

patent certification or statement and 

would not delay approval of a pending 

505(b)(2) application or ANDA. 

Similarly, if an amendment to change 

the patent use code is submitted more 

than 30 days after a corresponding 

change in approved product labeling, 

then the amendment lacks a clear 

temporal or substantive link to the 

specific section(s) of approved product 

labeling claimed by the patent, and the 

patent information is untimely filed. 

An applicant with a pending 505(b)(2) 

application or ANDA that seeks to 

confirm that a newly listed patent was 

untimely filed (and may not require a 

patent certification in accordance with 

§ 314.50(i)(4) or § 314.94(a)(12)(vi)) 

should contact the Orange Book staff. 

Irrespective of whether the patent was 

untimely filed (and thus late-listed as to 

the pending 505(b)(2) application or 

ANDA) or timely filed (and thus ‘‘later 

listed’’ as to the pending 505(b)(2) 

application or ANDA), a paragraph IV 

certification submitted for a patent filed 

with FDA after the date on which a 


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505(b)(2) application or ANDA (that is 

later determined to be substantially 

complete) was submitted will not give 

rise to a 30-month stay (see section 

505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C 

Act and section II.G). 

We note, however, that a 505(b)(2) 

application or ANDA submitted after 

the untimely filed patent is listed in the 

Orange Book is required to submit an 

appropriate patent certification or 

statement to the patent. As we 

explained in the 1994 final rule, ‘‘[t]he 

approach adopted by the Agency as best 

embodying the compromise adopted by 

Congress requires that if an NDA 

applicant submits required patent 

information on an approved drug 

product more than 30 days after 

issuance of the patent, FDA will publish 

the untimely information, but will not 

require ANDA and 505(b)(2) applicants 

with pending applications that have 

previously submitted a certification, i.e. 

those applicants that would be 

prejudiced by the late submission, to 

recertify to the new patent. Only 

applicants that initially submit ANDA’s 

or 505(b)(2) applications after the 

submission of the patent information or 

whose pending applications do not 

contain a valid certification at the time 

of submission would be required to 

submit a certification as to that patent. 

. . . While this could result in two 

categories of ANDA’s for a pioneer drug, 

those without certifications for the latefiled patent and those with certifications 

for that patent, this approach is the best 

means for discouraging manipulation of 

the patent filing scheme and providing 

optimum notice of applicable patents’’ 

(59 FR 50338 at 50340, response to 

comment 7). 

We remind NDA holders that patents 

issued after approval of a drug under 

section 505(c) of the FD&C Act include 

reissued patents (see section II.B.1.e) as 

well as patents that claim a drug 

product listed in the discontinued 

section of the Orange Book. With 

reference to the latter category, we note 

that a 505(b)(2) or ANDA applicant may 

rely upon a drug product listed in the 

discontinued section of the Orange Book 

to the extent that the product was not 

withdrawn for reasons of safety or 

effectiveness (see § 314.151 with respect 

to ANDAs). Accordingly, we encourage 

NDA holders to ensure that they 

continue to comply with the statutory 

requirements for patent listing for 

products that have been discontinued 

from marketing. 

We also are proposing to revise 

§ 314.50(i)(4) to remove an incorrect 

reference to the possible submission of 

a certification under § 314.50(i)(1)(ii) 

after the NDA holder’s untimely filing of 

patent information. If a 505(b)(2) 

applicant is required to submit a patent 

certification to untimely filed patent 

information as provided in proposed 

§ 314.50(i)(4), a ‘‘no relevant patents’’ 

statement under § 314.50(i)(1)(ii) would 

not be an acceptable patent certification. 

Finally, we are proposing to revise the 

heading for § 314.53(d)(3) to ‘‘newly 

issued patents’’ to better characterize 

the text and emphasize its applicability 

to patents issued after approval of an 

NDA or supplement. We also are 

proposing to revise the heading for 

proposed §§ 314.50(i)(4) and 

314.94(a)(12)(vi) to ‘‘untimely filing of 

patent information’’ and to make 

conforming revisions to the text of these 

sections for consistent use of 

terminology. 

II.B.2.c. Where to send submissions of 

Forms FDA 3542a and 3542 (proposed 

§ 314.53(d)(4)). We are proposing to 

require that patent information filed on 

Form FDA 3542 upon and after approval 

of an NDA or supplement be submitted 

directly to the Orange Book staff 

through the OGD Document Room. The 

Orange Book staff will send an archival 

copy of this patent information to 

CDER’s Central Document Room for 

filing with the NDA. 

Our proposal to require that NDA 

holders submit post-approval patent 

information directly to the Orange Book 

staff is intended to facilitate prompt 

listing of patent information in the 

Orange Book after Form FDA 3542 has 

been officially received by the Agency. 

Currently, many NDA holders submit a 

duplicate or courtesy copy of Form FDA 

3542 to the Orange Book staff 

electronically or via facsimile at the 

time of their submission of Form FDA 

3542 to CDER’s Central Document 

Room. This patent information is listed 

in the Orange Book upon receipt by the 

Orange Book staff, and the Orange Book 

explains that the date on which patent 

information is published ‘‘may not 

reflect the official receipt date as 

described in 21 CFR 314.53(d)(5).’’ 

However, this practice may result in 

publication of patent information prior 

to receipt by the official repository 

identified in our regulations and cause 

confusion for prospective first 

applicants and applicants with a 

pending 505(b)(2) application or ANDA 

seeking to determine whether or not the 

patent is late-listed. Proposed 

§ 314.53(d)(4) designates the OGD 

Document Room as an official 

repository for submissions of Form FDA 

3542, and proposed § 314.53(d)(5) (see 

section II.B.2.d) clarifies that the 

submission date of patent information 

provided by an NDA holder after 

approval of an application is the earlier 

of the date on which Form FDA 3542 is 

date-stamped by the OGD Document 

Room or officially received 

electronically by FDA though the 

Electronic Submissions Gateway. These 

proposed revisions to the regulations are 

intended to enhance efficiency and 

ensure that patent information is 

promptly listed after its receipt. 

We note, however, that patent 

information submitted on Form FDA 

3542a with the filing of an NDA, 

amendment, or supplement, and prior to 

approval of the application must 

continue to be submitted directly to the 

NDA as required by § 314.50(h) or 

§ 314.70(f), as appropriate. An applicant 

should not submit a copy of Form FDA 

3542a to the Orange Book staff; the 

Orange Book staff should only receive 

patent information submitted after 

approval of the NDA or supplement. An 

applicant should not submit a copy of 

the patent to FDA with submission of 

Form FDA 3542a or 3542. 

II.B.2.d. Submission date of patent 

information (proposed § 314.53(d)(5)). 

We are proposing to revise 

§ 314.53(d)(5) to clarify, for purposes of 

§ 314.53(d)(3), that the submission date 

of patent information provided by an 

NDA holder after approval of an 

application is the earlier of the date on 

which Form FDA 3542 is date-stamped 

by the OGD Document Room or 

officially received electronically by FDA 

though the Electronic Submissions 

Gateway (i.e., at the completion of 

electronic transmission). Our current 

regulations state that the information 

shall be considered submitted to FDA 

on the date it is received by the Central 

Document Room. We note that patent 

information sent to another location at 

FDA is not considered received by FDA 

for purposes of § 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 (i)(6) or § 314.94(a)(12)(vi) and 

(a)(12)(viii), respectively, unless it is 

sent to the official repository identified 

in the regulation. 

These proposed revisions are 

intended to remove any ambiguity about 

the date of submission in light of the 

implications of untimely filing of patent 

information on the patent certification 

obligations of 505(b)(2) applicants and 

ANDA applicants that rely upon the 

listed drug (see §§ 314.50(i)(4) and 

314.94(a)(12)(vi)). In this regard, we 

note that the patent certification 

obligations of a 505(b)(2) or ANDA 

applicant arise upon the receipt by the 

official repository at FDA of the NDA 

holder’s submission of patent 

information for a listed drug rather than 

the timing of publication of the patent 


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information in the Orange Book (see 

section 505(b)(2)(A) and (j)(2)(A)(vii) of 

the FD&C Act; see also Teva Pharms., 

USA, Inc. v. Leavitt, 548 F.3d 103, at 

108 (D.C. Cir. 2008) (noting that FDA 

‘‘has consistently required ANDA 

applicants to certify to patents recently 

submitted to FDA, even if FDA had not 

yet published the patent in any version 

of the Orange Book’’)). 

However, for purposes of eligibility 

for 180-day exclusivity, an ANDA 

applicant is not permitted to submit a 

paragraph IV certification to a patent 

(e.g., a recently issued patent that claims 

the RLD) before the first working day 

after the day the patent is listed in the 

Orange Book (see section II.D.1.b.ii and 

II.E.4). 

In addition, proposed § 314.53(d)(5) 

would change the addressee to whom 

submission of Form FDA 3542 should 

be sent from the Central Document 

Room to the OGD Document Room or 

the Electronic Submissions Gateway, 

consistent with proposed § 314.53(d)(4) 

discussed in section II.B.2.c. 

II.B.3. Public Disclosure of Patent 

Information (Proposed § 314.53(e)) 

We are proposing to delete the 

reference in § 314.53(e) to monthly 

supplements to the Orange Book 

because the Agency no longer arranges 

for publication of monthly printed 

supplements to the Orange Book. Patent 

information listed in the Orange Book, 

which may be accessed from the 

Agency’s Web site, has been updated on 

a daily basis for several years. This 

correction to § 314.53(e) is consistent 

with our proposed revision of the 

definition of ‘‘the list’’ in § 314.3(b) to 

mean the list of approved drug products 

published in FDA’s current ‘‘Approved 

Drug Products With Therapeutic 

Equivalence Evaluations’’ available 

electronically on FDA’s Web site at 

http://www.fda.gov/cder. 

Section 314.53(e) provides that copies 

of the patent information submitted on 

Form FDA 3542 may be requested from 

FDA’s Freedom of Information Staff. We 

are proposing to revise § 314.53(e) to 

replace the reference to a request for 

copies of the ‘‘file’’ to copies of the 

‘‘submitted patent information.’’ This 

revision is proposed for clarity and does 

not represent a substantive change. We 

note, for example, that some prospective 

505(b)(2) or ANDA applicants have 

requested copies of the patent 

information submitted on Form FDA 

3542 for patents listed for a listed drug 

in the Orange Book to determine the 

scope of the labeling identified by the 

NDA holder as relating to the use 

claimed by the patent. Copies of Form 

FDA 3542 also have been requested to 

obtain address information for the agent 

or representative authorized to receive 

notice of patent certification if the 

patent owner or NDA holder does not 

reside or have a place of business in the 

United States. We anticipate additional 

requests for the information submitted 

on Form FDA 3542 and may elect to 

proactively post on FDA’s Web site a 

copy of Form FDA 3542 for patents 

listed in the Orange Book in advance of 

a request under the Freedom of 

Information Act (see Presidential 

Documents, Memorandum for the Heads 

of Executive Departments and Agencies 

on Transparency and Open Government 

(January 21, 2009) (74 FR 4685, January 

26, 2009); see also Office of the Attorney 

General, Memorandum for the Heads of 

Executive Departments and Agencies on 

The Freedom of Information Act (March 

19, 2009), available at http://

www.usdoj.gov/ag/foia-memomarch2009.pdf). 

II.B.4. Correction or Change of Patent 

Information (Proposed § 314.53(f)) 

We are proposing to revise § 314.53(f) 

to differentiate the procedure for 

correction or change of patent 

information by the NDA holder 

(proposed § 314.53(f)(2)) from the 

procedure for requests by persons other 

than the NDA holder. Proposed 

§ 314.53(f) also would address certain 

issues that have arisen regarding 

method-of-use patents and enhance 

FDA’s response to challenges to the 

accuracy or relevance of submissions of 

this patent information to the Agency. 

We are proposing to redesignate the 

current text of § 314.53(f) as 

§ 314.53(f)(1). We are proposing to add 

new § 314.53(f)(2) to implement section 

505(j)(5)(D)(i)(I)(bb)(CC) of the FD&C 

Act, as added by the MMA, and to make 

other changes for the efficient 

enforcement of the FD&C Act. 

Table 4 summarizes the proposed 

changes related to correction or change 

of patent information: 

TABLE 4—HIGHLIGHTS OF PROPOSED CHANGES REGARDING CORRECTION OR CHANGE OF PATENT INFORMATION 1

Current regulations Proposed revisions to regulations 

Correction of patent information errors (§ 314.53(f)) ................................ Correction or change of patent information—Requests by persons 

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

• If any person disputes the accuracy or relevance of patent information submitted to FDA under § 314.53 and published by FDA in the 

list, that person must first notify FDA (OGD Document Room, Attn: 

Orange Book Staff) in writing stating the grounds for disagreement. 

FDA then will request that the NDA holder confirm the correctness of 

the patent information..

• If any person disputes the accuracy or relevance of patent information submitted to FDA under § 314.53 and published by FDA in the 

list, that person must first notify FDA (OGD Document Room, Attn: 

Orange Book Staff) in a written or electronic communication titled 

‘‘314.53(f) Patent Listing Dispute’’ that states the grounds for disagreement. FDA then will request that the NDA holder confirm the 

correctness of the patent information within 30 days. 

• For listed patents that claim an approved method of using the drug 

product, FDA will request that the NDA holder confirm the correctness of the ‘‘Use Code’’ in the Orange Book, and provide information 

on the specific approved use claimed by the patent that enables 

FDA to make a determination in accordance with section 

505(b)(2)(B) or (j)(2)(C)(viii) of the FD&C Act. 

• Unless the NDA holder withdraws or amends its patent information in 

response to FDA’s request to confirm the correctness of the patent 

information, FDA will not change the patent information in the list. 

• Unless the NDA holder withdraws or amends its patent information in 

response to FDA’s request to confirm the correctness of the patent 

information, FDA will not change the patent information in the list. 

—If there is insufficient information to make a determination in accordance with section 505(b)(2)(B) or (j)(2)(C)(viii) of the FD&C Act and 

the NDA holder has confirmed the correctness of its description of 

the specific approved use claimed by the patent, the Agency will review the proposed labeling for the 505(b)(2) application or ANDA 

with deference to the 505(b)(2) or ANDA applicant’s interpretation of 

the scope of the patent. 


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TABLE 4—HIGHLIGHTS OF PROPOSED CHANGES REGARDING CORRECTION OR CHANGE OF PATENT INFORMATION 1— 

Continued 

Current regulations Proposed revisions to regulations 

Correction or change of patent information—Requests by the NDA 

holder (§ 314.53(f)(2)). 

• If the NDA holder determines that a patent or patent claim no longer 

meets the statutory requirements for listing, the NDA holder must 

promptly notify FDA to withdraw the patent information and request 

that the patent information be removed from the list. 

• If the NDA holder is required by court order to amend patent information or withdraw a patent from the list, it must submit a copy of 

the order to FDA (OGD Document Room, Attn: Orange Book Staff) 

within 14 days of order entry. FDA will remove a patent from the list 

if there is no first applicant eligible for 180-day exclusivity or upon 

the expiration of the 180-day period. 

• If the term of a listed patent is extended under 35 U.S.C. 156(e), the 

NDA holder must submit on Form FDA 3542 a correction to the patent expiration date within 30 days of receipt of a certificate of extension or documentation of an extension of the patent term. 

• Corrections or changes to previously submitted patent information, 

other than withdrawal of a patent and requests to remove a patent 

from the list (delisting requests), must be submitted on Form FDA 

3542 or 3542a, as appropriate. 

• Withdrawal of a patent and delisting requests must be submitted as 

described in § 314.53(d)(4), except it need not be submitted on Form 

FDA 3542. The patent withdrawal and delisting request must contain 

the NDA number, each product to which the request applies, and the 

patent number. 

1These highlights describe important proposed revisions to our regulations, but should not be relied upon in place of the proposed regulation. 

II.B.4.a. Requests by persons other 

than the NDA holder—patents that 

claim an approved method of using the 

drug product (proposed § 314.53(f)(1)). 

To efficiently implement the statutory 

provisions in section 505(b)(2)(B) and 

(j)(2)(C)(viii) of the FD&C Act, we are 

proposing to enhance the mechanism 

for challenging the accuracy or 

relevance of information with respect to 

method-of-use patents submitted to the 

Agency under § 314.53 and listed in the 

Orange Book. 

In the preamble to the June 2003 final 

rule on patent submission and listing 

requirements, we discussed our 

longstanding position, codified in 

§ 314.53(b) and (c)(2), that ‘‘only 

method-of-use patents that claim a use 

of the drug product in the pending or 

approved application must be 

submitted’’ (68 FR 36676 at 36681). The 

June 2003 final rule further explained: 

‘‘The declarant must describe each 

individual method of use for which a 

patent is submitted for listing, and 

identify the corresponding language 

found in the labeling of the approved 

NDA that corresponds to that method of 

use. This information will expedite our 

review of ANDA and 505(b)(2) 

applications that do not seek approval 

for all the approved uses. In 

determining whether an ANDA 

applicant can ‘carve out’ the method of 

use, rather than certify to the listed 

patent, we will rely on the description 

of the approved use provided by the 

NDA holder or patent owner in the 

patent declaration and listed in the 

Orange Book’’ (68 FR 36676 at 36682). 

An NDA holder or patent owner must 

provide adequate information in its 

submission of patent information to 

enable potential 505(b)(2) and ANDA 

applicants to avail themselves of the 

statutory provision that permits a 

505(b)(2) or ANDA applicant to not 

certify to a patent by stating that it is not 

seeking approval for the method of use 

claimed by the listed patent (see section 

505(b)(2)(B) and (j)(2)(C)(viii) of the 

FD&C Act, respectively) and carving out 

from product labeling the corresponding 

use information. Our July 2007 revision 

of Forms FDA 3542a and 3542 clarifies, 

in its instructions, that ‘‘[t]he use code 

designates a method of use patent that 

claims the approved indication or use of 

a drug product. Each approved use 

claimed by the patent should be 

separately identified in this section and 

contain adequate information to assist 

505(b)(2) and ANDA applicants in 

determining whether a listed method of 

use patent claims a use for which the 

505(b)(2) or ANDA applicant is not 

seeking approval’’ (Form FDA 3542, 

section 4.2b). 

Section 314.53(f) currently provides 

that, upon notification of the grounds 

for a disagreement with the accuracy or 

relevance of the patent submission, FDA 

will request that the NDA holder 

confirm the correctness of the patent 

information or omission of patent 

information. Proposed § 314.53(f)(1) 

would establish a 30-day timeframe in 

which the NDA holder is required to 

respond to FDA’s request in order to 

facilitate timely resolution of the patent 

listing dispute. 

Proposed § 314.53(f)(1) also would 

further specify that, in response to 

notification of a patent listing dispute 

for a listed patent that claims an 

approved method of using the drug 

product, FDA will request that the NDA 

holder confirm the correctness of its 

description of the approved indication 

or method of use that has been included 

as the ‘‘use code’’ in the Orange Book, 

and provide information on the specific 

approved use claimed by the patent that 

enables the Agency to make a 

determination in accordance with 

section 505(b)(2)(B) or (j)(2)(C)(viii) of 

the FD&C Act. If the patent has been 

listed and the NDA holder confirms the 

accuracy of the patent information, fails 

to timely respond to FDA’s request 

under § 314.53(f), or submits a revision 

to the use code that does not provide 

adequate clarity for FDA to determine 

whether the scope of the proposed 

labeling carve-out would be appropriate 

based on the NDA holder’s use code and 

approved labeling, FDA is proposing to 

review a proposed labeling carve-out(s) 

for the 505(b)(2) application or ANDA 

with deference to the 505(b)(2) or ANDA 

applicant’s interpretation of the scope of 

the patent. In determining whether a 

proposed omission of use information 


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from labeling is appropriate, the Agency 

will consider the use code and labeling 

information submitted by the NDA 

holder on Form FDA 3542, the history 

of labeling changes related to approval 

of an indication(s) for the drug product, 

the 505(b)(2) or ANDA applicant’s 

interpretation of the scope of the patent, 

the need for consistent labeling among 

products approved under section 505(j) 

of the FD&C Act, and the requirements 

of §§ 314.94(a)(8)(iv) and 314.127(a)(7), 

as appropriate. 

The following hypothetical example 

illustrates our approach under proposed 

§ 314.53(f)(1) to determining whether an 

ANDA applicant’s proposed labeling 

carve-out would be appropriate: The 

NDA holder submits Form FDA 3542 to 

the Office of Generic Drugs, Document 

Room, Attention: Orange Book Staff, 

within 30 days after issuance of the ’321 

patent claiming a method of using the 

drug product Gaindrolone. The NDA 

holder provided the use code ‘‘to 

promote weight gain after weight loss in 

certain types of patients’’ for each patent 

that it submitted for listing in the 

Orange Book, but did not specifically 

identify the approved use(s) (e.g., 

patient population(s)) claimed by the 

patent. In section 4.2a of Form FDA 

3542, the NDA holder further identified 

the patented method of use claimed in 

patent claims 8, 9, and 10 of the ’321 

patent with specific reference to the 

following sections of the approved 

labeling for the drug product: 

Indications and Usage (‘‘indicated as 

adjunctive therapy to promote weight 

gain after weight loss following 

extensive surgery, chronic infections, or 

severe trauma’’) and Dosage and 

Administration. Applicant A submits an 

ANDA that cites Gaindrolone as the 

basis for ANDA submission and 

contains a 505(j)(2)(A)(viii) statement 

with respect to the ’321 patent. 

Applicant A also notifies the Agency in 

a written communication titled 

‘‘314.53(f) Patent Listing Dispute’’ that 

the use code listed in the Orange Book 

for the ’321 patent is overbroad as 

Applicant A interprets the scope of the 

’321 patent to be limited to ‘‘adjunctive 

therapy to promote weight gain after 

weight loss following chronic 

infections.’’ Applicant A contends that 

other approved patient populations are 

not within the scope of the ’321 patent. 

FDA subsequently provides the NDA 

holder with the Applicant A’s basis for 

disagreement with the accuracy of the 

listed patent information and requests 

that the NDA holder confirm the 

correctness of the description of the 

specific approved use claimed by the 

patent or revise the description within 

30 days. The NDA holder confirms the 

use code ‘‘to promote weight gain after 

weight loss in certain types of patients’’ 

and thus does not provide adequate 

clarity for the Agency to make a 

determination in accordance with 

section 505(j)(2)(A)(viii) of the FD&C 

Act on whether Applicant A could carve 

out the patented use in ‘‘certain types of 

patients’’ and seek approval for the 

remaining uses. Accordingly, FDA 

reviews the proposed ANDA labeling 

with deference to Applicant A’s 

interpretation of the scope of the patent 

and approves the ANDA for ‘‘adjunctive 

therapy to promote weight gain after 

weight loss following extensive surgery 

or severe trauma.’’ As noted in the June 

2003 final rule, ‘‘the claim-by-claim 

listing of method-of-use patents will 

permit ANDA and 505(b)(2) applicants 

to assess whether they are seeking 

approval for a use claimed in the listed 

patent, and thus determine whether to 

submit a patent certification or a section 

viii statement. Additionally, we [FDA] 

can verify that the certification or 

statement is correct, and that only the 

appropriate methods of use are included 

in the proposed labeling for the ANDA 

or 505(b)(2) drug product’’ (68 FR 36676 

at 36685). Applicant A has a strong 

incentive to interpret the scope of the 

patent correctly to avoid being subject to 

patent infringement litigation following 

ANDA approval and potentially 

enjoined from marketing its product. 

The use code submitted by the NDA 

holder remains listed in the Orange 

Book (compare June 2003 final rule (68 

FR 36676 at 36683) (‘‘[u]se codes are 

intended to alert ANDA and 505(b)(2) 

applicants to the existence of a patent 

that claims an approved use. They are 

not meant to substitute for the 

applicant’s review of the patent and the 

approved labeling’’). 

In the same example above, we note 

that if the NDA holder had responded 

to FDA’s request by revising the 

description of the specific approved use 

claimed by the patent in a manner that 

provided sufficient information for the 

Agency to make a determination in 

accordance with section 

505(j)(2)(A)(viii) of the FD&C Act on 

whether Applicant A could carve out 

the patented use, FDA would have no 

occasion to review the proposed ANDA 

labeling with deference to Applicant A’s 

interpretation of the scope of the patent. 

For example, if the NDA holder 

submitted a revised Form 3542 that 

provided a revised use code 

(hypothetically ‘‘to promote weight gain 

after weight loss following chronic 

infections or severe trauma’’) and 

specifically referred to the 

corresponding portion of the approved 

labeling, there would be sufficient 

information for the Agency to make a 

determination in accordance with 

section 505(j)(2)(A)(viii) of the FD&C 

Act. Accordingly, there would be no 

ambiguity that would warrant review of 

the proposed ANDA labeling with 

deference to Applicant A’s 

interpretation of the scope of the patent, 

even if Applicant A’s interpretation 

differed from that of the NDA holder. 

As previously discussed in the June 

2003 final rule, we reiterate that the 

Agency’s role in patent listing is 

ministerial and does not involve 

substantive review of patents (see 68 FR 

36676 at 36683). Rather, our proposed 

revisions to the regulations in 314.53(f) 

are intended to provide the Agency with 

the information necessary to implement 

section 505(b)(2)(B) and (j)(2)(C)(viii) of 

the FD&C Act. FDA believes that 

enhancing the mechanism for 

challenging overbroad use codes listed 

in the Orange Book may cause NDA 

holders to be more circumspect in their 

original submission of patent 

information to FDA. Accordingly, we 

expect that there will rarely be a need 

for the Agency to review the proposed 

labeling for the 505(b)(2) application or 

ANDA with deference to the 505(b)(2) or 

ANDA applicant’s interpretation of the 

scope of the patent. However, we invite 

comment on this proposed approach to 

enhancing FDA’s response to challenges 

to the accuracy or relevance of 

submissions of patent information to the 

Agency, while maintaining the Agency’s 

ministerial role in patent listing. 

II.B.4.b. Requests by NDA Holder To 

Remove Patent Information From the 

List (Proposed § 314.53(f)(2)) 

II.B.4.b.i. Patents or patent claims that 

no longer meet the statutory 

requirements for listing. Section 

1102(a)(2) of the MMA amends section 

505(j)(5)(D)(i)(I) of the FD&C Act to 

define certain events that constitute 

forfeiture of 180-day exclusivity. As 

noted in section I, we are implementing 

the 180-day exclusivity provisions of 

the MMA directly from the statute and 

will determine if additional rulemaking 

is necessary in the future. Where a novel 

issue of interpretation is raised by a 

particular factual scenario regarding 

forfeiture of 180-day exclusivity, we 

may open a public docket or otherwise 

seek comment from affected parties in 

advance of taking action (see section 

I.D). However, we are proposing at this 

time to add § 314.53(f)(2) regarding 

requests by an NDA holder to remove 

patent information from the list to 

implement section 

505(j)(5)(D)(i)(I)(bb)(CC) of the FD&C 


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Act (forfeiture of 180-day exclusivity 

due to failure to market where the 

patent or patent information that 

qualified the first applicant for 180-day 

exclusivity is withdrawn by the NDA 

holder), and to clarify our current 

practice with respect to withdrawal of a 

patent or patent information by an NDA 

holder. 

Under proposed § 314.53(f)(2), if the 

NDA holder determines that a patent or 

patent claim (e.g., a method-of-use 

claim) no longer meets the statutory 

requirements for listing, the NDA holder 

is required to promptly notify FDA to 

withdraw the patent or patent 

information and request that the patent 

or patent information be removed from 

the list. Circumstances under which a 

patent or patent claim no longer meets 

the statutory requirements for listing 

include, but are not limited to, a judicial 

finding of invalidity or unenforceability 

for a listed patent, from which no 

appeal has been or can be taken, or a 

court order to amend patent information 

or withdraw a patent from the list. We 

note that an NDA applicant that 

determined that a patent or patent claim 

submitted on Form FDA 3542a no 

longer met the statutory requirements 

for listing prior to NDA approval would 

‘‘withdraw’’ the patent or patent claim 

by not including the patent or patent 

claim in its submission of Form FDA 

3542 upon approval of the NDA or NDA 

supplement. There is no need to submit 

a request to remove the patent or patent 

claim from the list because such patent 

information is listed in the Orange Book 

only upon approval of the NDA or NDA 

supplement. 

The FD&C Act does not provide an 

independent cause of action for a 

505(b)(2) or ANDA applicant seeking an 

order requiring an NDA holder to 

correct or delete patent information 

listed in the Orange Book (see section 

505(c)(3)(D)(ii)(II) and (j)(5)(C)(ii)(II) of 

the FD&C Act; see also Mylan 

Pharmaceuticals, Inc. v. Thompson, 268 

F.3d 1323 (Fed. Cir. 2001) (holding that 

the pre-MMA statutory scheme did not 

recognize a cause of action for delisting 

a patent from the Orange Book, and that 

‘‘such an action would be a private right 

of action barred by the [act]’’)). If a 

505(b)(2) or ANDA applicant 

successfully asserts a counterclaim to a 

patent infringement action to obtain an 

order requiring the NDA holder to 

amend or withdraw patent information 

from the list (see section 

505(c)(3)(D)(ii)(I) and (j)(5)(C)(ii)(I) of 

the FD&C Act), the NDA holder must 

withdraw the patent or patent 

information and request that the patent 

or patent information be removed from 

the list. The Agency will not remove the 

patent or patent information in response 

to a request, accompanied by a copy of 

the court order, from the 505(b)(2) or 

ANDA applicant or on its own. We are 

proposing to require an NDA holder to 

submit a copy of a court order requiring 

amendment or withdrawal of patent 

information to the Orange Book Staff 

through the Office of Generic Drugs 

Document Room within 14 calendar 

days of the date on which the order was 

entered. By providing a 14-day 

timeframe within which an NDA holder 

must notify FDA of this type of court 

order, the proposed regulation would 

facilitate the NDA holder’s compliance 

with obligations under the FD&C Act 

and applicable regulations and ensure 

that pending 505(b)(2) applications or 

ANDAs that have provided a patent 

certification to the amended or 

withdrawn patent are not 

inappropriately delayed if they are 

otherwise eligible for approval. The 

Orange Book Staff subsequently will 

forward a copy of the court order to the 

NDA through the CDER Central 

Document Room. 

We recognize that for patents that 

meet the statutory criteria for listing in 

the Orange Book, fewer than all of the 

patent claims may be the subject of 

litigation against a particular 505(b)(2) 

or ANDA applicant. In such a case, a 

judicial finding of invalidity for certain 

patent claims and withdrawal of that 

patent information by submission of an 

amended Form FDA 3542 may not 

necessarily be reflected in the Orange 

Book (unless, for example, all drug 

product claims were invalidated and 

only a method-of-use claim remained). 

Accordingly, it would be prudent for 

current and prospective 505(b)(2) and 

ANDA applicants to be aware of 

relevant court decisions in patent 

litigation (see also the 1994 final rule 

(59 FR 50338 at 50346) (noting the 

prudence of conducting patent searches 

to identify patents that may be ineligible 

for listing in the Orange Book but that 

may be infringed by a proposed 

product)). 

Consistent with our current practice, 

proposed § 314.53(f)(2) states that we 

will remove a patent from the Orange 

Book when the NDA holder has 

informed us that the patent no longer 

meets the statutory requirements for 

listing if there is no first applicant 

eligible for 180-day exclusivity or upon 

the expiration of the 180-day exclusivity 

period of a first applicant. 

Proposed § 314.53(f)(2) also applies to 

amendment of the patent information to 

remove a claim (drug substance, drug 

product, or method of use) from the list. 

For example, if a patent is listed in the 

Orange Book as claiming the drug 

product and a method of use, and an 

NDA holder withdrew only the drug 

product claim and requested that the 

drug product claim be removed from the 

list, we would remove the drug product 

claim from the Orange Book if there is 

no first applicant eligible for 180-day 

exclusivity or upon the expiration of the 

180-day exclusivity period of a first 

applicant. This provision is intended to 

address scenarios in which an ANDA 

applicant has submitted a paragraph IV 

certification with respect to the drug 

substance or drug product claim and a 

505(j)(2)(C)(viii) statement with respect 

to a method-of-use claim for a single 

patent. 

When an NDA holder has withdrawn 

a patent and submitted to FDA a request 

to remove the patent from the Orange 

Book, we currently identify this request 

in a separate column in the Orange Book 

titled ‘‘Delist Requested.’’ If an NDA 

holder withdraws a patent claim (e.g., a 

method-of-use claim in a patent that 

also claims the drug product) and 

submits to FDA a request to remove the 

patent claim from the Orange Book, we 

intend to identify this request with a 

symbol (e.g., an asterisk) in the column 

for that claim. These notations signal 

that the patent or patent claim remains 

listed in the Orange Book only to 

preserve a first applicant’s eligibility for 

180-day exclusivity for their pending 

ANDA or during the period of 180-day 

exclusivity after approval of the first 

applicant’s ANDA. While the patent or 

patent claims remain listed in the 

Orange Book, subsequent ANDA 

applicants must submit or maintain an 

appropriate patent certification or 

statement with respect to the patent or 

patent claims for which the delisting 

request has been submitted. This 

requirement is consistent with 

preservation of a first applicant’s 

eligibility for 180-day exclusivity 

because the 180-day exclusivity period 

bars approval of subsequent ANDAs for 

the same drug product that also contain 

a paragraph IV certification to the patent 

(see section 505(j)(5)(B)(iv)(I) of the 

FD&C Act). However, a 505(b)(2) 

applicant is not required to certify or 

maintain a previous certification to the 

patent for which a request to remove the 

patent from the list has been submitted, 

because such a patent remains listed in 

the Orange Book only for purposes of 

preserving a first ANDA applicant’s 

eligibility for 180-day exclusivity. 

An applicant can determine that a 

patent or patent claim has been removed 

from the Orange Book if it no longer 

appears in the Orange Book patent 

listings for the drug product at issue. In 

addition, FDA maintains a separate Web 

page linked from the ‘‘search by patent’’ 


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option on the Orange Book Web page 

that identifies patents that have been 

recently delisted (currently located at 

http://www.accessdata.fda.gov/scripts/

cder/ob/docs/delist.cfm). 

II.B.4.b.ii. Patent term restoration. 

Proposed § 314.53(f)(2)(ii) directs NDA 

holders to submit a correction to the 

expiration date of their listed patent if 

the term of the patent is extended under 

the patent term restoration provisions of 

35 U.S.C. 156, and sets a timeframe for 

compliance. With respect to patents 

eligible for listing in the Orange Book, 

the Hatch-Waxman Amendments 

generally provide that the terms of 

certain patents may be extended for a 

period of up to 5 years if the patent 

claims a product or method of using a 

product that has been subject to a 

defined regulatory review period before 

commercial marketing or use (see 35 

U.S.C. 156(a)). We are proposing to 

require the NDA holder to submit the 

correction to the patent expiration date 

on Form FDA 3542 within 30 calendar 

days of receipt of a certificate of 

extension as described in 35 U.S.C. 

156(e)(1) or documentation of an 

extension of the term of the patent as 

described in 35 U.S.C. 156(e)(2). The 30- 

day timeframe within which an NDA 

holder must notify FDA of the patent 

term extension is consistent with the 

statutory timeframe set forth in section 

505(c)(2) of the FD&C Act for filing with 

FDA the patent number and patent 

expiration date of any patent that claims 

the drug or method of using the drug 

and is issued after NDA approval. 

Although extension of the patent term of 

a previously issued patent is not 

explicitly within the scope of section 

505(c)(2) of the FD&C Act, the proposed 

30-day timeframe for submission of a 

correction of the patent expiration date 

is consistent with the objective of 

ensuring that prospective 505(b)(2) and 

ANDA applicants have timely notice of 

changes to the asserted patent coverage 

for a listed drug. 

II.B.4.b.iii. Submissions to FDA. 

Proposed § 314.53(f)(2)(iii) would 

require that corrections or changes to 

previously submitted patent information 

(other than withdrawal of a patent or 

requests to remove a patent from the 

list) must be submitted on Form FDA 

3542a or 3542, as appropriate. This 

proposed requirement is intended to 

facilitate listing of patent information in 

the Orange Book and ensure that patent 

information is accompanied by the 

patent declaration verification required 

by § 314.53(c)(2)(i)(Q) and (c)(2)(ii)(R) 

and set forth in the certification 

requirements of Form FDA 3542a or 

3542, respectively. We note that we will 

not accept corrections or changes that 

are not submitted on the appropriate 

forms. However, an NDA holder may 

elect to submit a cover letter 

highlighting the corrections or changes 

made in the accompanying Form FDA 

3542. An NDA holder’s withdrawal of 

fewer than all of a previously submitted 

patent’s claims (e.g., withdrawal of the 

method of use claim(s) for a patent that 

also claims the drug product) would be 

considered a correction or change to 

patent information for purposes of 

proposed § 314.53(f)(2)(iii) because the 

patent would remain listed in the 

Orange Book. 

However, proposed § 314.53(f)(2)(iv) 

clarifies that an NDA holder’s 

withdrawal of a patent and request to 

remove a patent from the Orange Book 

is not required to be submitted on Form 

FDA 3542a (with respect to preapproval withdrawal of a patent) or FDA 

Form FDA 3542. The withdrawal of a 

patent must be submitted as an 

amendment to the NDA if the 

application has not been approved. 

After NDA approval, the withdrawal of 

a patent must be submitted to the 

Orange Book Staff through the OGD 

Document Room and must specify the 

patent number, the application number, 

and each product(s) approved in the 

application to which the request 

applies. The Orange Book Staff 

subsequently will forward a copy of the 

patent withdrawal to the NDA through 

the CDER Central Document Room. 

II.C. Patent Certification (Proposed 

§§ 314.50(i) and 314.94(a)(12)) 

II.C.1. Method-of-Use Patents (Proposed 

§§ 314.50(i)(1)(iii) and 314.94(a)(12)(iii)) 

We are proposing to revise 

§§ 314.50(i)(1)(iii) and 314.94(a)(12)(iii) 

to clarify that a 505(b)(2) or ANDA 

applicant that is not seeking approval 

for any indications or other conditions 

of use that are covered by a method-ofuse patent for the listed drug(s) relied 

upon or RLD, respectively, and has 

omitted corresponding labeling from its 

proposed product may submit a 

statement under section 505(b)(2)(B) or 

505(j)(2)(A)(viii), respectively, instead of 

a patent certification with respect to any 

method-of-use claims. The proposed 

addition of the phrase ‘‘or other 

conditions of use’’ to §§ 314.50(i)(1)(iii) 

and 314.94(a)(12)(iii) reflects that a 

method-of-use patent that claims a use 

other than an indication may be 

submitted for listing in the Orange Book 

and may be the subject of a statement 

under section 505(b)(2)(B) or 

505(j)(2)(A)(viii) with an accompanying 

labeling carve-out. This proposed 

revision is intended to conform with 

current Agency practice. 

II.C.2. Method-of-Manufacturing Patents 

(Proposed Deletion of §§ 314.50(i)(2) 

and 314.94(a)(12)(iv)) 

The current regulations in 

§§ 314.50(i)(2) and 314.94(a)(12)(iv) 

state that a 505(b)(2) or ANDA 

applicant, respectively, is not required 

to make a patent certification with 

respect to any patent that claims only a 

method of manufacturing the drug 

product (method-of-manufacturing 

patent). This has been incorrectly 

interpreted by certain applicants to 

mean that a manufacturer could elect to 

submit such a patent for listing. In 2003, 

§ 314.53(b) was amended to state, 

among other things, that process patents 

(i.e., method-of-manufacturing patents) 

must not be submitted to FDA (68 FR 

36676 at 36679). Therefore, we are 

proposing that current §§ 314.50(i)(2) 

and 314.94(a)(12)(iv) be removed (and 

reserved) to ensure consistency and 

clarity in our regulations. 

II.C.3. Licensing Agreement (Proposed 

§ 314.50(i)(3)) 

We are proposing to revise 

§ 314.50(i)(3) regarding licensing 

agreements to remove the references to 

an ‘‘immediate effective date’’ and 

clarify that the patent owner with whom 

the applicant has a licensing agreement 

may consent to approval of the 505(b)(2) 

application (if otherwise justified) as of 

a specific date. These proposed 

revisions reflect that there may be 

barriers to approval other than the 

patent that is the subject of the licensing 

agreement. In addition, the proposed 

revision acknowledges that a patent 

owner may consent to approval as of a 

specific date. 

This proposed revision does not alter 

the current requirements for a 505(b)(2) 

(or ANDA) applicant that submits a 

paragraph IV certification to a patent 

that claims the listed drug relied upon 

and for which the applicant has a 

licensing agreement with the patent 

owner (see proposed §§ 314.50(i)(3) and 

314.94(a)(12)(v)). A 505(b)(2) or ANDA 

applicant must comply with the 

statutory requirements for sending 

notice of paragraph IV certification 

under section 505(b)(3) and (j)(2)(B) of 

the FD&C Act, respectively, with respect 

to each listed patent for which it has 

submitted a paragraph IV certification 

notwithstanding the applicant’s 

statement that it has been granted a 

patent license. 


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II.D. Notice of Paragraph IV 

Certification (Proposed §§ 314.52 and 

314.95) 

II.D.1. Timing of Notice 

A 505(b)(2) or ANDA applicant 

submitting a paragraph IV certification 

is required to give notice of the patent 

challenge to the holder of the NDA for 

the listed drug(s) relied upon or RLD, 

respectively, and each owner of the 

patent that is the subject of the 

certification within a specified 

timeframe (see section 505(b)(3) and 

(j)(2)(B) of the FD&C Act). We are 

proposing to revise our regulations to 

clearly delineate the two limitations on 

the timeframe within which notice can 

be provided to the NDA holder and each 

patent owner of a paragraph IV 

certification to a listed patent: (1) The 

date before which notice may not be 

given and (2) the date by which notice 

must be given. The MMA amended the 

FD&C Act to establish the date by which 

notice of a paragraph IV certification 

must be given to the NDA holder and 

each patent owner. Table 5 summarizes 

the proposed changes related to the 

timing of providing notice of a 

paragraph IV certification. 

TABLE 5—HIGHLIGHTS OF PROPOSED CHANGES REGARDING TIMING OF NOTICE OF PARAGRAPH IV CERTIFICATION 1

Current regulations Proposed revisions to regulations 

Sending the notice (§§ 314.52(b) and 314.95(b)) Sending the notice (§§ 314.52(b)(1) and (b)(2) and 314.95(b)(1) and 

(b)(2)) 

• 505(b)(2) applicant must send notice required by § 314.52(a) when it 

receives from FDA an acknowledgment letter stating that its 

505(b)(2) application has been filed. 

• Except as provided in § 314.52(d), a 505(b)(2) applicant must send 

notice required by § 314.52(a) on or after the date it receives from 

FDA a paragraph IV acknowledgment letter, but not later than 20 

days after the date of the postmark on the paragraph IV acknowledgment letter. 

• Any required notice is invalid if it is sent before the 505(b)(2) applicant’s receipt of a paragraph IV acknowledgment letter. The applicant will not have complied with § 314.52(b) until it sends valid notice. 

• ANDA applicant must send notice required by § 314.95(a), when it 

receives from FDA an acknowledgment letter stating that its ANDA is 

sufficiently complete to permit a substantive review. 

• Except as provided in § 314.95(d), an ANDA applicant must send notice required by § 314.95(a) on or after the date it receives from FDA 

an acknowledgment letter or a paragraph IV acknowledgment letter, 

but not later than 20 days after the date of the postmark on the acknowledgment letter or paragraph IV acknowledgment letter. 

• Any required notice is invalid if it is sent before the ANDA applicant’s 

receipt of an acknowledgment letter or a paragraph IV acknowledgment letter, or before the first working day after the day the patent is 

published in the list. The applicant will not have complied with 

§ 314.95(b) until it sends valid notice. 

• The 20-day clock begins on the day after the date of the postmark 

on the paragraph IV acknowledgment letter. When the 20th day falls 

on Saturday, Sunday, or a Federal holiday, the 20th day will be the 

next day that is not a Saturday, Sunday, or Federal holiday. 

Sending the notice (§§ 314.52(b) and 314.95(b)) Sending the notice (§§ 314.52(b)(3) and 314.95(b)(3) 

• At the same time, the 505(b)(2) or ANDA applicant must amend its 

application to include a statement certifying that notice of paragraph 

IV certification has been provided to each person identified under 

§ 314.52(a) or § 314.95(a), respectively, and that notice met the content requirement under § 314.52(c) or § 314.95(c), respectively. 

• At the same time the 505(b)(2) or ANDA applicant sends the notice 

required by § 314.52(a) or § 314.95(a), respectively, it must submit 

an amendment to its 505(b)(2) application that includes a statement 

certifying that the notice of paragraph IV certification has been provided to each person under § 314.52(a) or § 314.95(a), respectively, 

and that notice met the content requirement under § 314.52(c) or 

§ 314.95(c), respectively. 

1These highlights describe important proposed revisions to our regulations, but should not be relied upon in place of the proposed regulation. 

II.D.1.a. Date before which notice may 

not be given. We are proposing to clarify 

the text of our regulations to reflect our 

longstanding practice that notice of a 

paragraph IV certification may not be 

sent by a 505(b)(2) or ANDA applicant 

unless and until we have notified the 

applicant that its application has been 

filed or received, as appropriate, in an 

acknowledgment letter or a paragraph 

IV acknowledgment letter (see proposed 

§§ 314.52(b)(1) and 314.95(b)(1)). 

Sections 314.52(b) and 314.95(b) 

currently require that a 505(b)(2) and 

ANDA applicant, respectively, send 

notice of a paragraph IV certification 

when it receives from FDA an 

acknowledgment letter stating that the 

application is sufficiently complete to 

permit a substantive review. An NDA, 

including a 505(b)(2) application, is 

deemed sufficiently complete to permit 

a substantive review if it is filed by the 

60th day after submission (see 

§ 314.101(a)(1) and proposed 

§ 314.101(a)(2)). An ANDA is received 

when FDA has made a threshold 

determination that the ANDA is 

substantially complete and has sent the 

ANDA applicant an acknowledgment 

letter or paragraph IV acknowledgment 

letter (see § 314.101(b)). We previously 

have explained that notice of a 

paragraph IV certification is to be sent 

only after the 505(b)(2) or ANDA 

applicant has received acknowledgment 

from FDA that its application has been 

determined to be acceptable for review 

because such notice subjects the 

505(b)(2) or ANDA applicant to the risk 

that it will be sued for patent 

infringement (see ‘‘Abbreviated New 

Drug Application Regulations’’; 

proposed rule (54 FR 28872; July 10, 

1989) (1989 proposed rule); see also 35 

U.S.C. 271(e)(2)). The receipt of notice 

of a paragraph IV certification by a 

patent owner or the NDA holder (or 

their representatives) begins a 45-day 

period within which the NDA holder or 

patent owner must initiate a patent 

infringement action against the 505(b)(2) 

or ANDA applicant in order to obtain, 

in certain cases, a statutory 30-month 

stay of approval of the application while 

the patent infringement litigation is 

pending (section 505(c)(3)(C) and 

(j)(5)(B)(iii) of the FD&C Act). 

The FD&C Act requires that a notice 

of paragraph IV certification must state 


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that the 505(b)(2) application or ANDA 

containing the certification ‘‘has been 

submitted’’ (see section 505(b)(3)(D)(i) 

and (j)(2)(B)(iv)(I) of the FD&C Act). As 

we noted in the preamble to the 1989 

proposal to implement the HatchWaxman Amendments, however, ‘‘[t]he 

statute and legislative history of Title I 

[of the Hatch-Waxman Amendments] 

demonstrate that Congress did not 

intend incomplete application 

submissions to trigger legal action by a 

patent owner or approved application 

holder’’ (1989 proposed rule, 54 FR 

28872 at 28887). By requiring that a 

505(b)(2) application has been filed or 

an ANDA has been received before 

notice of a paragraph IV certification 

can be given, we ensure that the NDA 

holder and patent owner do not 

needlessly expend resources to initiate 

litigation with respect to an application 

that is incomplete and therefore may not 

be reviewed by the Agency (see 1989 

proposed rule, 54 FR 28872 at 28887 

and 1994 final rule, 59 FR 50338 at 

50349–50350). Accordingly, our current 

regulations require that a 505(b)(2) or 

ANDA applicant’s notice of a paragraph 

IV certification must include a 

statement that FDA has filed the NDA 

(in the case of a 505(b)(2) application) 

or has received the ANDA (see 

§§ 314.52(c)(1) and 314.95(c)(1)). 

Despite the language in our existing 

regulations and the preamble to the 

1989 proposed rule, we have continued 

to receive inquiries from the public 

regarding whether notice of paragraph 

IV certification may be sent before the 

filing of a 505(b)(2) application or 

receipt of an ANDA. Some have 

expressed uncertainty after enactment of 

the MMA because the FD&C Act 

requires that notice be sent ‘‘not later 

than 20 days after the date of the 

postmark on the notice with which 

[FDA] informs the applicant’’ that its 

505(b)(2) application or ANDA has been 

filed, without explicitly establishing a 

date earlier than which notice may not 

be provided (see section 505(b)(3)(B)(i) 

and (j)(2)(B)(ii)(I) of the FD&C Act). 

We are proposing to amend 

§§ 314.52(b) and 314.95(b) by revising 

and redesignating the current text as 

paragraphs (b)(1) and (b)(3) and adding 

a new paragraph (b)(2). Proposed 

§ § 314.52(b)(2) and 314.95(b)(2) state 

that any notice sent before the receipt of 

an FDA acknowledgment letter or 

paragraph IV acknowledgment letter is 

invalid (and thus does not trigger either 

the 45-day period in which the NDA 

holder and each patent owner may 

initiate a patent infringement action and 

obtain a 30-month stay or the beginning 

of any related 30-month period) and 

will not be considered to comply with 

the FD&C Act’s notice requirement until 

valid notice is sent. We also are 

proposing to revise § 314.95(b)(2) to 

state that any notice sent before the first 

working day after the day the patent is 

published in the Orange Book (the list) 

is invalid and will not be considered to 

comply with the FD&C Act’s notice 

requirement (see discussion in section 

II.D.1.b.ii). 

An applicant that prematurely sends 

notice of a paragraph IV certification 

must resend notice within the required 

timeframe in order to satisfy the notice 

requirement of the FD&C Act and, in the 

case of a first applicant, qualify for 180- 

day exclusivity. To help ensure that 

notices of paragraph IV certifications are 

not sent prematurely, we also are 

proposing to amend § § 314.52(c)(3) and 

314.95(c)(3) to require that each 

505(b)(2) or ANDA applicant include, in 

any notice of paragraph IV certification 

related to its application, a statement 

that it has received an acknowledgment 

letter or paragraph IV acknowledgment 

letter. We recognize that this proposed 

requirement may have the effect of 

delaying the provision of notice of 

paragraph IV certification by a 505(b)(2) 

applicant (but not an ANDA applicant) 

by approximately 2 weeks after the 

505(b)(2) application is filed, because an 

NDA is considered filed 60 days after 

submission, but our proposed definition 

of a ‘‘paragraph IV acknowledgment 

letter’’ for a 505(b)(2) application is the 

filing communication that is generally 

mailed by the 74th day after the date of 

submission of the 505(b)(2) application 

in accordance with the performance 

goal established under the current 

reauthorization of the prescription drug 

user fee program in FDASIA (see section 

II.D.3.b). We recognize that this would 

potentially delay the initiation of patent 

infringement litigation by an NDA 

holder or patent owner and any 

corresponding 30-month stay of 

approval of the 505(b)(2) application by 

approximately 2 weeks. We invite 

comment on this approach to premature 

notice of a paragraph IV certification for 

a 505(b)(2) application, especially with 

respect to notice sent after a 505(b)(2) 

application is filed (60th day after 

submission) and before a paragraph IV 

acknowledgment letter (generally sent 

by the 74th day after submission) is 

received. 

There have been some instances in 

which an applicant seeks to submit an 

amendment containing a paragraph IV 

certification to its 505(b)(2) application 

or ANDA prior to filing or receipt of the 

application as described in § 314.101(a) 

and (b), respectively, and receipt of an 

acknowledgment letter or a paragraph 

IV acknowledgment letter. For example, 

an applicant may seek to amend its 

ANDA to add a new strength of the drug 

product (see § 314.95(d)(3)). We are 

proposing to revise §§ 314.52(d)(2) and 

314.95(d)(2) to clarify that an applicant 

submitting an amendment containing a 

paragraph IV certification must comply 

with the timeframes set forth in 

§§ 314.52(b) and 314.95(b) and wait 

until it has received an acknowledgment 

letter or a paragraph IV 

acknowledgment letter before sending 

notice of its paragraph IV certification to 

the NDA holder and each patent owner. 

This approach ensures that a notice of 

paragraph IV certification is not sent 

before we have accepted for substantive 

review the underlying application to 

which the notice relates (i.e., before we 

have filed the 505(b)(2) application or 

received the ANDA). As one Federal 

district court observed in upholding 

FDA’s interpretation of the statute in 

this scenario, ‘‘[i]f an ANDA applicant 

could send Paragraph IV notice when 

amending an ANDA that has not yet 

been accepted as received, the applicant 

could accelerate the timing provisions 

and litigation process well beyond the 

framework that Congress intended’’ (SB 

Pharmco Puerto Rico, Inc. v. Mutual 

Pharmaceutical Co., 552 F. Supp. 2d 

500, 510 (E.D. Pa.), appeal dismissed, 

2008 U.S. App. LEXIS 27672 (Fed. Cir. 

2008) (holding that notice of a 

paragraph IV certification sent 

concurrent with submission of an 

amendment to an ANDA that had not 

yet been accepted for filing ‘‘was not 

valid or timely’’ under section 

505(j)(2)(B)(ii)(II) of the FD&C Act)). 

Thus, if an ANDA applicant submits 

an amendment containing a paragraph 

IV certification before it has received an 

acknowledgment letter or a paragraph 

IV acknowledgment letter advising that 

the ANDA has been received for 

substantive review, the applicant is 

required to send notice of its paragraph 

IV certification within 20 days after the 

date of the postmark on the 

acknowledgment letter or paragraph IV 

acknowledgment letter, as applicable. It 

is important to note that the relevant 

date for purposes of determining first 

applicant eligibility for 180-day 

exclusivity based upon submission of a 

paragraph IV certification contained in 

an amendment is the date of submission 

of the amendment (i.e., the date on 

which the amendment was officially 

received (date-stamped) by the OGD 

Document Room) even though the 

acknowledgment letter or paragraph IV 

acknowledgment letter may state that 

the ANDA was received for substantive 

review on the date on which the original 

ANDA was submitted (i.e., the date on 


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which the ANDA was officially received 

(date-stamped) by the OGD Document 

Room) or, in the case of an ANDA that 

OGD initially refused to receive under 

§ 314.101(d) or (e), the date on which 

the deficiencies were resolved. 

II.D.1.b. Date by which notice must be 

given. The MMA amended the FD&C 

Act to require that 505(b)(2) and ANDA 

applicants provide notice of a paragraph 

IV certification to the NDA holder and 

each patent owner in accordance with 

the following timeframes: 

• If the paragraph IV certification is 

included in an original 505(b)(2) 

application or ANDA, or in an 

amendment to such application that is 

submitted before the applicant receives 

an acknowledgment letter or paragraph 

IV acknowledgment letter, not later than 

20 days after the date of the postmark 

on the notice from FDA informing the 

applicant that its application has been 

filed or received (see section 

505(b)(3)(B)(i) and (j)(2)(B)(ii)(I) of the 

FD&C Act), or 

• If the paragraph IV certification is 

included in any other amendment or in 

a supplement, at the time the applicant 

submits the amendment or supplement 

(see section 505(b)(3)(B)(ii) and 

505(j)(2)(B)(ii)(II) of the FD&C Act). 

II.D.1.b.i. Determining the timeframe 

for sending notice after receipt of an 

acknowledgment letter or a paragraph 

IV acknowledgment letter. We are 

proposing to revise §§ 314.52(b)(1) and 

314.95(b)(1) to require that an applicant 

must send notice of a paragraph IV 

certification contained in a 505(b)(2) 

application or ANDA on or after the 

date on which it receives an 

acknowledgment letter or a paragraph 

IV acknowledgment letter, but not later 

than 20 days after the date of the 

‘‘postmark’’ (see proposed definition 

below) on the acknowledgment letter or 

paragraph IV acknowledgment letter. As 

discussed in sections II.A.2.u and 

II.A.2.y, we are proposing a broader 

definition of the term ‘‘postmark’’ and, 

as applied to paragraph IV 

acknowledgment letters for 505(b)(2) 

applications, an alternate interpretation 

of the term ‘‘postmark’’ to reflect current 

OND practice regarding the mailing of 

filing communications. For purposes of 

proposed § 314.52(b) and (c) only, the 

‘‘date of the postmark’’ on the paragraph 

IV acknowledgment letter for a 505(b)(2) 

application is considered to be 4 

calendar days after the date on which 

the filing communication is signed by 

the signatory authority (generally the 

Division Director or designee in OND) 

unless OND sends the filing 

communication to the applicant via 

electronic transmission. If OND sends 

the filing communication via electronic 

transmission, then our proposed 

definition of ‘‘postmark’’ in § 314.3(b) 

would apply. We recognize that 

issuance of the filing communication 

within 14 days after the 60-day filing 

date described in § 314.101(a)(1) and 

(a)(2) represents a performance goal 

under the current reauthorization of the 

prescription drug user fee program in 

FDASIA. Accordingly, an applicant that 

has submitted a 505(b)(2) application 

containing a paragraph IV certification 

and has received neither a refuse-to-file 

letter within 60 days nor a filing 

communication within 74 days after 

FDA receives the 505(b)(2) application 

should contact FDA to request issuance 

of the filing communication. We invite 

comment on whether an alternate 

approach should be taken. With 

reference to an acknowledgment letter 

or a paragraph IV acknowledgment 

letter for an ANDA, we recognize that 

there may be scenarios in which the 

postmark on the envelope containing an 

acknowledgment letter or a paragraph 

IV acknowledgment letter is illegible or 

inadvertently absent. We invite 

comment on the interpretation of the 

term ‘‘postmark’’ in the context of an 

acknowledgment letter or a paragraph 

IV acknowledgment letter for a 505(b)(2) 

application or an ANDA, and whether 

our regulations should be amended to 

define differently the specific date on 

which the 20-day notice period begins. 

The MMA does not specify how the 

20-day period for providing notice of a 

paragraph IV certification is to be 

calculated. We are proposing in 

§§ 314.52(b)(1) and 314.95(b)(1) to 

calculate this notice period in the same 

way that we calculate the 45-day period 

within which each patent owner and 

NDA holder may initiate a patent 

infringement action (which may, if other 

applicable requirements are satisfied, 

trigger a 30-month stay of approval of a 

505(b)(2) application or ANDA) 

following receipt of notice of a 

paragraph IV certification (see 

§ 314.107(f)). Specifically, we propose 

that the first day of the 20-day period 

begin on the day after the date of the 

postmark on the acknowledgment letter 

or paragraph IV acknowledgment letter. 

The 20-day period is proposed to 

include all calendar days, except that if 

the 20th day falls on a Saturday, 

Sunday, or Federal holiday, the last day 

of the 20-day period will be considered 

to be the next day that is not a Saturday, 

Sunday, or Federal holiday. This 

approach reflects the most conservative 

interpretation of the statute and is the 

calculation method currently used by 

most ANDA applicants. 

There will be no regulatory benefit or 

consequence for applicants based on 

when they provide notice of a paragraph 

IV certification contained in an original 

application, as long as notice is 

provided within the 20-day timeframe 

required by the MMA. An ANDA 

applicant that does not comply with the 

statutory timeframe in section 

505(j)(2)(B)(ii)(I) and (j)(2)(B)(ii)(II) of 

the FD&C Act for providing notice of its 

paragraph IV certification will be 

subject to administrative consequences 

(see section II.D.5). 

II.D.1.b.ii. Determining the timeframe 

for sending notice of a paragraph IV 

certification upon submission of an 

amendment or supplement. We are 

proposing to revise §§ 314.52(d) and 

314.95(d) to implement section 

505(b)(3)(B)(i), (b)(3)(B)(ii), 

(j)(2)(B)(ii)(I), and (j)(2)(B)(ii)(II) of the 

FD&C Act and for the efficient 

enforcement of the FD&C Act. Our 

proposed revisions clarify the 

applicable timeframe in which a 

505(b)(2) or ANDA applicant must send 

notice of a paragraph IV certification 

submitted in an amendment or 

supplement to its 505(b)(2) application 

or ANDA, respectively. We are 

proposing to revise and redesignate the 

current text of §§ 314.52(d) and 

314.95(d) as paragraph (d)(1) to 

accommodate the proposed inclusion of 

additional paragraphs to §§ 314.52(d) 

and 314.95(d). Table 6 summarizes the 

proposed changes related to the timing 

of providing notice of paragraph IV 

certification(s) submitted in an 

amendment or supplement to a 

505(b)(2) application or ANDA. 

TABLE 6—HIGHLIGHTS OF PROPOSED CHANGES REGARDING TIMING OF NOTICE OF PARAGRAPH IV CERTIFICATION IN AN

AMENDMENT OR SUPPLEMENT 1

Current regulations Proposed revisions to regulations 

Amendment to an application or an abbreviated application 

(§§ 314.52(d) and 314.95(d)) 

Amendment or supplement to a 505(b)(2) application or an ANDA 

(§§ 314.52(d)(1) and 314.95(d)(1)) 


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TABLE 6—HIGHLIGHTS OF PROPOSED CHANGES REGARDING TIMING OF NOTICE OF PARAGRAPH IV CERTIFICATION IN AN

AMENDMENT OR SUPPLEMENT 1—Continued 

Current regulations Proposed revisions to regulations 

• If an application or abbreviated application is amended to include the 

certification described in §§ 314.50(i) or 314.94(a)(12)(i)(A)(4), respectively, the applicant must send the notice required by 

§§ 314.52(a) or 314.95(a), respectively, at the same time the amendment is submitted to FDA 

After receipt of an acknowledgment letter or paragraph IV acknowledgment letter: 

• If an applicant submits an amendment or supplement to its 

505(b)(2) application or ANDA that includes a paragraph IV certification, the applicant must send notice required by § 314.52(a) 

or § 314.95(a), respectively, at the same time the amendment is 

submitted to FDA. 

• Notice of paragraph IV certification is required regardless of 

whether notice already has been provided for another paragraph 

IV certification contained in the application or in an amendment 

or supplement to the application. 

Amendment to a 505(b)(2) application or an ANDA (§§ 314.52(d)(2) 

and 314.95(d)(2)) 

Before receipt of an acknowledgement letter or paragraph IV acknowledgment letter: 

• If an applicant submits a paragraph IV certification in an amendment to a 505(b)(2) application or ANDA, the applicant must 

send notice required by § 314.52(a) or § 314.95(a), respectively, 

in accordance with the procedures in § 314.52(b) or § 314.95(b). 

• If an ANDA applicant timely provides notice of paragraph IV certification in accordance with § 314.95(b), FDA will base its determination of whether the applicant is a first applicant on the date 

of submission of the amendment containing the paragraph IV 

certification. 

Amendment to a 505(b)(2) application or an ANDA (§§ 314.52(d)(3) 

and 314.95(d)(3)) 

• An applicant that submits an amendment or supplement to its 

505(b)(2) application or ANDA to seek approval of a new strength 

must provide notice of any paragraph IV certification in accordance 

with §§ 314.52(d)(1) and (d)(2) or §§ 314.95(d)(1) and (d)(2), as applicable. 

1These highlights describe important proposed revisions to our regulations, but should not be relied upon in place of the proposed regulation. 

We are proposing to revise 

§§ 314.52(d) and 314.95(d) (redesignated 

as §§ 314.52(d)(1) and 314.95(d)(1), 

respectively) to require that an applicant 

send notice of a paragraph IV 

certification contained in an 

amendment to an application that has 

been received for substantive review or 

in a supplement to an approved 

application at the same time that the 

amendment or supplement is submitted 

to FDA. Our proposed revisions clarify 

the requirement in our current 

regulations for an applicant to send 

notice of a paragraph IV certification at 

the same time that the amendment is 

submitted to FDA by distinguishing 

between: (1) Amendments submitted 

after the application has been received 

for substantive review as indicated by 

the receipt of an acknowledgment letter 

(if, as to an ANDA, the original 

application did not contain a paragraph 

IV certification) or paragraph IV 

acknowledgment letter and (2) 

amendments submitted before an 

application has been received for 

substantive review (see proposed 

§§ 314.52(d)(2) and 314.95(d)(2) and 

section II.D.1.b.i.). The MMA amended 

the FD&C Act to require that notice of 

a paragraph IV certification contained in 

a supplement to an approved 505(b)(2) 

application or ANDA be sent at the 

same time that the supplement is 

submitted to FDA, and our proposed 

revision to §§ 314.52(d)(1) and 

314.95(d)(1) incorporates this 

requirement (see section 505(b)(3)(B)(ii) 

and (j)(2)(B)(ii)(II) of the FD&C Act). 

In proposed §§ 314.52(d)(1) and 

314.95(d)(1), we reiterate the statutory 

requirement that notice of a paragraph 

IV certification in an amendment or 

supplement must be provided regardless 

of whether the applicant has already 

given notice with respect to another 

paragraph IV certification contained in 

the 505(b)(2) application or ANDA or in 

an amendment or supplement to the 

505(b)(2) application or ANDA. The 

phrase ‘‘another paragraph IV 

certification’’ may refer to a previous 

paragraph IV certification to a different 

listed patent for the listed drug relied 

upon or RLD or, for certain amendments 

and supplements (see section II.F), a 

previous paragraph IV certification to 

the same listed patent. For example, if 

an ANDA applicant submitted a 

paragraph IV certification to the ’246 

patent (a listed patent claiming the drug 

product for the listed drug relied upon) 

in its original application, and 

subsequently submitted an amendment 

to its pending ANDA to change the 

formulation, the ANDA applicant would 

be required to provide a new patent 

certification to the ’246 patent (see 

proposed § 314.96(d)(1) and section 

II.F.1). If this ANDA applicant 

submitted a paragraph IV certification to 

the ’246 patent in its amendment, the 

ANDA applicant would be required to 

send notice of its second paragraph IV 

certification to the ’246 patent to the 

NDA holder and each patent owner at 

the same time the amendment to the 

ANDA is submitted to FDA. 

If an applicant submits an amendment 

containing a paragraph IV certification 

to its 505(b)(2) application or ANDA 

before the applicant has received an 

acknowledgment letter (if, as to an 

ANDA, the original application did not 

contain a paragraph IV certification) or 

a paragraph IV acknowledgment letter, 

proposed §§ 314.52(d)(2) and 

314.95(d)(2) require that the applicant 

send notice of its paragraph IV 

certification in accordance with the 

procedures described in §§ 314.52(b) 

and 314.95(b), respectively. In this 

circumstance, the 505(b)(2) or ANDA 

applicant must send notice of the 

paragraph IV certification contained in 


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its amendment on or after the date it 

receives an acknowledgment letter or 

paragraph IV acknowledgment letter, 

but not later than 20 days after the date 

of the postmark on the letter. This 

requirement reflects our longstanding 

policy that notice of a paragraph IV 

certification may not be sent unless and 

until we have notified the applicant that 

its application has been filed or 

received, as appropriate (see section 

II.D.1.a). 

It should be noted that a paragraph IV 

certification submitted in an 

amendment after the 505(b)(2) 

application or ANDA is submitted but 

before the applicant receives a 

paragraph IV acknowledgment letter is 

considered part of the original 505(b)(2) 

application or ANDA solely for the 

purpose of determining the appropriate 

timeframe for sending notice of 

paragraph IV certification. The 

availability of a 30-month stay for patent 

infringement litigation initiated within 

the statutory timeframe in response to a 

paragraph IV certification submitted in 

an amendment to a 505(b)(2) application 

or an ANDA continues to be determined 

by whether the patent at issue was filed 

with FDA before the date on which the 

original 505(b)(2) application or ANDA 

(excluding an amendment or 

supplement) was submitted (see section 

505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C 

Act; see also proposed § 314.107(b)(2) 

and section II.M.2.b). For purposes of 

determining an ANDA applicant’s 

eligibility for 180-day exclusivity and 

the date from which a first ANDA 

applicant’s compliance with section 

505(j)(5)(D)(i)(IV) of the FD&C Act is 

assessed, the date of the submission of 

the paragraph IV certification is the date 

on which the amendment was 

submitted. An amendment seeking 

approval for a different strength of a 

drug product thus may have a different 

submission date than the original ANDA 

submission for purposes of evaluating 

an ANDA applicant’s eligibility for 180- 

day exclusivity for that new drug 

product and the date from which a first 

ANDA applicant’s compliance with 

section 505(j)(5)(D)(i)(IV) of the FD&C 

Act is assessed. 

Proposed §§ 314.52(d)(3) and 

314.95(d)(3) require that an applicant 

that submits an amendment or 

supplement to a 505(b)(2) application or 

ANDA that contains a paragraph IV 

certification and seeks approval for a 

different strength of the drug product 

must adhere to the timing requirements 

for notice in §§ 314.52(d)(1) or (d)(2) 

and 314.95(d)(1) or (d)(2), as applicable. 

Unlike other amendments and 

supplements to a 505(b)(2) application 

or ANDA, an amendment or supplement 

seeking approval of a different strength 

may refer to a different listed drug than 

the listed drug identified in the original 

505(b)(2) application or ANDA (see 

section 505(b)(4)(B) and (j)(2)(D)(ii) of 

the FD&C Act). Accordingly, we have 

separately described this type of 

amendment or supplement to clarify 

applicable regulatory requirements. 

There are a few situations in which 

the relationship between an 

acknowledgment letter or paragraph IV 

acknowledgment letter and the timing of 

notice for a paragraph IV certification 

contained in an amendment or 

supplement to a 505(b)(2) application or 

ANDA may seem complicated. For 

example, in the case of a 505(b)(2) or 

ANDA applicant that submits an 

original application containing a 

paragraph III certification to a listed 

patent and receives an acknowledgment 

letter (as distinguished from a paragraph 

IV acknowledgment letter) indicating 

that the 505(b)(2) application or ANDA 

has been received for substantive 

review, if the applicant subsequently 

submits an amendment containing a 

paragraph IV certification to a listed 

patent, the applicant need not wait to 

receive a paragraph IV acknowledgment 

letter before sending notice in 

accordance with § 314.52(d)(1) or 

§ 314.95(d)(1). 

Also, we note that FDA may send an 

acknowledgment letter for certain types 

of supplements (e.g., a supplement to an 

ANDA seeking approval for a new 

strength of a drug product; a 505(b)(2) 

supplement to an NDA seeking approval 

for a new indication, new dosage 

regimen, new route of administration, or 

a change from prescription use to OTC 

status for all conditions of use). 

However, this practice would not alter 

the 505(b)(2) or ANDA applicant’s 

statutory obligation to send notice of a 

paragraph IV certification at the time the 

supplement is submitted to FDA (and 

not at the time the paragraph IV 

acknowledgment letter for the 

supplement may be received). 

We interpret the requirement in 

proposed § 314.52(d)(1) or § 314.95(d)(1) 

to send notice of a paragraph IV 

certification at the same time that the 

amendment or supplement to the 

application is submitted to FDA to mean 

that notice to the NDA holder and each 

patent owner must be sent on the same 

day that the amendment or supplement 

to the application is submitted to FDA. 

It should be noted that the controlling 

date for purposes of first applicant 

eligibility is the date on which the 

amendment or supplement to the ANDA 

containing a paragraph IV certification 

is submitted (i.e., officially received 

(date-stamped) by the OGD Document 

Room) as long as notice is timely 

provided in accordance with the statute. 

Due to a technical difference in the 

method by which FDA determines the 

date of submissions to FDA (using a 

date of receipt rule) and the date on 

which an applicant sends notice of a 

paragraph IV certification to the NDA 

holder and each patent owner (using a 

date of mailing rule), these dates may 

differ. For example, Applicant A 

submits an amendment containing a 

paragraph IV certification to its ANDA 

on August 2 and sends notice of the 

paragraph IV certification to the NDA 

holder and each patent owner on that 

same day. The amendment to the ANDA 

is date-stamped by the OGD Document 

Room on August 3. Applicant A has 

complied with the statutory requirement 

to send notice of its paragraph IV 

certification at the same time the 

amendment or supplement to the ANDA 

is submitted despite the difference in 

the date on which the amendment was 

officially received and the date on 

which the notice of paragraph IV 

certification was sent because both the 

amendment and notice(s) were actually 

sent on the same day. 

If an ANDA applicant does not 

provide notice of a paragraph IV 

certification on the same day that an 

amendment or supplement is submitted, 

FDA will consider the paragraph IV 

certification to be effective only as of the 

date that the applicant has both 

submitted the amendment or 

supplement containing the paragraph IV 

certification and sent the notice (see 

Purepac Pharmaceutical Co. v. 

Thompson, 354 F.3d 877 (D.C. Cir. 

2004)). 

To qualify as a first applicant eligible 

for 180-day exclusivity under section 

505(j)(5)(B)(iv)(II)(bb) of the FD&C Act, 

an applicant must, among other things, 

submit a paragraph IV certification on 

the ‘‘first day on which a substantially 

complete application containing a 

[paragraph IV certification] is 

submitted.’’ Because daily electronic 

updates to the Orange Book generally do 

not occur until the afternoon (Eastern 

Standard Time), the opportunity to be a 

first applicant with respect to a patent 

that is newly listed in the Orange Book 

(i.e., to submit an amendment to the 

ANDA containing a paragraph IV 

certification and send notice of the 

paragraph IV certification on that same 

day) could be affected by, among other 

things, the time zone in which the 

ANDA applicant resides. To ensure that 

all ANDA applicants (irrespective of 

time zone) have a reasonable 

opportunity to be a first applicant with 

respect to a newly listed patent, we are 

proposing that any notice of paragraph 


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IV certification is invalid if it is sent 

before the first working day after the day 

the patent is listed in the Orange Book 

(see proposed §§ 314.95(b)(2) and 

314.94(a)(12)(viii)(C)(1)(ii), discussed in 

section II.E.4). The term ‘‘working day’’ 

has the meaning provided in 21 CFR 

1.377 (‘‘any day from Monday through 

Friday, excluding Federal holidays’’). 

This approach is intended to promote 

equity among ANDA applicants and 

reduce the burden on industry and on 

the Agency associated with serial 

submissions of amendments and 

multiple notices of paragraph IV 

certifications related to a newly-issued 

patent. When a new patent is issued by 

the PTO, the NDA holder has 30 days 

within which to submit the patent 

information to FDA for listing. An 

ANDA applicant does not know if or 

when the patent may be submitted to 

FDA, and when it is submitted, there 

may be a delay in the patent’s 

appearance in the Orange Book. 

Therefore, if an ANDA applicant 

reasonably believes a patent could be 

listed for an RLD, it will often submit a 

paragraph IV certification to FDA and 

send notice to the NDA holder and 

patent owner each day during the 30- 

day period after issuance of the new 

patent. ANDA applicants have adopted 

this practice in an attempt to satisfy the 

certification and notice requirements on 

the first date on which the patent is 

listed in the Orange Book and thus 

qualify as a first applicant. FDA’s 

proposal is intended to eliminate the 

need for these burdensome serial 

certifications. 

The following example illustrates our 

approach: The NDA holder submits 

Form FDA 3542 to the Office of Generic 

Drugs, Document Room, Attention: 

Orange Book Staff, within 30 days after 

issuance of the ’123 patent claiming the 

drug product Litigatolol. Form FDA 

3542 is date-stamped by the OGD 

Document Room on Friday, August 5 

and listed in the Orange Book, which is 

updated at 3 p.m. Eastern Standard 

Time on that date. Applicant B and 

Applicant C have submitted ANDAs for 

Litigatolol and have received 

acknowledgment letters indicating that 

their ANDAs have been received for 

substantive review. Applicant B is 

located in California and submits an 

amendment to its ANDA containing a 

paragraph IV certification to the ’123 

patent and sends notice to the NDA 

holder and each patent owner late in the 

afternoon, Pacific Time, on Friday, 

August 5. Applicant C is located in New 

Jersey and would have been unable to 

submit an amendment to its ANDA 

containing a paragraph IV certification 

to the ’123 patent and send notice to the 

NDA holder and each patent owner 

before the end of the working day on 

Friday, August 5. Applicant C submits 

the amendment and sends notice on 

Monday, August 8. Prior to these 

amendments, no ANDA had contained a 

paragraph IV certification to a patent 

listed for Litigatolol. Applicant B 

prematurely submitted its amendment 

containing a paragraph IV certification, 

and its notice of paragraph IV 

certification is invalid because it was 

sent before the first full working day 

after the patent is listed in the Orange 

Book. Only Applicant C has submitted 

the first substantially complete ANDA 

containing a paragraph IV certification 

for purposes of first applicant eligibility. 

It should be noted that if there is a 

delay between FDA’s receipt of new 

patent information and publication of 

the patent information in the Orange 

Book, the actual date of publication of 

the patent information in the Orange 

Book provides the date from which the 

validity of the ANDA applicant’s notice 

of paragraph IV certification will be 

assessed for purposes of first applicant 

eligibility (compare section II.D.3 

regarding determination of a 505(b)(2) or 

ANDA applicant’s patent certification 

obligations and the availability of a 30- 

month stay based on patent information 

in FDA’s possession). 

II.D.1.c. Certification of provision of 

notice. We are proposing to amend 

§§ 314.52(b) and 314.95(b) by revising 

and redesignating certain text as new 

paragraph (b)(3). Proposed 

§§ 314.52(b)(3) and 314.95(b)(3) describe 

the current requirement for 505(b)(2) 

and ANDA applicants, respectively, to 

amend their applications at the time 

that they provide notice of a paragraph 

IV certification to include a statement 

certifying that notice has been provided 

to the NDA holder and each patent 

owner as required by §§ 314.52(a) and 

314.95(a) and has met the content 

requirements for notice of a paragraph 

IV certification as described in 

§§ 314.52(c) and 314.95(c). We are 

proposing to clarify that a copy of the 

notice of paragraph IV certification itself 

does not need to be submitted to FDA 

in the amendment. 

We describe acceptable methods for 

delivery of notice of paragraph IV 

certification and documentation of 

timely delivery and receipt of such 

notice in section II.D.4. 

II.D.2. Notice Required for All Paragraph 

IV Certifications 

The MMA requires applicants 

submitting 505(b)(2) applications and 

ANDAs to provide notice for all 

paragraph IV certifications submitted to 

FDA on or after August 18, 2003, 

regardless of whether the applicant had 

previously given notice of a paragraph 

IV certification contained in its 

application or an amendment or 

supplement to the application (see 

section 505(b)(3)(B) and (j)(2)(B)(ii) of 

the FD&C Act). 

We are proposing to require a 

505(b)(2) or ANDA applicant to provide 

a new notice of paragraph IV 

certification to a patent for which it 

previously had provided notice if the 

applicant submits an amendment or 

supplement to the 505(b)(2) application 

or ANDA for certain changes to the 

proposed product that should be 

accompanied by a new patent 

certification (see section II.F). 

II.D.3. Contents of Notice 

We are proposing to revise 

§§ 314.52(c) and 314.95(c) regarding the 

contents of notice of a paragraph IV 

certification to incorporate requirements 

added by the MMA and to support the 

efficient enforcement of our regulations. 

We note, however, that the Agency 

neither assesses the adequacy of the 

contents of a 505(b)(2) or ANDA 

applicant’s notice of paragraph IV 

certification nor the applicant’s stated 

basis for certifying that a listed patent is 

invalid, unenforceable, or will not be 

infringed by its proposed drug product. 

In our final rule implementing the 

patent and exclusivity provisions of the 

Hatch-Waxman amendments, we stated 

that ‘‘the agency does not have the 

expertise or the desire to become 

involved in issues concerning patent 

law and sufficiency of notice. . . . 

Disputes involving the sufficiency of the 

notice [i.e., the detailed statement of the 

factual and legal basis behind the 

applicant’s opinion that the patent is 

invalid, unenforceable, or not infringed] 

must be resolved by the applicant, 

patent owner, and holder of the 

approved application rather than by 

action on the part of FDA’’ (59 FR 50338 

at 50349, October 3, 1994). 

We also are revising §§ 314.52(c) and 

314.95(c) to require the 505(b)(2) or 

ANDA applicant to cite section 

505(b)(3)(D) and (j)(2)(B)(iv), 

respectively, as amended by the MMA, 

in the notice of paragraph IV 

certification. 

Table 7 summarizes the proposed 

changes related to content of a notice of 

paragraph IV certification. 


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TABLE 7—HIGHLIGHTS OF PROPOSED CHANGES REGARDING CONTENT OF A NOTICE OF PARAGRAPH IV CERTIFICATION 1

Current regulations Proposed revisions to regulations 

Content of a notice (§§ 314.52(c)) and 314.95(c)) Content of a notice (§§ 314.52(c)) and 314.95(c)) 

• The 505(b)(2) or ANDA applicant must cite section 505(b)(3)(B) or 

505(j)(2)(B)(ii) of the FD&C Act, as appropriate, and the notice must 

also include, but not be limited to, the following information: 

• The 505(b)(2) or ANDA applicant must cite section 505(b)(3)(D) or 

505(j)(2)(B)(iv) of the FD&C Act, as appropriate, and the notice must 

also include, but is not limited to, the following information: 

—(1) A statement that a 505(b)(2) application submitted by the applicant has been filed by FDA; or a statement that FDA has received an ANDA submitted by the applicant containing any required bioavailability (BA) or bioequivalence (BE) data or information. —(1) A statement that a 505(b)(2) application that contains any required BA or BE data has been submitted by the applicant and 

filed by FDA; or a statement that FDA has received an ANDA 

submitted by the applicant containing any required BA or BE 

data or information. 

—(2) The NDA or ANDA number. —(2) The NDA or ANDA number. 

—(3) The established name, if any, of the proposed drug product. 

—(4) The active ingredient, strength, and dosage form of the proposed drug product. 

—(3) A statement that the applicant has received the acknowledgment letter or paragraph IV acknowledgment letter for the 

505(b)(2) application or ANDA. 

—(5) The patent number and expiration date, as submitted to the 

Agency or as known to the applicant, of each patent alleged to 

be invalid, unenforceable, or not infringed. 

—(6) A detailed statement of the factual and legal basis of the applicant’s opinion that the patent is not valid, unenforceable, or 

will not be infringed. 

—(7) If the applicant does not reside or have a place of business 

in the U.S., the name and address of an agent in the U.S. authorized to accept service of process for the applicant. 

—(4) The established name, if any, of the proposed drug product. 

—(5) The active ingredient, strength, and dosage form of the proposed drug product. 

—(6) The patent number and expiration date of each patent on the 

list alleged to be invalid, unenforceable, or not infringed. 

—(7) A detailed statement of the factual and legal basis of the applicant’s opinion that the patent is not valid, unenforceable, or 

will not be infringed. 

—(8) If the applicant alleges that the patent will not be infringed 

and may later decide to file a civil action for declaratory judgment in accordance with section 505(c)(3)(D) and 505(j)(5)(C) of 

the FD&C Act, then the notice must be accompanied by an offer 

of confidential access to the 505(b)(2) application or ANDA for 

the sole and limited purpose of evaluating possible infringement 

of the patent that is the subject of the paragraph IV certification. 

—(9) If the applicant does not reside or have a place of business 

in the U.S., the name and address of an agent in the U.S. authorized to accept service of process for the applicant. 

1These highlights describe important proposed revisions to our regulations, but should not be relied upon in place of the proposed regulation. 

II.D.3.a. Statement that any required 

bioavailability or bioequivalence studies 

for a 505(b)(2) application have been 

submitted. The MMA amended the 

FD&C Act to require that the notice of 

paragraph IV certification for a 505(b)(2) 

application include a statement that ‘‘an 

application that contains data from 

bioavailability or bioequivalence 

studies’’ has been submitted to FDA 

(section 505(b)(3)(D)(i) of the FD&C 

Act). This statutory provision parallels 

the content requirements for notice of 

paragraph IV certification for an ANDA 

(see section 505(j)(2)(B)(iv)(I) of the 

FD&C Act). Consistent with our 

previous implementation of the 

statutory requirement for ANDAs in 

§ 314.95(c), proposed § 314.52(c)(1) 

requires that a notice of a paragraph IV 

certification for a 505(b)(2) application 

state that data from ‘‘any required 

bioavailability or bioequivalence 

studies’’ (emphasis added) have been 

submitted. This qualifier reflects that 

FDA may exercise its scientific 

judgment to determine what 

bioavailability and bioequivalence 

studies may be needed for certain 

505(b)(2) applications and ANDAs (see, 

e.g., § 314.54(a)(1) and (a)(2) (citing 

§§ 314.50(d)(3) and 320.21(a)(2) and (f)); 

compare § 320.21(b)(2)). 

A 505(b)(2) application may seek to 

rely upon non-product-specific 

published literature or other studies 

necessary for approval for which the 

applicant has no right of reference or 

use. This type of 505(b)(2) application 

generally would not require studies 

showing relative bioavailability or 

bioequivalence because the 505(b)(2) 

application is not relying upon the 

Agency’s finding of safety and/or 

effectiveness for a listed drug. In the 

absence of a listed drug, there is not 

likely to be a specific drug for use as a 

comparator in a relative bioavailability 

or bioequivalence study. However, such 

a 505(b)(2) application must establish 

that reliance on the studies described in 

the literature is scientifically 

appropriate. Further, a 505(b)(2) 

application that did not rely upon a 

listed drug would not require a patent 

certification or statement, and thus there 

would be no occasion for a notice of 

paragraph IV certification. 

II.D.3.b. Statement confirming receipt 

of an acknowledgment letter or a 

paragraph IV acknowledgment letter. 

We are proposing to revise 

§§ 314.52(c)(3) and 314.95(c)(3) to add a 

new requirement for 505(b)(2) and 

ANDA applicants, respectively, to 

facilitate compliance with and 

enforcement of section 505(b)(3)(B)(i), 

(b)(3)(B)(ii), (j)(2)(B)(ii)(I), and 

(j)(2)(B)(ii)(II) of the FD&C Act regarding 

the timing of notice of paragraph IV 

certification. Proposed §§ 314.52(c)(3) 

and 314.95(c)(3) require a 505(b)(2) and 

ANDA applicant, respectively, to 

include a statement in its notice of 

paragraph IV certification that the 

applicant has received an 

acknowledgment letter or a paragraph 

IV acknowledgment letter for its 

505(b)(2) application or ANDA. This 

requirement is intended to ensure that 

a notice of paragraph IV certification is 

not sent before FDA has determined that 

the 505(b)(2) application or ANDA 

containing the certification is acceptable 

for substantive review and has issued an 

acknowledgment letter or a paragraph 

IV acknowledgment letter (see section 

II.D.1.a). 

II.D.3.c. Documentation that 

paragraph IV certification was 

submitted and notice was sent only for 

patents listed in the Orange Book. We 

are proposing to revise §§ 314.52(c)(6) 

and 314.95(c)(6) to specify that notice of 

a paragraph IV certification (and 

therefore the underlying paragraph IV 

certification as well) must only be sent 

for a patent that is listed in the Orange 

Book for the listed drug(s) relied upon 


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for a 505(b)(2) application or for the 

RLD for an ANDA. We are proposing to 

add the phase ‘‘on the list’’ to proposed 

§§ 314.52(c)(6) and 314.95(c)(6) to 

qualify the patents for which a notice of 

paragraph IV certification must be sent. 

As discussed in section II.D.4.b, we 

are proposing to require an ANDA 

applicant to include a dated printout of 

the Orange Book entry for the RLD that 

includes the patent that is the subject of 

the notice of paragraph IV certification 

in its amendment certifying that notice 

of paragraph IV certification has been 

sent and documenting that notice has 

been received (see proposed 

§ 314.95(e)). A 505(b)(2) applicant may 

elect to submit a copy of the Orange 

Book patent listing for the listed drug(s) 

relied upon with its 505(b)(2) 

application, amendment, or supplement 

containing a paragraph IV certification 

to describe the applicant’s 

understanding of the most current 

patent information listed in the Orange 

Book at the time of submission. We 

note, however, that a 505(b)(2) or ANDA 

applicant’s patent certification 

obligations and the availability of a 30- 

month stay under section 505(c)(3)(C) 

and (j)(5)(B)(iii) of the FD&C Act are 

determined based on patent information 

in FDA’s possession, even if such 

information is not accurately listed in 

the Orange Book (see Teva Pharms., 

USA, Inc. v. Leavitt, 548 F.3d 103, at 

105 (D.C. Cir. 2008) (‘‘FDA insists 

reality matters’’)). 

In addition, we are proposing to 

delete the phrase ‘‘as submitted to the 

agency or as known to the applicant’’ 

from §§ 314.52(c)(6) and 314.95(c)(6), as 

this phrase is over-inclusive. It does not 

accurately describe the universe of 

patents for which a paragraph IV 

certification may be submitted and thus 

is inapplicable to the content 

requirements for notice of a paragraph 

IV certification. Although an applicant 

may submit a certification pursuant to 

section 505(b)(2)(A)(i) or 

505(j)(2)(A)(vii)(I) of the FD&C Act 

(‘‘paragraph I certification’’) with 

respect to patent information that has 

not been filed with FDA and is not 

listed in the Orange Book, such a patent 

could not be the basis for a paragraph 

IV certification. 

II.D.3.d. Offer of confidential access 

accompanying notice. The MMA 

established conditions under which a 

505(b)(2) or ANDA applicant may bring 

a declaratory judgment action to obtain 

‘‘patent certainty’’ (i.e., obtain a judicial 

determination of noninfringement, 

invalidity, or unenforceability) with 

respect to a listed patent for which it 

has given notice of a paragraph IV 

certification but has not been sued by 

the NDA holder or any patent owner 

within the statutory timeframe (see 

section 505(c)(3)(D) and (j)(5)(C) of the 

FD&C Act). As a precondition to filing 

an action for declaratory judgment to 

establish patent noninfringement (as 

distinguished from patent invalidity or 

unenforceability), the applicant must 

provide a document offering the NDA 

holder and each patent owner 

confidential access to the 505(b)(2) 

application or ANDA for the sole and 

limited purpose of assessing patent 

noninfringement (see section 

505(c)(3)(D)(i)(III) and (j)(5)(C)(i)(III) of 

the FD&C Act). Because this offer of 

confidential access, if made, is required 

to accompany the notice of paragraph IV 

certification, we are proposing to revise 

§§ 314.52(c) and 314.95(c) to reference 

the statutory requirement for an offer of 

confidential access (see section 

505(c)(3)(D)(i)(I)(cc) and (j)(5)(C)(i)(I)(cc) 

of the FD&C Act). Our proposed 

regulations do not otherwise address the 

offer of confidential access because the 

process for seeking a declaratory 

judgment does not involve FDA. 

II.D.4. Documentation of Timely 

Sending and Receipt of Notice 

We are proposing to revise 

§§ 314.52(e) and 314.95(e) to clarify the 

requirements for submission of an 

amendment to a 505(b)(2) application or 

ANDA, respectively, containing 

documentation of timely sending of 

notice of paragraph IV certification and 

confirmation of receipt of same by the 

NDA holder and each patent owner. In 

addition, we are proposing to revise 

§§ 314.52 and 314.95 to expand the list 

of acceptable delivery methods that may 

be used to send notice of paragraph IV 

certification to the NDA holder and each 

patent owner. These proposed revisions 

are intended to facilitate compliance 

with the statutory requirements 

regarding timing of notice of paragraph 

IV certification and related regulatory 

provisions. 

Table 8 summarizes the proposed 

changes regarding documentation of 

timely sending and receipt of notice of 

paragraph IV certification: 

TABLE 8—HIGHLIGHTS OF PROPOSED CHANGES REGARDING DOCUMENTATION OF TIMELY SENDING AND RECEIPT OF

NOTICE OF PARAGRAPH IV CERTIFICATION 1

Current regulations Proposed revisions to regulations 

Notice of certification (§§ 314.52(a) and 314.95(a)) Notice of certification (§§ 314.52(a) and 314.95(a)) 

• 505(b)(2) or ANDA applicant must send notice of paragraph IV certification by registered or certified mail, return receipt requested, to 

each patent owner and the NDA holder. 

• 505(b)(2) or ANDA applicant must send notice of paragraph IV certification by registered or certified mail, return receipt requested, or 

by a designated delivery service, to each patent owner and the NDA 

holder. 

• 505(b)(2) or ANDA applicant may send notice by an alternative 

method only if FDA has agreed in advance that the method will 

produce an acceptable form of documentation. 

Documentation of receipt of notice (§§ 314.52(e) and 314.95(e)) Documentation of timely sending and receipt of notice (§§ 314.52(e) 

and 314.95(e)) 

• Applicant must amend its 505(b)(2) application or ANDA to document the date of receipt of the notice of paragraph IV certification by 

each patent owner and NDA holder provided the notice. 

• Applicant must amend its 505(b)(2) application or ANDA to provide 

documentation of the date of receipt of the notice of paragraph IV 

certification by each patent owner and NDA holder provided the notice. 

• Applicant must include a copy of the return receipt or other similar 

evidence of the date the notification was received. 

—FDA will accept as adequate documentation of the date of receipt a 

return receipt or a letter acknowledging receipt by the person provided the notice. 

—FDA will accept as adequate documentation of the date of receipt a 

return receipt, signature proof of delivery by a designated delivery 

service, or a letter acknowledging receipt by the person provided notice. 

• An applicant may rely on another form of documentation only if FDA 

has agreed to such documentation in advance. 

—Amendment must be submitted to FDA within 30 days after the last 

date on which notice was received by a patent owner or NDA holder. 


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TABLE 8—HIGHLIGHTS OF PROPOSED CHANGES REGARDING DOCUMENTATION OF TIMELY SENDING AND RECEIPT OF

NOTICE OF PARAGRAPH IV CERTIFICATION 1—Continued 

Current regulations Proposed revisions to regulations 

• Amendment also must include adequate documentation that notice 

was sent on a date that complies with the timeframe required by 

§ 314.52(b) or (d) or § 314.95(b) or (d), as applicable. 

—FDA will accept a copy of the registered mail receipt, certified mail 

receipt, or receipt from a designated delivery service, as adequate 

documentation of the date of delivery. 

• An ANDA applicant’s amendment must include a dated printout of 

the Orange Book entry for the RLD that includes the patent that is 

the subject of the paragraph IV certification. 

• An applicant may rely on another form of documentation only if FDA 

has agreed in advance. 

1These highlights describe important proposed revisions to our regulations, but should not be relied upon in place of the proposed regulation. 

II.D.4.a. Acceptable methods of 

sending notice of paragraph IV 

certification. A 505(b)(2) or ANDA 

applicant currently is required to send 

notice of a paragraph IV certification to 

the NDA holder and each patent owner 

by registered or certified mail, return 

receipt requested, unless FDA agrees in 

advance to another method of delivery 

(see §§ 314.52(a) and (e) and 314.95(a) 

and (e)). We are proposing to revise 

§§ 314.52(a) and (e) and 314.95(a) and 

(e) to provide applicants with the option 

of sending notice of paragraph IV 

certification by a designated delivery 

service, as defined in proposed 

§§ 314.52(g)(1) and 314.95(g)(1). Section 

505(b)(2) and ANDA applicants often 

request permission to send notice of a 

paragraph IV certification by a major 

commercial delivery service instead of 

the U.S. Postal Service (for example, to 

send notice of a paragraph IV 

certification to a patent owner who 

resides outside of the United States). 

Because we routinely grant these 

requests, we are proposing to amend our 

regulations to provide the option to all 

505(b)(2) and ANDA applicants to send 

notice of paragraph IV certification by 

the U.S. Postal Service or a designated 

delivery service. We propose to define 

a ‘‘designated delivery service’’ in 

§§ 314.52(g)(1) and 314.95(g)(1) to mean 

any delivery service provided by a trade 

or business that the Agency determines: 

(1) Is available to the general public 

throughout the United States; (2) 

records electronically to its database, 

kept in the regular course of its 

business, or marks on the cover in 

which any item referred to in this 

section is to be delivered, the date on 

which such item was given to such 

trade or business for delivery; and (3) 

provides overnight or 2-day delivery 

service throughout the United States. 

This proposed definition is adapted 

from definition of ‘‘designated delivery 

service’’ in 26 U.S.C. 7502(f)(2) 

(governing timely mailing treated as 

timely filing and paying by the IRS). As 

noted in proposed §§ 314.52(g)(2) and 

314.95(g)(2), FDA will periodically issue 

guidance describing designated delivery 

services that meet these criteria. 

Our proposal to revise §§ 314.52(a) 

and (e) and 314.95(a) and (e) to provide 

applicants with the option of sending 

notice of paragraph IV certification by a 

designated delivery service, as defined 

in proposed §§ 314.52(g)(1) and 

314.95(g)(1), differs from an earlier 

proposal to provide additional methods 

of sending notice of paragraph IV 

certification (see ‘‘New Drugs for 

Human Use; Clarification of 

Requirements for Patent Holder 

Notification; Proposed Rule’’ 63 FR 

11174; March 6, 1998) (Patent Holder 

Notification proposed rule). The Patent 

Holder Notification proposed rule 

would have permitted a 505(b)(2) or 

ANDA applicant to send notice of 

paragraph IV certification ‘‘by mail or 

personal delivery’’ (including overnight 

delivery service, electronic mail, and 

facsimile) if the applicant obtained a 

verification of receipt. We received 

comments objecting to certain aspects of 

the Patent Holder Notification Proposed 

Rule—in particular, notice by electronic 

methods of delivery such as electronic 

mail or facsimile—and withdrew the 

proposed rule (see ‘‘New Drugs for 

Human Use; Clarification of 

Requirements for Patent Holder 

Notification; Withdrawal’’ 65 FR 12154; 

March 8, 2000) (Withdrawal of Patent 

Holder Notification proposed rule). 

With respect to notification by overnight 

delivery service, two comments on the 

Patent Holder Notification proposed 

rule supported this alternate method of 

delivery if a signed verification of 

receipt of notice by the NDA holder or 

each patent owner was provided (see 

Docket No. FDA–1997–P–0417–0011 

and FDA–1997–P–0417–0012, available 

at http://www.regulations.gov). Another 

comment objected to notification by 

overnight delivery service because 

receipt of bulk deliveries (containing 

multiple envelopes and packages) to 

large corporations is acknowledged by a 

single signature. This commenter 

expressed concern that an overnight 

delivery service envelope containing a 

notice of paragraph IV certification may 

not ensure timely receipt by a 

responsible person. Given that receipt of 

notice of paragraph IV certification 

begins a statutory 45-day period within 

which a patent infringement action 

must be filed to obtain, under certain 

circumstances, a 30-month stay, a 

signature acknowledging receipt of the 

specific envelope was preferred by this 

commenter (see Docket No. FDA–1997– 

P–0417–0010, available at http://

www.regulations.gov). 

In light of the frequency with which 

FDA receives requests to send notice by 

overnight delivery services, we invite 

comment on our current proposal to 

provide applicants with the option of 

sending notice of paragraph IV 

certification by a designated delivery 

service, as defined in proposed 

§§ 314.52(g)(1) and 314.95(g)(1). 

We also are proposing to add 

§§ 314.52(a)(4) and 314.95(a)(4) and 

revise §§ 314.52(e) and 314.95(e) to 

clarify that a 505(b)(2) or ANDA 

applicant may send notice of paragraph 

IV certification by an alternative method 

(i.e., a method other than registered or 

certified mail, return receipt requested, 

or a designated delivery service) only if 

FDA has agreed in advance that the 

method will produce an acceptable form 

of documentation. 

In addition, we are proposing to 

revise the introductory text of 

§ 314.52(a) to refer to each patent that 

claims the listed drug or drugs relied 

upon or that claims a use for such listed 

drug or drugs and for which the 

applicant submits a paragraph IV 

certification. This revision is proposed 


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for clarity and does not represent a 

substantive change. 

II.D.4.b. Amendment documenting 

timely sending and confirmation of 

receipt of notice of paragraph IV 

certification. We are proposing to revise 

§§ 314.52(e) and 314.95(e) to facilitate 

implementation of section 

505(b)(3)(B)(i), (b)(3)(B)(ii), 

(j)(2)(B)(ii)(I), and (j)(2)(B)(ii)(II) of the 

FD&C Act and for the efficient 

enforcement of the FD&C Act. 

A 505(b)(2) or ANDA applicant that 

has submitted one or more paragraph IV 

certifications currently must submit an 

amendment to its application 

documenting the date on which notice 

of paragraph IV certification was 

received by the NDA holder and each 

patent owner (see §§ 314.52(e) and 

314.95(e)). As discussed in section 

II.D.1.b, the MMA amended the FD&C 

Act to require that a 505(b)(2) and 

ANDA applicant provide notice of a 

paragraph IV certification in accordance 

with the timeframes described in 

section 505(b)(3)(B)(i), (b)(3)(B)(ii), 

(j)(2)(B)(ii)(I), and (j)(2)(B)(ii)(II) of the 

FD&C Act (see proposed §§ 314.52(b) 

and (d) and 314.95(b) and (d)). Our 

proposed revisions to §§ 314.52(e) and 

314.95(e) require a 505(b)(2) and ANDA 

applicant, respectively, to establish 

compliance with this statutory 

requirement by also submitting in its 

amendment documentation that the 

notice of paragraph IV certification was 

sent on a date that complies with the 

timeframe required by § 314.52(b) or (d) 

or § 314.95(b) or (d), as applicable. For 

administrative efficiency, we are 

proposing to require that a 505(b)(2) or 

ANDA applicant submit the amendment 

containing documentation of timely 

sending and receipt of notice of 

paragraph IV certification within 30 

days after the last date on which notice 

was received by a person described in 

§ 314.52(a) or § 314.95(a), respectively. 

The proposed requirement for 

documentation that notice of paragraph 

IV certification was timely sent can be 

satisfied by submitting a copy of the 

registered mail receipt or certified mail 

receipt issued by the U.S. Postal Service 

that bears a postmark documenting the 

date of mailing or by submitting a copy 

of the receipt from a designated delivery 

service, as defined in proposed 

§§ 314.52(g) and 314.95(g). With respect 

to documentation of the date of receipt 

of notice of paragraph IV certification, 

we are proposing to revise §§ 314.52(e) 

and 314.95(e) to include acceptance of 

signature proof of delivery by a 

designated delivery service as adequate 

documentation. A single document may 

be adequate to document both timely 

sending and receipt of notice of 

paragraph IV certification if it contains 

the information required by proposed 

§§ 314.52(e) and 314.95(e). 

In addition, we are proposing to 

require that ANDA applicants include 

in their amendment a dated printout of 

the Orange Book entry for the RLD that 

includes the patent that is the subject of 

the notice of paragraph IV certification. 

This requirement is intended to ensure 

that a paragraph IV certification that 

may qualify an ANDA applicant for 180- 

day exclusivity is submitted only for a 

listed patent and is not prematurely or 

inappropriately sent before the first 

working day after the day the patent is 

listed in the Orange Book (see proposed 

§§ 314.95(b)(2) and 

314.94(a)(12)(viii)(C)(1)(ii)). 

The following example illustrates our 

approach: The NDA holder timely 

submits Form FDA 3542 to the Office of 

Generic Drugs, Document Room, 

Attention: Orange Book Staff, at 4 p.m., 

Eastern Standard Time, on the 30th day 

after issuance of the ’456 patent 

claiming the drug product 

Procrastinadipine. Form FDA 3542 is 

date-stamped by the Office of Generic 

Drugs, Document Room on Friday, 

October 1 and listed in the Orange Book 

on the afternoon of Monday, October 4. 

Applicant D and Applicant E have 

submitted ANDAs for Procrastinadipine 

and each has received an 

acknowledgment letter indicating that 

its ANDA has been received for 

substantive review. 

Applicant D is aware that the ’456 

patent was issued by the PTO on 

September 1 and understands that for 

the ’456 patent to be timely filed under 

section 505(c)(2) of the FD&C Act, the 

NDA holder must file the patent 

information with FDA no later than 

October 1. Applicant D submits an 

amendment to its ANDA containing a 

paragraph IV certification to the ’456 

patent and sends notice to the NDA 

holder and each patent owner on 

October 1 in an effort to have submitted 

the first substantially complete ANDA 

containing a paragraph IV certification 

to a patent listed for Procrastinadipine. 

However, Applicant D is unable to 

submit the required printout (see 

proposed § 314.95(b)(2)) of the Orange 

Book entry for the RLD that includes the 

patent that is the subject of the 

paragraph IV certification because the 

’456 patent has not yet been listed in the 

Orange Book. Applicant E submits on 

Tuesday, October 5 (i.e., the first 

working day after the day the patent is 

listed in the Orange Book) an 

amendment to its ANDA containing a 

paragraph IV certification to the ’456 

patent and the required printout of the 

Orange Book entry and sends notice to 

the NDA holder and each patent owner 

on that same day. 

Prior to these amendments, no ANDA 

had contained a paragraph IV 

certification to a patent listed for 

Procrastinadipine. Applicant D’s notice 

of paragraph IV certification is 

premature and thus invalid because the 

’456 patent had not yet been listed in 

the Orange Book. Only Applicant E has 

submitted the first substantially 

complete ANDA containing a paragraph 

IV certification for purposes of first 

applicant eligibility. 

II.D.5. Administrative Consequence for 

Late Notice 

The MMA does not specify a 

consequence for 505(b)(2) or ANDA 

applicants that do not send notice of a 

paragraph IV certification within the 

timeframe required by the FD&C Act 

(i.e., within 20 days after the date of the 

postmark on the paragraph IV 

acknowledgment letter or on the date 

that an amendment or supplement 

containing a paragraph IV certification 

is submitted to FDA). In response to our 

Request for MMA Comments, we 

received comments suggesting that we 

create an administrative consequence 

for late notice (see, e.g., PhRMA MMA 

Comment at 1 to 2). In light of the 

importance of the timing of sending 

notice of paragraph IV certification to 

the statutory scheme, we agree that it is 

appropriate to propose an 

administrative consequence for ANDA 

applicants who are late in providing 

notice. 

After considering several suggestions 

for administrative consequences, 

including those submitted to us in 

response to our Request for MMA 

Comments, we are proposing to address 

ANDA applicants that fail to timely 

provide notice of a paragraph IV 

certification by moving forward the date 

of submission of the ANDA by the 

number of days beyond the required 

time frame that the applicant delayed in 

sending its notice (see proposed 

§ 314.101(b)(4)). Consequently, an 

ANDA applicant may lose its first 

applicant status and thus its eligibility 

for 180-day exclusivity as a result of 

providing late notice (see section 

505(j)(5)(B)(iv) of the FD&C Act), if 

another applicant submits a 

substantially complete ANDA 

containing a paragraph IV certification 

on the same first day and provides 

timely notice. Also, an ANDA applicant 

that fails to timely provide notice of 

paragraph IV certification may 

experience a delay in the review queue 

for its ANDA consistent with the revised 

date of submission. We note that this 

proposed administrative consequence 


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would not reduce the 30-month 

timeframe set forth in section 

505(j)(5)(D)(i)(I)(aa)(BB) and 

(j)(5)(D)(i)(IV) of the FD&C Act in the 

forfeiture calculus for a first applicant; 

rather, the 30-month period would 

begin on the revised date of submission. 

We believe that the proposed 

administrative consequence for ANDA 

applicants appropriately balances the 

purposes served by the requirement for 

timely notice of paragraph IV 

certifications with the legislative goal of 

speeding the availability of lower cost 

alternatives to approved drugs. Certain 

options we considered as alternatives 

did not seem to provide as measured a 

balance. For example, we considered 

deeming paragraph IV certifications for 

which notice had been provided after 

the statutory timeframe to not be 

‘‘lawfully maintained’’ (see section 

505(j)(5)(B)(iv)(bb) of the FD&C Act). 

Under this interpretation, however, an 

ANDA applicant would certainly lose 

its eligibility for 180-day exclusivity as 

a result of sending late notice, regardless 

of the amount of time its notice was 

delayed (e.g., even if its notice were one 

day late). We decline to adopt this 

approach because it seems 

disproportionately punitive. 

We are not proposing a similar 

consequence for 505(b)(2) applicants 

that fail to timely provide notice of a 

paragraph IV certification because 

505(b)(2) applicants are not eligible for 

180-day exclusivity and we are unable 

to extend the review clock as an 

administrative consequence for an NDA 

(including a 505(b)(2) application) 

subject to the Prescription Drug User 

Fee Act Reauthorization Performance 

Goals and Procedures (see http://

www.fda.gov/ForIndustry/UserFees/

PrescriptionDrugUserFee/

ucm119243.htm; see also 21 CFR 

314.100). As described below, we 

considered other possible 

administrative consequences for any 

505(b)(2) applicants that fail to provide 

notice of a paragraph IV certification 

within the statutory timeframe; 

however, we are declining to propose an 

administrative consequence at this time. 

The implications of late notice of a 

paragraph IV certification by a 505(b)(2) 

applicant differ from those of an ANDA 

applicant that may otherwise be eligible 

for 180-day exclusivity. A 505(b)(2) 

application that contains a paragraph IV 

certification could not be approved until 

the 505(b)(2) applicant had provided 

notice of its paragraph IV certification to 

the NDA holder and each patent owner 

and the respective 45-day periods for 

each recipient of notice had expired 

without the filing of a legal action for 

patent infringement (see § 314.107(f)(2)). 

A 505(b)(2) applicant that provides late 

notice of a paragraph IV certification 

risks that the NDA holder or patent 

owner will file an action for patent 

infringement within the 45-day period 

after notice, and that any resultant 30- 

month stay will delay approval by a 

period of time commensurate with the 

505(b)(2) applicant’s delay in providing 

notice of its paragraph IV certification. 

We considered the suggestion, 

submitted in response to our Request for 

MMA Comments, that we ‘‘creat[e] an 

automatic regulatory presumption 

which could be used by the court 

hearing the patent infringement action 

that the ANDA or 505(b)(2) applicant 

‘failed to reasonably cooperate in 

expediting the action’ within the 

meaning of [section 505(c)(3)(C) and 

(j)(5)(B)(iii) of the FD&C Act]’’ (see 

PhRMA MMA Comment at 2). However, 

we decline to propose this approach 

because it is not necessary to properly 

implement the statutory goal of 

adequate notice and opportunity to 

defend certain intellectual property 

rights prior to approval. 

II.E. Amended Patent Certifications 

(Proposed §§ 314.50(i)(6) and 

314.94(a)(12)(viii)) 

We are proposing to revise 

§§ 314.50(i)(6) and 314.94(a)(12)(viii) 

regarding submission of amended patent 

certifications by 505(b)(2) and ANDA 

applicants, respectively, to reflect 

revisions to the FD&C Act made by the 

MMA and for the efficient enforcement 

of the FD&C Act. A 505(b)(2) or ANDA 

applicant would be required to submit 

an amended patent certification to 

provide, for example, a certification to 

a recently issued patent listed by the 

NDA holder after submission of a 

505(b)(2) application or ANDA that 

relies upon the listed drug, or to change 

its certification to a patent for which the 

applicant had previously submitted a 

patent certification. As discussed in this 

section of the document, submission of 

an amended patent certification also 

would be required for a reissued patent 

and for a revision to a prior certification 

in the event that a patent or patent 

information has been withdrawn from 

listing in the Orange Book. 

We are proposing to revise the 

introductory text of § 314.94(a)(12)(viii) 

to remove the provision that restricts an 

ANDA applicant from amending a 

paragraph IV certification to a paragraph 

III certification in certain circumstances. 

Currently, § 314.94(a)(12)(viii) provides 

that an ANDA applicant that has 

submitted a paragraph IV certification 

may not amend its patent certification to 

a paragraph III certification (delaying 

approval until the date on which such 

patent will expire) if a patent 

infringement action has been filed 

against another applicant that had 

submitted a paragraph IV certification. 

The current regulation provides that an 

ANDA applicant is permitted to amend 

its patent certification to a paragraph III 

certification in these circumstances only 

if the Agency has determined that no 

applicant is entitled to 180-day 

exclusivity or the patent expired while 

patent infringement litigation was 

pending or before the end of the 180-day 

exclusivity period. We have determined, 

however, that it is not necessary to 

restrict submission of an amended 

patent certification under these 

circumstances because 180-day 

exclusivity does not extend beyond 

patent expiry. Accordingly, an applicant 

that amended its paragraph IV 

certification to a paragraph III 

certification would not be eligible for 

approval until patent expiration and 

thus would not undermine a first 

applicant’s 180-day exclusivity as to 

that patent. The MMA specifically 

provides that a first applicant’s 180-day 

exclusivity would, in any event, 

terminate upon expiration of all of the 

patents as to which the applicant 

submitted a paragraph IV certification 

qualifying it for 180-day exclusivity (see 

section 505(j)(5)(D)(i)(VI) of the FD&C 

Act; see also § 314.94(a)(12)(viii)). 

There are several circumstances in 

which amending to a paragraph III 

certification is appropriate, including 

when an applicant is no longer seeking 

approval before the patent expires or 

when required by the terms of a 

settlement agreement between parties in 

patent infringement litigation. This 

proposal would facilitate amendment of 

paragraph IV certifications to paragraph 

III certifications in such circumstances. 

We also are proposing to revise 

§§ 314.50(i)(6)(i) and 314.94(a)(12)(viii) 

to require that a 505(b)(2) or ANDA 

applicant submit an amended patent 

certification as an amendment to its 

pending application (including a 

supplemental 505(b)(2) application or 

supplemental ANDA (see §§ 314.70(i) 

and 314.97(c), respectively)) and not by 

letter. This requirement will facilitate 

appropriate management of amended 

patent certifications. 

Table 9 summarizes the proposed 

changes regarding amended patent 

certifications: 


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TABLE 9—HIGHLIGHTS OF PROPOSED CHANGES REGARDING AMENDED PATENT CERTIFICATIONS1

Current regulations Proposed revisions to regulations 

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

• Amended patent certification must be submitted as an amendment to 

a pending 505(b)(2) application or ANDA or by letter to an approved 

application. 

• Amended patent certification must be submitted as an amendment to 

the 505(b)(2) application or ANDA and may no longer be submitted 

by letter. 

Amended Certifications (§ 314.94(a)(12)(viii) only) Amended Certifications (§ 314.94(a)(12)(viii) only) 

• ANDA applicants restricted from amending a paragraph IV certification to a paragraph III certification in certain circumstances when 

another ANDA applicant has been sued for patent infringement. 

• Deletion of restriction on ANDA applicants from amending a paragraph IV certification to a paragraph III certification. 

After a Finding of Infringement (§§ 314.50(i)(6)(i) and 

314.94(a)(12)(viii)(A)) 

After a Finding of Infringement (§§ 314.50(i)(6)(i) and 

314.94(a)(12)(viii)(A)) 

• Change from paragraph IV certification to paragraph III certification 

required after a final judgment is entered finding the patent to be infringed. 

• Provision applies if patent infringement action initiated within 45 days 

of receipt of notice of paragraph IV certification. 

• Change from paragraph IV certification to paragraph III certification 

required after court enters final decision from which no appeal has 

been or can be taken, or signs settlement order or consent decree 

with a finding of infringement (unless the patent also is found invalid). An applicant may instead provide a statement under 

§ 314.50(i)(1)(iii) or § 314.94(a)(12)(iii) with respect to a method-ofuse patent if the 505(b)(2) application or ANDA is amended such 

that the applicant is no longer seeking approval for a method of use 

claimed by the patent. 

• Provision applies if patent infringement action initiated after receipt of 

notice of paragraph IV certification, irrespective of whether the action 

is brought within the 45-day period. 

After Removal of a Patent from the List (§§ 314.50(i)(6)(ii) and 

314.94(a)(12)(viii)(B)) 

• If a patent is removed from the list, any applicant with a pending application (including a tentatively approved application with a delayed 

effective date) who has made a certification with respect to such patent must amend its certification. 

• A patent that is the subject of a lawsuit under § 314.107(c) shall not 

be removed from the list until FDA determines either that no delay in 

effective dates of approval is required under that section as a result 

of the lawsuit, that the patent has expired, or that any such period of 

delay in effective dates of approval is ended. 

• Applicant must submit a ‘‘no relevant patents’’ certification or, if other 

relevant patents claim the drug, must amend the patent certification 

to refer only to those relevant patents. 

After Request to Remove a Patent or Patent Information from the List 

(§§ 314.50(i)(6)(ii) and 314.94(a)(12)(viii)(B)) 

• If the list reflects that an NDA holder has requested that a patent be 

removed from the list and: 

—no ANDA applicant is eligible for 180-day exclusivity based on a 

paragraph IV certification to that patent, the patent will be removed and any applicant with a pending 505(b)(2) application or 

ANDA (including a tentatively approved 505(b)(2) application or 

ANDA) who has certified to that patent must submit an amendment to withdraw the certification. 

—one or more first applicants are eligible for 180-day exclusivity 

based on a paragraph IV certification to that patent, the patent 

shall remain listed until any 180-day exclusivity is extinguished. 

• If one or more first applicants are eligible for 180-day exclusivity 

based on a paragraph IV certification to a patent that has been reissued, then the first applicant must submit a paragraph IV certification to the reissued patent within 30 days of listing to have lawfully 

maintained its paragraph IV certification for purposes of eligibility for 

180-day exclusivity. 

• A 505(b)(2) applicant is not required to provide or maintain a certification to a patent that remains listed only for purposes of a first applicant’s 180-day exclusivity. 

• After any applicable 180-day exclusivity period has ended, the patent 

will be removed and any pending ANDA (including a tentatively approved ANDA) that contains a certification to the patent must be 

amended to withdraw the certification. 

• If removal of a patent from the list results in no patents listed for the 

listed drug(s) identified in the 505(b)(2) application or ANDA, the applicant must submit an amended certification reflecting that there are 

no listed patents. 

Late submission of patent information (§§ 314.50(i)(4) and 

314.94(a)(12)(vi)) 

Untimely filing of patent information (§§ 314.50(i)(4) and 

314.94(a)(12)(vi)) 

• If a patent on the listed drug is issued and the NDA holder for 

the listed drug does not submit the required information on the 

patent within 30 days of patent issuance, an applicant who submitted a 505(b)(2) application or an ANDA for that drug that contained an appropriate patent certification before the submission 

of the patent information is not required to submit an amended 

certification. 

• (see Table 3) 


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TABLE 9—HIGHLIGHTS OF PROPOSED CHANGES REGARDING AMENDED PATENT CERTIFICATIONS1—Continued 

Current regulations Proposed revisions to regulations 

• An applicant whose 505(b)(2) application or ANDA is submitted 

after a late submission of patent information, or whose pending 

505(b)(2) application or ANDA was previously submitted but did 

not contain an appropriate patent certification at the time of the 

patent submission, must submit a certification under 

(§ 314.50(i)(1)(i) or § 314.94(a)(12)(i) or a statement under 

§ 314.50(i)(1)(iii) or § 314.94(a)(12)(iii) as to that patent. 

Patents Claiming the Drug Substance, Drug Product, or Method of Use 

(§§ 314.50(i)(1)(i)(A) and 314.94(a)(12)(i)(A)) 

Patents Claiming the Drug Substance, Drug Product, or Method of Use 

(§§ 314.50(i)(1)(i)(A) and 314.94(a)(12)(i)(A)) 

• A 505(b)(2) application and ANDA are required to contain a patent certification or statement for each patent issued by the PTO 

that, in the opinion of the applicant and to the best of its knowledge, claims the listed drug relied upon or RLD or that claims an 

approved use for such drug for which the applicant is seeking 

approval and for which information is required to be filed under 

section 505(b) and (c) of the FD&C Act and § 314.53. 

• (No substantive revisions) 

Other Amendments (§§ 314.50(i)(6)(iii)(A)(2) and 

314.94(a)(12)(viii)(C)(1)(ii)) 

• Except as provided in §§ 314.50(i)(4) and (i)(6)(iii)(B) and 

314.94(a)(12)(vi) and (a)(12)(viii)(C)(2)), an applicant must submit a 

patent certification or statement if, after submission of the 505(b)(2) 

application or ANDA, a new patent is issued by the PTO that, in the 

opinion of the applicant and to the best of its knowledge, claims the 

listed drug or RLD or that claims an approved use for such drug and 

for which information is required to be filed under section 505(b) and 

(c) of the FD&C Act and § 314.53. 

• For a paragraph IV certification, the certification must not be submitted earlier than the first working day after the day the patent is 

published in the list. 

Other Amendments (§§ 314.50(i)(6)(iii)(A) and 314.94(a)(12)(viii)(C)(1)) Other Amendments (§§ 314.50(i)(6)(iii)(A)(1) and 

314.94(a)(12)(viii)(C)(1)(i)) 

• [Amended patent certification required upon patent expiration 

under existing requirement for submission of amended certification if, at any time before approval, the submitted certification 

is no longer accurate.] 

• [Upon patent expiration, FDA will consider the 505(b)(2) or ANDA 

applicant to have constructively changed its patent certification to a 

paragraph II certification.] 

Other Amendments (§§ 314.50(i)(6)(iii)(B) and 314.94(a)(12)(viii)(C)(2)) Other Amendments (§§ 314.50(i)(6)(iii)(B) and 314.94(a)(12)(viii)(C)(2)) 

• An applicant is not required to amend a submitted certification in 

response to patent information submitted after approval of the 

505(b)(2) application or ANDA (unless a patent certification is required with a supplement to the 505(b)(2) application or ANDA). 

• An applicant is not required to submit a supplement to change a 

submitted certification in response to patent information submitted 

after approval of the 505(b)(2) application or ANDA (unless a patent 

certification is required with a supplement to the 505(b)(2) application 

or ANDA). 

1These highlights describe important proposed revisions to our regulations, but should not be relied upon in place of the proposed regulation. 

II.E.1. Amended Patent Certifications 

After a Finding of Infringement 

We are proposing to amend 

§§ 314.50(i)(6)(i) and 

314.94(a)(12)(viii)(A) to reflect changes 

to the FD&C Act made by the MMA that 

clarify the requirements for a 505(b)(2) 

or ANDA applicant, respectively, to 

amend their paragraph IV certification 

after a judicial finding of patent 

infringement. As further discussed in 

section II.M, the MMA amended section 

505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C 

Act to specify the types of court 

decisions that will terminate a 30-month 

stay of approval, given that many patent 

infringement actions previously had 

been concluded without a ‘‘final 

judgment’’ regarding infringement being 

entered by a court. With respect to a 

505(b)(2) or ANDA applicant that had 

submitted a paragraph IV certification 

resulting in a patent infringement 

action, the FD&C Act provides that if, 

before the expiration of the 30-month 

stay of approval, the district court 

hearing the patent infringement action 

decides that the patent has been 

infringed and the district court’s 

judgment is either not appealed or is 

affirmed on appeal, the 505(b)(2) 

application or ANDA may be approved 

on the date specified by the district 

court that is not earlier than the date of 

expiration of the patent (including any 

patent extension) and of any applicable 

exclusivity (see section 

505(c)(3)(C)(ii)(II) and (j)(5)(B)(iii)(II)(bb) 

of the FD&C Act and 35 U.S.C. 

271(e)(4)(A)). 

We are proposing to amend 

§§ 314.50(i)(6)(i) and 

314.94(a)(12)(viii)(A) to require that a 

505(b)(2) and ANDA applicant, 

respectively, submit an amendment to 

change its paragraph IV certification to 

a paragraph III certification (stating that 

the patent will expire on a specific date) 

or, if appropriate, to a statement under 

section 505(b)(2)(B) or (j)(2)(A)(viii) of 

the FD&C Act if a ‘‘court enters a final 

decision from which no appeal has been 

or can be taken’’ that the patent at issue 

has been infringed. After a final court 

decision of patent infringement from 

which no appeal has been or can be 

taken, a 505(b)(2) or ANDA applicant 

can no longer lawfully maintain a 

paragraph IV certification that the 

patent is invalid or will not be infringed 

by the manufacture, use, or sale of the 

drug for which the 505(b)(2) application 

or ANDA has been submitted (see, e.g., 

Mylan Labs., Inc. v. Thompson, 389 

F.3d 1272, 1281 (D.C. Cir. 2004) 

(concluding that after the district court’s 

finding of patent validity and 

infringement, the ANDA applicant’s 

paragraph IV certification was ‘‘at 

variance with the legal reality’’ and ‘‘no 

longer accurate’’)). These proposed 

revisions to §§ 314.50(i)(6)(i) and 


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314.94(a)(12)(viii)(A) reflect a change to 

the current text requiring a 505(b)(2) or 

ANDA applicant to amend its paragraph 

IV certification if a ‘‘final judgment’’ has 

been entered finding the patent to be 

infringed. 

Proposed §§ 314.50(i)(6)(i) and 

314.94(a)(12)(viii)(A) also would require 

a 505(b)(2) and ANDA applicant, 

respectively, to submit an amendment 

to change its paragraph IV certification 

to a paragraph III certification or, if 

appropriate, to a statement under 

section 505(b)(2)(B) or 505(j)(2)(A)(viii) 

of the FD&C Act if a court signs a 

settlement order or consent decree in 

the action that includes a finding that 

the patent is infringed, unless the final 

decision, settlement order or consent 

decree also finds the patent to be 

invalid. For a first ANDA applicant, 

submission of an amendment that 

changes the paragraph IV certification 

that qualified the applicant for 180-day 

exclusivity to a paragraph III 

certification or a statement under 

section 505(j)(2)(A)(viii) of the FD&C 

Act has implications for continuing 

eligibility for 180-day exclusivity (see 

section 505(j)(5)(D)(i)(III) of the FD&C 

Act). We note, however, that if a 

settlement is reached without a finding 

of patent infringement or invalidity, 

then a paragraph IV certification may 

continue to be appropriate. For 

example, if the 505(b)(2) or ANDA 

applicant is granted a patent license 

such that the applicant would be 

permitted to obtain approval and 

commence marketing prior to patent 

expiration, the 505(b)(2) or ANDA 

applicant would maintain its paragraph 

IV certification with respect to the 

patent at issue and should submit an 

amendment pursuant to proposed 

§§ 314.50(i)(3) and 314.94(a)(12)(v) to 

advise the Agency of the patent 

licensing agreement. Such an 

amendment must include a written 

statement by the applicant that it has 

been granted a patent license and a 

written statement from the patent owner 

confirming the licensing agreement and 

consenting to approval of the 

application as of a specific date (see 

proposed §§ 314.50(i)(3) and 

314.94(a)(12)(v)). 

We are proposing to apply the 

requirement that a 505(b)(2) or ANDA 

applicant must submit an amendment to 

change its paragraph IV certification to 

a paragraph III certification or, if 

appropriate, to a statement under 

section 505(b)(2)(B) or 505(j)(2)(A)(viii) 

of the FD&C Act after a judicial finding 

of patent infringement irrespective of 

whether the patent infringement action 

was brought within 45 days of receipt of 

the notice of paragraph IV certification 

(see proposed §§ 314.50(i)(6)(i) and 

314.94(a)(12)(viii)(A)). A patent 

infringement action initiated outside of 

the 45-day period following receipt of a 

notice of paragraph IV certification is 

not eligible for a 30-month stay of 

approval while the patent infringement 

litigation is pending (see 

§ 314.107(b)(3)). However, the rationale 

for an amended patent certification in 

the event that the patent is found valid 

and infringed applies with equal force 

to a legal action for infringement of a 

listed patent that was brought outside of 

the 45-day period (see 35 U.S.C. 

271(e)(4)). Thus, we are proposing to 

remove the phrase ‘‘within 45 days of 

the receipt of notice sent under 

[§ 314.52 or § 314.95, respectively]’’ 

from the description of the patent 

infringement action to which 

§§ 314.50(i)(6)(i) and 

314.94(a)(12)(viii)(A) apply. This 

proposed revision would clarify, for 

example, that the approval of a 505(b)(2) 

application or ANDA that contained a 

paragraph IV certification but was not 

subject to a 30-month stay still may be 

delayed by the intervening grant of 

pediatric exclusivity under section 

505A(b)(1)(B) of the FD&C Act after a 

judicial finding of infringement of the 

patent for which the paragraph IV 

certification had been submitted (see 

Mylan Labs., Inc. v. Thompson, 332 F. 

Supp. 2d 106 (D.D.C.), aff’d, 389 F.3d 

1272 (D.C. Cir. 2004); see also proposed 

§ 314.107(b)(4) and (e)(1)(vi)). 

As explained in proposed 

§§ 314.50(i)(6)(i) and 

314.94(a)(12)(viii)(A), an applicant may 

change its paragraph IV certification for 

a method-of-use patent to a statement 

under section 505(b)(2)(B) or 

505(j)(2)(A)(viii) of the FD&C Act only if 

the applicant amends its 505(b)(2) 

application or ANDA, respectively, such 

that the applicant is no longer seeking 

approval for a method of use claimed by 

the patent (see §§ 314.50(i)(1)(iii) and 

314.94(a)(12)(iii)). 

II.E.2. Amended Certifications After 

Request by the NDA Holder To Remove 

a Patent or Patent Information From the 

List 

We are proposing to revise 

§§ 314.50(i)(6)(ii) and 

314.94(a)(12)(viii)(B) to clarify the 

circumstances and timeframe in which 

a 505(b)(2) or ANDA applicant, 

respectively, must submit an amended 

patent certification to its 505(b)(2) 

application or ANDA after an NDA 

holder has requested removal of a patent 

or patent information from the list 

(‘‘patent delisting’’). These proposed 

revisions also describe our current 

practice regarding patent delisting as it 

relates to the eligibility of one or more 

first ANDA applicants for 180-day 

exclusivity. 

An NDA holder may request removal 

of a patent or patent information from 

the list in accordance with a court order 

or on its own initiative, if it determines 

that the patent or patent information no 

longer meets the statutory criteria for 

listing (see section 505(b)(1) and (c)(2) 

of the FD&C Act). Since April 18, 2008, 

FDA has identified in the Orange Book 

(the list) those patents for which an 

NDA holder has withdrawn the patent 

and submitted a request for removal of 

the patent from the list. We are 

proposing to revise §§ 314.50(i)(6)(ii) 

and 314.94(a)(12)(viii)(B) to state that if 

an NDA holder has requested removal of 

a patent or patent information from the 

list, the patent or patent information 

will be removed if no ANDA applicant 

has submitted a paragraph IV 

certification to the patent or no ANDA 

applicant is eligible for 180-day 

exclusivity. Upon removal of the patent 

or patent information from the list, any 

applicant with a pending 505(b)(2) 

application or ANDA (including a 

tentatively approved 505(b)(2) 

application or ANDA) must submit an 

amendment to its application to 

withdraw its certification to the patent. 

However, if an NDA holder has 

requested removal of a patent or patent 

information from the list and one or 

more first ANDA applicants are eligible 

for 180-day exclusivity, FDA will not 

remove the patent or patent information 

from the list until we have determined 

that no first applicant still is eligible for 

180-day exclusivity (see section 

505(j)(5)(D) of the FD&C Act regarding 

forfeiture of 180-day exclusivity) or the 

180-day exclusivity is extinguished (see 

proposed §§ 314.50(i)(6)(ii) and 

314.94(a)(12)(viii)(B)). Otherwise, if the 

NDA holder withdrew the patent or 

patent information for which a first 

ANDA applicant had submitted the 

certification that qualified it for 180-day 

exclusivity and FDA immediately 

removed the patent or patent 

information from the list, the first 

applicant would be required to 

withdraw its patent certification and 

could not ‘‘lawfully maintain’’ its 

paragraph IV certification (as the ANDA 

would no longer be considered to be one 

containing a paragraph IV certification) 

(see section 505(j)(5)(B)(iv)(II)(bb) and 

(j)(5)(D)(i)(III) of the FD&C Act). In 

addition, if FDA immediately removed 

a patent or patent information from the 

list upon the NDA holder’s request 

when one or more first applicants were 

eligible for 180-day exclusivity, it could 

result in ANDA applicants withdrawing 

corresponding patent certifications 


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prematurely and thus undermining a 

first applicant’s 180-day exclusivity. We 

also are proposing to revise the heading 

for §§ 314.50(i)(6)(ii) and 

314.94(a)(12)(viii)(B) by replacing the 

phrase ‘‘after removal of a patent’’ with 

‘‘after request to remove a patent or 

patent information’’ to emphasize that 

FDA will not remove a patent or patent 

information from the list until we have 

determined that no first applicant is 

eligible for 180-day exclusivity. 

An NDA holder’s withdrawal of a 

patent or patent information is 

implicitly an acknowledgment that the 

standard for patent listing set forth in 

section 505(b) and (c) of the FD&C Act 

can no longer be met. Nevertheless, a 

patent for which the NDA holder has 

requested removal may remain listed for 

180-day exclusivity purposes. For a 

patent that remains listed for purposes 

of 180-day exclusivity after an NDA 

holder has withdrawn the patent or 

patent information and requested that 

FDA remove the patent or patent 

information from the list, the 

requirements for providing a patent 

certification will differ between 

505(b)(2) applicants and ANDA 

applicants. A 505(b)(2) applicant is 

neither eligible for nor blocked by 180- 

day generic drug exclusivity. 

Accordingly, we are proposing to revise 

§ 314.50(i)(6)(ii) to exempt a 505(b)(2) 

applicant from the requirement to 

provide or maintain a certification to a 

patent that is identified in the Orange 

Book as remaining listed only for 

purposes of a first applicant’s 180-day 

generic drug exclusivity. Because one or 

more ANDA applicants may be eligible 

for 180-day exclusivity, ANDA 

applicants are required to provide an 

appropriate patent certification to each 

patent listed in the Orange Book (except 

as provided in § 314.94(a)(12)(vi)), 

including to a patent that is listed with 

a notation indicating that the NDA 

holder has requested removal of the 

patent or patent information from the 

Orange Book. Once FDA has determined 

that no first applicant is eligible for 180- 

day exclusivity, or such exclusivity is 

extinguished, and has removed the 

patent information from the Orange 

Book, an ANDA applicant must submit 

an amendment to its pending ANDA to 

withdraw the certification. 

We are proposing to delete the 

statement in current §§ 314.50(i)(6)(ii) 

and 314.94(a)(12)(viii)(B) regarding the 

timing of removal of a patent or patent 

information that is the subject of a 

patent infringement lawsuit under 

§ 314.107(c). This statement would be 

replaced by the broader criterion, 

discussed earlier in this section, that a 

patent will not be removed from the list 

until FDA has determined that any 180- 

day exclusivity is extinguished. This 

proposed revision reflects our current 

practice. 

We also are proposing to add a 

statement to emphasize that if a 

505(b)(2) or ANDA applicant submits an 

amendment to withdraw a paragraph IV 

certification, the 505(b)(2) application or 

ANDA will no longer be considered to 

be one containing a paragraph IV 

certification to the patent. In addition, 

we are proposing a conforming revision 

to § 314.94(a)(12)(viii) to clarify that 

once an amendment is submitted to 

change a certification, the ANDA will 

no longer be considered to contain the 

prior certification. This is consistent 

with the Agency’s practice for amended 

patent certifications for 505(b)(2) 

applications (see § 314.50(i)(6)). 

Finally, we are proposing to relocate 

within §§ 314.50(i)(6)(ii) and 

314.94(a)(12)(viii)(B) and revise the 

current statement regarding submission 

of an amended patent certification after 

removal of a patent from the list. This 

proposed revision is intended to clarify 

rather than substantively change our 

current requirements. If removal of a 

patent from the list results in there 

being no patents listed for the listed 

drug(s) identified in the 505(b)(2) 

application or the RLD identified in the 

ANDA, the applicant must submit an 

amended certification under 

§ 314.50(i)(1)(ii) or § 314.94(a)(12)(ii), as 

appropriate, to reflect that there are no 

listed patents. We note, however, that if 

a 505(b)(2) or ANDA applicant fails to 

submit an amended patent certification 

after removal of a patent from the list, 

the Agency will consider the 505(b)(2) 

or ANDA applicant to have 

constructively withdrawn its patent 

certification to the delisted patent 

(compare Ranbaxy Labs. Ltd. v. FDA, 

307 F. Supp. 2d 15, 21 (D.D.C.), aff’d, 

2004 U.S. App. LEXIS 8311 (D.C. Cir. 

2004); see also section II.E.4). With 

respect to any patents that remain listed 

for the listed drug(s) identified in the 

505(b)(2) application or for the RLD 

identified in the ANDA, it is expected 

that the applicant would maintain an 

accurate patent certification consistent 

with current regulatory requirements 

(see §§ 314.50(i)(6)(iii) and 

314.94(a)(12)(viii)(C)). We seek 

comment on this approach. 

II.E.3. Amended Certifications Upon 

Patent Reissuance 

In section II.B.1.e, we describe certain 

proposed revisions to our regulations to 

clarify our requirements regarding an 

NDA holder’s submission of patent 

information related to reissued patents. 

Because the listing of a reissued patent 

may require submission of an amended 

patent certification by a 505(b)(2) or 

ANDA applicant under our current 

regulations, we are describing in this 

section of the document an applicant’s 

patent certification obligations with 

respect to a reissued patent. 

Sections 314.50(i)(6)(iii) and 

314.94(a)(12)(viii)(C) require that a 

505(b)(2) and ANDA applicant submit 

an amended patent certification if, at 

any time before approval of the 

505(b)(2) application or ANDA, the 

applicant learns that the submitted 

certification is no longer accurate. As a 

general rule, we require a 505(b)(2) or 

ANDA applicant to provide an 

appropriate patent certification or 

statement with respect to a reissued 

patent, unless either the original patent 

or the reissued patent was not timely 

filed by the NDA holder for listing in 

the Orange Book (see §§ 314.50(i)(4) and 

314.94(a)(12)(vi)). As noted in section 

II.B.1.e, if a 505(b)(2) or ANDA 

applicant is not required to provide a 

patent certification or statement to the 

original patent because it was untimely 

filed (and late-listed as to the pending 

505(b)(2) application or ANDA), the 

505(b)(2) or ANDA applicant would not 

be required to provide a patent 

certification or statement to the reissued 

patent even if timely filed following 

reissuance. 

We require a 505(b)(2) or ANDA 

applicant to provide an amended patent 

certification or statement to the reissued 

patent, even though a patent 

certification or statement may already 

have been submitted for the original 

patent, because the scope of claims may 

be narrowed or, in certain 

circumstances, broadened upon 

reissuance of the patent (see 35 U.S.C. 

251). A change in the scope of the 

patent claims may result in the reissued 

patent being listed in the Orange Book 

with a revised designation by the NDA 

holder regarding whether the patent 

claims the drug substance, drug 

product, and/or a method of use, or the 

reissued patent may be listed with a 

revised use code. Accordingly, 

submission of an amendment to a 

pending 505(b)(2) application or ANDA 

is necessary to provide an appropriate 

patent certification or statement to the 

reissued patent, even if the type of 

patent certification (e.g., a paragraph III 

certification) does not differ from that 

submitted for the original patent. 

If an ANDA applicant submitted a 

paragraph IV certification to the original 

listed patent and continues to opine that 

the reissued patent is invalid or will not 

be infringed by the manufacture, use, or 

sale of the drug for which the 

application is submitted, then we are 


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6846 Federal Register / Vol. 80, No. 25 / Friday, February 6, 2015 / Proposed Rules 

proposing that the applicant must 

submit an amendment to its pending 

ANDA that contained a paragraph IV 

certification to the reissued patent 

within 30 days of the date of listing of 

the reissued patent in the Orange Book 

to lawfully maintain its paragraph IV 

certification for purposes of eligibility 

for 180-day exclusivity (see proposed 

§ 314.94(a)(12)(viii)(B)). Both 505(b)(2) 

and ANDA applicants are required to 

provide notice of the paragraph IV 

certification to the reissued patent and 

comply with other applicable regulatory 

requirements at the time of submission 

of the amendment containing the 

paragraph IV certification. We seek 

comment on this proposal. 

An amended patent certification to 

the reissuance of an original patent for 

which a paragraph IV certification 

previously was submitted may have 

implications for the 30-month stay 

provisions of the FD&C Act: 

• If a 505(b)(2) or ANDA applicant 

submitted a paragraph IV certification to 

the original patent and a patent 

infringement action was initiated within 

45 days of its notice of the paragraph IV 

certification to the original patent, the 

resulting 30-month stay would not be 

affected solely by reissuance of the 

patent, recertification, and renotification 

and would continue subject to 

§ 314.107. 

• If a 505(b)(2) or ANDA applicant 

submitted a statement under section 

505(b)(2)(B) or section 505(j)(2)(A)(viii) 

of the FD&C Act, respectively, or a 

paragraph III certification to the original 

patent and subsequently submitted a 

paragraph IV certification to the 

reissued patent, a 30-month stay would 

be available if a patent infringement 

action was initiated within 45 days of 

its notice of the paragraph IV 

certification to the reissued patent. 

• If a 505(b)(2) or ANDA applicant 

had previously submitted a paragraph 

IV certification to the original patent 

and no patent infringement action was 

initiated within 45 days of receipt of 

notice, no subsequent patent 

infringement action with respect to the 

reissued patent can give rise to a 30- 

month stay. 

This approach reflects our proposal to 

treat the original patent and the reissued 

patent as a ‘‘single bundle’’ of patent 

rights, albeit patent rights that have 

changed with reissuance, such that the 

patent information listed for the 

reissued patent would have been 

submitted under 505(b)(1) or 505(c)(2) 

of the FD&C Act at the time of listing of 

the original patent for purposes of 

section 505(c)(3)(C) and (j)(5)(B)(iii) of 

the FD&C Act. Although we recognize 

that a reissued patent may have a 

broadened scope of claims if applied for 

within 2 years from the grant of the 

original patent (see 35 U.S.C. 251), our 

proposal to consider the original patent 

and reissued patent together for 

purposes of administering the patent 

certification requirements of the FD&C 

Act and any 30-month stay of approval 

or 180-day exclusivity that relates to a 

paragraph IV certification is intended to 

provide a consistent and predictable 

approach to implementation of the 

FD&C Act. If FDA were to propose a 

different approach to the availability of 

a 30-month stay based on a paragraph IV 

certification to a reissued patent with 

broadened claims, the implementation 

of such an approach would require 

resources and patent expertise that FDA 

currently does not possess and would be 

inconsistent with the Agency’s 

ministerial role in patent listing. In any 

event, we do not expect that the 

scenario described here will occur 

frequently. 

An amended patent certification to 

the reissuance of an original patent for 

which a paragraph IV certification 

previously was submitted also may have 

implications for the 180-day exclusivity 

provisions of the FD&C Act. As 

described previously in this section of 

the document, if a one or more first 

ANDA applicants is eligible for 180-day 

exclusivity based on a paragraph IV 

certification to the original patent and 

the patent is reissued, the first ANDA 

applicant would be required to submit 

a paragraph IV certification to the 

reissued patent within 30 days of listing 

to be considered by FDA to have 

lawfully maintained its paragraph IV 

certification for purposes of section 

505(j)(5)(B)(iv)(II)(bb) and (j)(5)(D)(i)(III) 

of the FD&C Act. We note that the 

original patent, which qualified the first 

applicant for 180-day exclusivity, would 

remain listed in the Orange Book until 

FDA determined that any 180-day 

exclusivity is extinguished. Consistent 

with our current practice regarding 

requests for patent delisting, the original 

patent that qualified a first applicant for 

180-day exclusivity also would remain 

listed in the Orange Book even if the 

scope of the reissued patent is narrowed 

such that the patent is no longer eligible 

for listing pursuant to section 505(b)(1) 

or 505(c)(2) of the FD&C Act and the 

NDA holder has requested, as required, 

that the patent be delisted from the 

Orange Book (see proposed 

§ 314.53(f)(2) and section II.B.4.b). 

Given that FDA will continue to list a 

patent that qualified a first applicant for 

180-day exclusivity under specified 

circumstances even if the patent has 

been withdrawn by the NDA holder on 

its own initiative or after a judicial 

finding of invalidity or unenforceability, 

the fact that the original patent 

technically is surrendered upon 

reissuance is not relevant to FDA’s 

assessment of a first applicant’s 

continued eligibility for 180-day 

exclusivity. However, in recognition of 

the surrender of the original patent 

upon reissuance, we require a first 

applicant to maintain a paragraph IV 

certification to the reissued patent. If a 

first applicant submitted only a 

paragraph III certification or a 

505(j)(2)(A)(viii) statement to the 

reissued patent, we would consider the 

first applicant to have amended or 

withdrawn its paragraph IV certification 

to the patent for which it qualified for 

180-day exclusivity under section 

505(j)(5)(D)(i)(III) of the FD&C Act. 

If no applicant had submitted a 

paragraph IV certification to the original 

patent, the first ANDA applicant to 

submit a paragraph IV certification to 

the reissued patent could be eligible for 

180-day exclusivity, if no other 

applicant already has qualified as a first 

applicant based on an earlier paragraph 

IV certification to another listed patent. 

However, if a first applicant who 

qualifies as such based on a paragraph 

IV certification to the original patent 

forfeits 180-day exclusivity, 180-day 

exclusivity would not be available to a 

subsequent applicant that submitted a 

paragraph IV certification to the 

reissued patent (see section 

505(j)(5)(D)(iii)(II) of the FD&C Act). 

II.E.4. Other Amended Certifications 

Sections 314.50(i)(6)(iii) and 

314.94(a)(12)(viii)(C) require a 505(b)(2) 

and ANDA applicant, respectively, to 

amend a submitted certification if, at 

any time before approval of the 

application, the applicant learns that the 

submitted certification is no longer 

accurate. In Dr. Reddy’s Labs., Inc. v. 

Thompson, the district court held that 

our regulations ‘‘imposing a duty upon 

ANDA applicants to assure its 

certifications are accurate until the date 

of final approval is supported by [the] 

. . . express FDA authority [in section 

505(j)(4)(J) and (K) of the FD&C Act]’’ 

(302 F. Supp. 2d 340, 355 (D.N.J. 2003)) 

(see also section 505(e) of the FD&C 

Act). 

Over the years, many 505(b)(2) and 

ANDA applicants have neglected to 

amend a previously submitted patent 

certification after the patent has expired. 

The Agency’s longstanding position has 

been that a patent is relevant for 

purposes of 180-day exclusivity 

determinations ‘‘until the end of the 

term of the patent or applicable 180-day 


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exclusivity period, whichever occurs 

first’’ (1994 final rule, 59 FR 50338 at 

50348). Section 505(j)(5)(D)(i)(VI) of the 

FD&C Act, added by the MMA, is 

consistent with FDA’s longstanding 

position that 180-day exclusivity is 

extinguished upon expiration of the 

patent(s) on which exclusivity is based 

(see Docket No. FDA–2004–N–0062– 

0006 (comment submitted by PhRMA) 

at 5, available at http://

www.regulations.gov). 

Accordingly, we are proposing to 

codify our longstanding position that if 

an applicant that previously submitted 

a paragraph III certification, a paragraph 

IV certification, or a statement under 

section 505(b)(2)(B) or (j)(2)(A)(viii) of 

the FD&C Act with respect to a listed 

patent fails to amend its patent 

certification to a paragraph II 

certification upon patent expiration, the 

Agency will consider the 505(b)(2) or 

ANDA applicant to have constructively 

changed its patent certification to a 

paragraph II certification (see, e.g., 

Ranbaxy Labs. Ltd. v. FDA, 307 F. Supp. 

2d 15, 21 (D.D.C.), aff’d, 2004 U.S. App. 

LEXIS 8311 (D.C. Cir. 2004) (finding 

that upon patent expiration an ANDA 

applicant’s paragraph IV certifications 

‘‘became invalid, and either converted 

as a matter of law to Paragraph II 

certifications or became inaccurate, 

thereby creating both an obligation on 

[the ANDA applicant’s] . . . part to 

amend its ANDAs to reflect patent 

expiry and an inability on the part of the 

FDA to approve the ANDAs in their 

inaccurate form’’)). This approach also 

will clarify that any pediatric 

exclusivity will delay approval of a 

505(b)(2) application or ANDA upon 

patent expiry under section 

505A(b)(1)(B) and (c)(1)(B) of the FD&C 

Act, regardless of whether an applicant 

has amended its certification to a 

paragraph II certification. 

We also are proposing to amend 

§§ 314.50(i)(6)(iii)(A) and 

314.94(a)(12)(viii)(C)(1) by revising and 

redesignating the current text as 

paragraph (1) and paragraph (i), 

respectively, and adding a new 

paragraph (2) and paragraph (ii) to 

expressly codify the requirement for a 

505(b)(2) and ANDA applicant to submit 

a patent certification to a newly issued 

patent. Proposed 

§§ 314.50(i)(6)(iii)(A)(2) and 

314.94(a)(12)(viii)(C)(1)(ii) state that, 

except as provided in §§ 314.50(i)(4) 

and (i)(6)(iii)(B) and 314.94(a)(12)(vi) 

and (a)(12)(viii)(C)(2)), an applicant 

must submit a patent certification or 

statement if, after submission of the 

505(b)(2) application or ANDA, a new 

patent is issued by the PTO that, in the 

opinion of the applicant and to the best 

of its knowledge, claims the listed drug 

or RLD or that claims an approved use 

for such drug and for which information 

is required to be filed under section 

505(b) and (c) of the FD&C Act and 

§ 314.53. 

A 505(b)(2) and ANDA applicant 

currently are required to submit a patent 

certification or statement for each patent 

issued by the PTO that, in the opinion 

of the applicant and to the best of its 

knowledge, claims the listed drug or 

RLD or that claims an approved use for 

such drug for which the applicant is 

seeking approval and for which 

information is required to be filed under 

section 505(b) and (c) of the FD&C Act 

and § 314.53. Although the general 

requirement to submit a patent 

certification to a newly issued patent is 

established by §§ 314.50(i)(1)(i)(A) and 

314.94(a)(12)(i)(A) and implicit in the 

exceptions for late submission of patent 

information, we are proposing to 

expressly codify the requirement to 

submit a patent certification to a newly 

issued patent in the section of the 

regulations directed to amended patent 

certification. 

As discussed in section II.D.1.b.ii, we 

are proposing that a patent certification 

or statement by an ANDA applicant 

must not be submitted earlier than the 

first working day after the day the 

patent is published in the Orange Book 

(see proposed 

§ 314.94(a)(12)(viii)(C)(1)(ii)). Thus, for a 

paragraph IV certification, the 

certification must not be submitted 

earlier than the first working day after 

the day the patent is published in the 

Orange Book. This proposal is intended 

to discourage burdensome serial 

submissions of paragraph IV 

certifications and ensure that all ANDA 

applicants (irrespective of time zone) 

have a reasonable opportunity to be a 

first applicant with respect to a newly 

listed patent (see also proposed 

§ 314.95(b)(2)). 

In addition, we are proposing to 

revise §§ 314.50(i)(6)(iii) and 

314.94(a)(12)(viii)(C) to technically 

correct, but not substantively change, 

the reference to the lack of a 

requirement to ‘‘amend’’ a submitted 

patent certification after approval of a 

505(b)(2) application or ANDA, 

respectively. We are proposing to 

correct this statement to indicate that an 

applicant is not required to submit a 

supplement solely to change a 

submitted patent certification after 

approval of the application. This 

revision also reflects that any changes to 

an application after approval would be 

made in a supplement to the application 

and not in an amendment, as the current 

regulation describes. 

II.F. Patent Certification Requirements 

for Amendments and Supplements to 

505(b)(2) Applications and ANDAs 

(Proposed §§ 314.60, 314.70, 314.96, 

and 314.97) 

We are proposing to add §§ 314.60(f), 

314.70(i), 314.96(d), and 314.97(c) to 

clarify and augment the patent 

certification requirements for 

amendments and supplements 

described in §§ 314.50(i)(6)(iii) and 

314.94(a)(12)(viii)(C). Proposed 

§§ 314.60(f) and 314.96(d) would 

require an applicant to also submit a 

patent certification described in 

§§ 314.50(i) or 314.94(a)(12), as 

appropriate, if approval is sought for 

any of the following types of 

amendments to an original 505(b)(2) 

application or ANDA: (1) To add a new 

indication or other condition of use; (2) 

to add a new strength; (3) to make other 

than minor changes in product 

formulation; or (4) to change the 

physical form or crystalline structure of 

the active ingredient. 

Currently, an applicant that submits 

an amendment to a pending 505(b)(2) 

application or supplement or a pending 

ANDA or supplement is required to 

amend its patent certification if, at any 

time before approval, the applicant 

learns that the previously submitted 

patent certification is no longer accurate 

with respect to the pending application 

or supplement, as amended (see 

§§ 314.50(i)(6)(iii) and 

314.94(a)(12)(viii)(C), respectively, and 

section II.E.4). For example, an 

amendment to change the formulation 

of a proposed product in a 505(b)(2) 

application or ANDA would require a 

revised patent certification if, in the 

applicant’s opinion and to the best of its 

knowledge, the new formulation would 

infringe a listed patent for which it 

previously had filed a paragraph IV 

certification. 

Some NDA holders have expressed 

concern that a 505(b)(2) or ANDA 

applicant may change its proposed 

product in an amendment to a pending 

application, but not update its patent 

certification to correspond to the 

proposed product as changed by the 

amendment. For example, in 2003, FDA 

received a citizen petition submitted on 

behalf of Biovail Corporation requesting, 

among other things, that FDA require 

submission of a new patent certification 

upon amendment of the chemistry, 

manufacturing, and controls section of 

an ANDA (Docket No. FDA–2003–P– 

0519 (Biovail Petition), available at 

http://www.regulations.gov; see also 

PhRMA comment to Docket No. FDA– 

2002–N–0279–0061 at 9 to 10, available 

at http://www.regulations.gov). The 


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Biovail Petition recognized that even if 

the ANDA (or 505(b)(2)) applicant 

continued to assert that a paragraph IV 

certification was the appropriate patent 

certification for the changed product, 

the factual and legal basis of the 

applicant’s opinion that the patent will 

not be infringed may have changed in 

light of the changes in product 

formulation (see Biovail Petition at 4 to 

5). Biovail maintained that ‘‘[r]equiring 

a new patent certification whenever the 

CMC portion of an ANDA is amended 

will allow the NDA holder and patent 

owner to ensure that the impact of the 

amendment on patent infringement 

issues is addressed promptly’’ 

(Supplement to Biovail Petition at 1). 

We agree that certain changes to a 

proposed product submitted in a 

505(b)(2) application or ANDA should 

be accompanied by a new patent 

certification (see section II.F.2). To 

address these concerns and further 

clarify our requirements for submission 

of new patent certifications with an 

amendment to a 505(b)(2) application or 

ANDA, we are proposing to add 

§§ 314.60(f) and 314.96(d). If an 

applicant submits an amendment to a 

505(b)(2) application or ANDA for any 

of the categories of changes described in 

these provisions and does not submit a 

new patent certification, the applicant 

will be required to verify that the 

proposed change described in the 

amendment is not the type of change for 

which a new patent certification is 

required (e.g., the proposed formulation 

change meets the criteria for a ‘‘minor’’ 

formulation change). We seek comment 

on this proposal. 

We also are proposing to add 

§§ 314.70(i) and 314.97(c), and make 

conforming revisions to 

§§ 314.50(i)(6)(iii)(B) and 

314.94(a)(12)(viii)(C)(2), to clarify our 

requirements for submission of new 

patent certifications with a supplement 

to a 505(b)(2) application or ANDA. 

Proposed §§ 314.70(i) and 314.97(c) 

would require an applicant to also 

submit a patent certification described 

in § 314.50(i) or 314.94(a)(12), as 

appropriate, if approval is sought for 

either of the following types of 

supplements to a 505(b)(2) application 

or ANDA: (1) To add a new indication 

or other condition of use or (2) to add 

a new strength. 

FDA is not proposing to require a 

patent certification with a supplement 

to change the formulation or to change 

the physical form or crystalline 

structure of the active ingredient of a 

product approved in a 505(b)(2) 

application or ANDA. It is not necessary 

for FDA to use its limited resources to 

require patent certifications under these 

circumstances because the NDA holder 

for a listed drug and any patent owner 

can monitor postapproval changes in 

the formulation or active ingredient of a 

marketed drug product and address any 

patent-related concerns without the 

involvement of FDA. With respect to 

NDA supplements, it should be noted 

that these patent certification 

requirements apply to 505(b)(2) 

supplements, irrespective of whether 

the original application to which the 

supplement was submitted was 

approved as a stand-alone 505(b)(1) 

application or a 505(b)(2) application. A 

supplement to a 505(b)(2) application of 

the type described in proposed 

§ 314.70(i) is generally a 505(b)(2) 

supplement. 

Table 10 summarizes the proposed 

changes related to patent certification 

requirements for amendments and 

supplements to 505(b)(2) applications 

and ANDAs: 

TABLE 10—HIGHLIGHTS OF PROPOSED CHANGES REGARDING PATENT CERTIFICATION REQUIREMENTS FOR AMENDMENTS

AND SUPPLEMENTS TO 505(b)(2) APPLICATIONS AND ANDAS 1

Current regulations Proposed revisions to regulations 

Amended certifications—Other amendments (§§ 314.50(i)(6)(iii), 

314.94(a)(12)(viii)(C)) 

Amended certifications—Other amendments (§§ 314.50(i)(6)(iii), 

314.94(a)(12)(viii)(C)) 

• Except as otherwise provided, an applicant must amend a submitted certification if, at any time before approval of the 

505(b)(2) application or ANDA, the applicant learns that the submitted certification is no longer accurate. 

• Except as otherwise provided, an applicant must amend a submitted 

certification if, at any time before approval of the 505(b)(2) application or ANDA, the applicant learns that the submitted certification is 

no longer accurate. 

Patent certification requirements (§§ 314.60(f) and 314.96(d)). 

• Except as provided below, an amendment to a 505(b)(2) application 

or ANDA is required to contain patent certifications described in 

§§ 314.50(i) or 314.94(a)(12), respectively, if approval is sought for 

any of the following types of amendments or supplements: 

—(1) To add a new indication or other condition of use; 

—(2) to add a new strength; 

—(3) to make other than minor changes in product formulation; or 

—(4) to change the physical form or crystalline structure of the active ingredient. 

Patent certification requirements (§§ 314.70(i) and 314.97(c)). 

• Except as provided below, a supplement to a 505(b)(2) application 

or ANDA is required to contain patent certifications described in 

§§ 314.50(i) or 314.94(a)(12), respectively, if approval is sought for 

either of the following types of supplements: 

—(1) To add a new indication or other condition of use; or 

—(2) to add a new strength. 

• A supplement to a 505(b)(2) application that seeks approval to add a 

new indication or other condition of use is required to contain patent 

certifications described in § 314.50(i) only for patents that are identified as claiming an approved use. If the method-of-use patent is 

identified as also claiming the drug substance or drug product, the 

patent certification also must address the drug substance and/or 

drug product claims. 

1These highlights describe important proposed revisions to our regulations, but should not be relied upon in place of the proposed regulation. 


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We invite comment on this proposal 

and whether a new patent certification 

should be required with the submission 

of other types of amendments or 

supplements to a 505(b)(2) application 

or ANDA that may change the drug 

product in a manner that could be 

protected by patent. 

II.F.1. Types of Amendments or 

Supplements for Which Patent 

Certification is Required 

II.F.1.a. Amendments or supplements 

to add a new indication or other 

condition of use. Proposed 

§§ 314.60(f)(1), 314.70(i)(1)(i), 

314.96(d)(1), and 314.97(c)(1) require a 

505(b)(2) or ANDA applicant to submit 

a new patent certification with an 

amendment or supplement to add a new 

indication or other condition of use for 

the drug product that is the subject of 

the 505(b)(2) application or ANDA. 

Although most requests for approval of 

a different indication or condition of use 

by a 505(b)(2) applicant could not be 

made as an amendment to the 505(b)(2) 

application (see Separate Marketing 

Application Guidance at 4 to 5), there 

are certain scenarios in which an 

applicant may submit an amendment to 

a 505(b)(2) application (or ANDA) for a 

new indication or other condition of 

use. For example, a 505(b)(2) or ANDA 

applicant seeking approval for a drug 

product for which the indication has 

changed from prescription status to OTC 

use for the listed drug relied upon or 

RLD, as applicable, would be required 

to submit a new patent certification 

with an amendment or supplement to 

the application. These patent 

certification requirements are currently 

encompassed by §§ 314.50(i)(6)(iii) and 

314.94(a)(12)(viii)(C). Proposed 

§§ 314.60(f)(1), 314.70(i)(1)(i), 

314.96(d)(1), and 314.97(c)(1) would 

parallel the requirements for submission 

of patent information by an NDA 

applicant seeking approval of a 

supplement to add a new indication or 

other condition of use (see proposed 

§ 314.53(d)(2)(ii)). 

Currently, an applicant is required to 

submit a patent certification or 

statement with a 505(b)(2) supplement 

that seeks approval for a new indication 

or other condition of use (‘‘efficacy 

supplement’’). We are proposing to 

reduce the current patent certification 

requirements with respect to a 

supplement to a 505(b)(2) application 

that seeks approval for a new indication 

or other condition of use. Proposed 

§ 314.70(i)(2) states that a supplement to 

a 505(b)(2) application that only seeks 

approval to add a new indication or 

other condition of use is required to 

contain patent certifications described 

in § 314.50(i) only for patents that are 

identified as claiming an approved use. 

This proposed change preserves the 

NDA holder’s intellectual property 

rights without requiring the 505(b)(2) 

applicant to submit a duplicative 

certification to patents listed in the 

Orange Book for the listed drug relied 

upon that have not been identified by 

the NDA holder as claiming a method of 

use and would not be implicated by the 

efficacy supplement. We note, however, 

that if a method-of-use patent is 

identified as also claiming the drug 

substance or drug product, a statement 

under section 505(b)(2)(B) of the FD&C 

Act would not be sufficient. The 

505(b)(2) applicant’s patent certification 

also must address the drug substance 

and/or drug product claims in the 

patent. 

II.F.1.b. Amendments or supplements 

to add a new strength or change an 

existing strength. Proposed 

§§ 314.60(f)(2), 314.70(i)(1)(ii), 

314.96(d)(2), and 314.97(c)(2) would 

codify our current requirements with 

respect to an applicant’s submission of 

a new patent certification with an 

amendment or supplement to add a new 

strength for the drug product that is the 

subject of the 505(b)(2) application or 

ANDA. As noted in section II.A.2.q, it 

is our longstanding practice to regard 

different strengths of a drug product as 

different drug products (see Apotex, Inc. 

v. Shalala, 53 F. Supp. 2d 454 (D.D.C.), 

aff’d, 1999 U.S. App. LEXIS 29571 (D.C. 

Cir. 1999)). 

II.F.1.c. Amendments to make other 

than minor changes in product 

formulation. Proposed §§ 314.60(f)(3) 

and 314.96(d)(3) would require a 

505(b)(2) or ANDA applicant to submit 

a new patent certification with an 

amendment to make other than minor 

changes in the formulation of the drug 

product that is the subject of the original 

505(b)(2) application or ANDA. This 

enhanced patent certification 

requirement is intended to facilitate 

ongoing compliance with section 

505(b)(2)(A) and (j)(2)(A)(vii) of the 

FD&C Act. An applicant that submits a 

505(b)(2) application or ANDA 

containing a paragraph IV certification 

to a listed patent must reevaluate 

whether the patent certification 

continues to be accurate after a change 

to the formulation of the proposed 

product submitted in an amendment to 

the 505(b)(2) application or ANDA. By 

requiring a new patent certification and, 

with respect to a paragraph IV 

certification, a new notice of paragraph 

IV certification to be sent at the same 

time the amendment for the change in 

formulation is submitted to FDA, we 

aim to uphold the legislative balance of 

the Hatch-Waxman Amendments that 

facilitates the availability of generic 

drug products while protecting 

innovator intellectual property rights. 

We seek comment on this proposal. 

This requirement would apply to all 

amendments to change the formulation 

of a proposed product in an original 

505(b)(2) application or ANDA, except 

for minor changes in product 

formulation that FDA would regard as 

resulting in essentially the same 

product. A new patent certification 

would not be required if the new 

formulation in the amendment is 

qualitatively (Q1) the same as the 

previous formulation (i.e., contains all 

of the same inactive ingredients) and 

quantitatively (Q2) essentially the same 

(i.e., each inactive ingredient differs by 

no more than plus or minus 5 percent 

from the previous formulation). These 

limits correspond to the Agency’s policy 

on products that generally can be 

regarded as essentially the same (see, 

e.g., draft guidance for industry entitled 

‘‘Bioavailability and Bioequivalence 

Studies for Nasal Aerosols and Nasal 

Sprays for Local Action’’ (April 2003) at 

8, available at http://www.fda.gov/

downloads/Drugs/GuidanceCompliance

RegulatoryInformation/Guidances/

UCM070111.pdf; compare 

§ 314.70(b)(2)(i)), and thus a change 

within these limits would not be likely 

to affect an applicant’s patent 

certification. These limits also are 

similar to ‘‘Level 1’’ changes (those that 

are unlikely to have any detectable 

impact on formulation quality and 

performance) in components and 

composition of a drug product under the 

Agency’s Scale-Up and Postapproval 

Changes guidance (see guidance for 

industry entitled ‘‘Immediate Release 

Solid Oral Dosage Forms; Scale-Up and 

Postapproval Changes: Chemistry, 

Manufacturing, and Controls, In Vitro 

Dissolution Testing, and In Vivo 

Bioequivalence Documentation’’ 

(November 1995) at 6 to 8, available at 

http://www.fda.gov/downloads/Drugs/

GuidanceComplianceRegulatory

Information/Guidances/UCM070636.

pdf). 

It should be noted that an applicant 

seeking approval for an ANDA for a 

product intended for parenteral, 

ophthalmic, otic, or topical use must 

submit information to show that the 

proposed product contains the same 

inactive ingredients in the same 

concentration as the RLD, subject to 

exceptions specified in 

§ 314.94(a)(9)(iii) through (a)(9)(v). 

Additional regulatory considerations 

related to changes to the formulation of 

a drug product proposed in an 


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amendment to an ANDA are discussed 

in section II.G.1 to II.G.2 and II.L. 

II.F.1.d. Amendments to change the 

physical form or crystalline structure of 

the active ingredient. Proposed 

§§ 314.60(f)(4) and 314.96(d)(4) would 

require a 505(b)(2) or ANDA applicant 

to submit a new patent certification 

with an amendment to change the 

physical form (e.g., different waters of 

hydration, solvates, and amorphous 

forms) or crystalline structure of the 

active ingredient of the drug product 

that is the subject of the 505(b)(2) 

application or ANDA. For example, a 

new patent certification would be 

required for an amendment to an ANDA 

that includes a change to the physical 

form of the active ingredient to conform 

with the physical form(s) of the active 

ingredient described in a final USP 

monograph. 

These patent certification 

requirements apply to changes to the 

active ingredient that may be submitted 

as an amendment to a 505(b)(2) 

application or ANDA and do not alter 

the Agency’s policy regarding the types 

of different active ingredients (e.g., 

different salts, esters, and complexes of 

the same active moiety) that should be 

submitted in a separate application (see 

Separate Marketing Application 

Guidance; see also section II.G.3 to 

II.G.4). We note that the Agency has 

long considered different polymorphs to 

be the ‘‘same active ingredient’’ and 

pharmaceutical equivalents (see section 

1.7 of the preface to the Orange Book 

(33rd Edition, 2013, at xv). 

II.F.2. Requirements for Notice of 

Paragraph IV Certifications and 

Implications for 180-Day Exclusivity 

There are additional regulatory 

considerations related to the submission 

of a paragraph IV certification by an 

applicant required to submit a new 

patent certification with its amendment 

or supplement to a 505(b)(2) application 

or ANDA. As a preliminary matter, we 

note that notice is required for all 

paragraph IV certifications, irrespective 

of whether the applicant previously 

provided notice of paragraph IV 

certification to the same patent or to 

another patent claiming the listed drug 

relied upon or RLD (see section 

505(b)(3)(B) and (j)(2)(B)(ii) of the FD&C 

Act). If patent infringement litigation 

has been initiated in response to a 

previous notice of paragraph IV 

certification, a new paragraph IV 

certification submitted with an 

amendment or supplement to the 

505(b)(2) application or ANDA still 

requires formal notice in accordance 

with §§ 314.52 and 314.95. 

The new notice of paragraph IV 

certification must contain the 

information required by section 

505(b)(3)(D) and (j)(2)(B)(iv) of the FD&C 

Act and §§ 314.52(c) and 314.95(c), 

updated to correspond to the proposed 

product as changed by the amendment 

or supplement. For example, the 

detailed statement of the factual and 

legal basis of the applicant’s opinion 

that the patent is invalid, unenforceable, 

or will not be infringed by its proposed 

product must be updated, as necessary, 

by the 505(b)(2) or ANDA applicant to 

reflect the changes proposed in the 

amendment or supplement. The notice 

of paragraph IV certification also must 

clarify whether the amendment or 

supplement contains any required 

bioavailability or bioequivalence data 

that was necessary to support the 

proposed change to the 505(b)(2) 

application or ANDA. 

With respect to any listed patent 

challenged by the applicant in an 

amendment or supplement to the 

505(b)(2) application or ANDA for 

which the NDA holder or patent owner 

initiated patent infringement litigation 

within the statutory timeframe in 

response to notice of paragraph IV 

certification, the availability of a 30- 

month stay will depend upon whether 

the NDA holder filed information on the 

patent at issue with FDA prior to the 

date of submission of the 505(b)(2) 

application or the date of submission of 

the ANDA (which FDA later determined 

to be substantially complete) that refers 

to the listed drug claimed by the patent 

(see section 505(c)(3)(C) and (j)(5)(B)(iii) 

of the FD&C Act). Accordingly, a 30- 

month stay may result from initiation of 

a patent infringement action in response 

to a second notice of paragraph IV 

certification provided at the time of 

submission of an amendment or 

supplement to a 505(b)(2) application or 

ANDA if the patent was listed prior to 

the date of submission of the original 

505(b)(2) application or ANDA and, for 

example, the infringement action was 

warranted by the change proposed in 

the amendment or supplement. 

A first applicant that submits an 

amendment to its pending ANDA or a 

supplement would be considered to 

have lawfully maintained a paragraph 

IV certification to the patent upon 

which eligibility for 180-day exclusivity 

was based if the amendment or 

supplement is accompanied by another 

paragraph IV certification to the patent 

and notice of paragraph IV certification 

is sent in accordance with § 314.95(d). 

II.G. Amendments or Supplements to a 

505(b)(2) Application for a Different 

Drug and Amendments or Supplements 

to an ANDA That Reference a Different 

Listed Drug (Proposed §§ 314.60, 314.70, 

314.96, 314.97) 

The MMA added section 505(b)(4)(A), 

(b)(4)(B), (j)(2)(D)(i), and (j)(2)(D)(ii) to 

the FD&C Act, which generally prohibit 

the submission of certain types of 

changes in an amendment or a 

supplement to a 505(b)(2) application or 

an ANDA, respectively. We interpret 

these provisions in the context of the 

MMA’s amendment of section 

505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C 

Act to restrict the availability of a 30- 

month stay of approval in certain 

circumstances involving amendments 

and supplements to a 505(b)(2) 

application or ANDA and seek comment 

on this approach. 

Section 1101(a)(1)(A) of the MMA 

amended section 505(j) of the FD&C Act 

to generally prohibit an ANDA 

applicant from amending or 

supplementing an ANDA ‘‘to seek 

approval of a drug referring to a 

different listed drug from the listed drug 

identified in the application as 

submitted [to FDA]’’ (section 

505(j)(2)(D)(i) of the FD&C Act). The 

textual reference in the statute to ‘‘seek 

approval of a drug referring to a 

different listed drug’’ is clearly 

understood in the context of section 

505(j) of the FD&C Act and FDA’s 

regulatory scheme for the approval of 

ANDAs. An applicant that submits an 

ANDA for a duplicate of a listed drug 

is required to identify and rely upon the 

listed drug designated by FDA as the 

RLD (see § 314.94(a)(3)). An applicant 

also may petition FDA to request 

permission to submit an ANDA that 

differs from a selected listed drug in 

route of administration, dosage form, or 

strength, or that has one different active 

ingredient in a combination drug 

product (see section 505(j)(2)(C) of the 

FD&C Act). Accordingly, we are 

proposing to add §§ 314.96(c) and 

314.97(b) to state that an ANDA 

applicant may not amend or supplement 

an ANDA to seek approval of a drug 

referring to listed drug that is different 

from the RLD identified in the ANDA. 

An ANDA applicant that seeks to refer 

to a listed drug different from the RLD 

identified in the initial ANDA must 

submit a new ANDA (see section 

505(j)(2)(D)(i) of the FD&C Act; see also 

section II.G.1 to II.G.2 of this document). 

Section 1101(b)(1)(A) of the MMA 

amended section 505(b) of the FD&C Act 

to generally prohibit an applicant from 

amending or supplementing ‘‘an 

application referred to in [section 


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505(b)(2)] to seek approval of a drug that 

is a different drug than the drug 

identified in the application as 

submitted to the Secretary.’’ Although 

section 1101(a) and (b) of the MMA are 

parallel in structure, the statutory text 

restricting an applicant from amending 

or supplementing a 505(b)(2) 

application in certain circumstances 

differs from the corresponding 

restrictions for ANDAs. Section 

505(b)(4)(A) prohibits an amendment or 

a supplement ‘‘to seek approval of a 

drug that is a different drug’’ (emphasis 

added) while section 505(j)(2)(D)(i) 

prohibits an amendment or supplement 

to an ANDA ‘‘to seek approval of a drug 

referring to a different listed drug’’ 

(emphasis added). 

The MMA also amended section 

505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C 

Act to permit a 30-month stay of 

approval of a 505(b)(2) application or 

ANDA only with respect to patents for 

which the NDA holder submitted 

information to FDA prior to the date of 

submission of the 505(b)(2) application 

or the date of submission of the ANDA 

(which FDA later determines to be 

substantially complete) that refers to the 

listed drug claimed by the patent. The 

‘‘date on which the application . . . was 

submitted’’ specifically excludes the 

date of submission of an amendment or 

supplement to a 505(b)(2) application or 

ANDA. Given this limitation on the 

patents that may give rise to a 30-month 

stay, the MMA may have created an 

incentive for a 505(b)(2) or ANDA 

applicant to seek approval for a change 

to a drug, or to reference a different 

listed drug, through an amendment or a 

supplement, rather than by submitting a 

new application. To address this 

concern, section 505(b)(4)(A) and 

(j)(2)(D)(i) of the FD&C Act ensure that 

505(b)(2) and ANDA applicants do not 

use the amendment or supplement 

process to evade the possibility of a 30- 

month stay of approval that otherwise 

would have applied if the 505(b)(2) 

applicant sought approval for a drug 

that is a different drug or if the ANDA 

applicant sought to refer to a different 

RLD in the original 505(b)(2) application 

or ANDA, respectively. Accordingly, we 

interpret section 505(b)(4)(A) of the 

FD&C Act in a manner that is consistent 

with the statutory text, accomplishes the 

statutory goal of preserving a 

meaningful opportunity for a single 30- 

month stay, and reflects, to the extent 

feasible, Congress’ expressed intent to 

preserve rather than disrupt FDA 

processes regarding submission of 

amendments and supplements to 

505(b)(2) applications and ANDAs. 

We propose that a drug will be 

considered a ‘‘different drug’’ for 

purposes of section 505(b)(4)(A) of the 

FD&C Act if it has been modified to 

have a different active ingredient, 

different route of administration, or 

different dosage form. Similarly, a drug 

will be considered to be a different drug 

if it has been modified to have different 

excipients that require either a separate 

clinical study to establish safety or 

effectiveness or, for topical products, 

that requires a separate in vivo 

demonstration of bioequivalence (see 

proposed §§ 314.60(e) and 314.70(h)). 

Consistent with FDA’s ‘‘bundling’’ 

policy in effect at the time of enactment 

of the MMA, an applicant may not seek 

approval for these types of changes to a 

drug through an amendment or 

supplement to the 505(b)(2) application; 

the applicant is required to submit a 

new 505(b)(2) application (see draft 

guidance for industry entitled 

‘‘Submitting Separate Marketing 

Applications and Clinical Data for 

Purposes of Assessing User Fees’’ 

(describing FDA’s bundling policy at the 

time of enactment of the MMA in 2003); 

see also Separate Marketing 

Applications Guidance). These changes 

to a drug product are significant enough 

that it is reasonable to assume that one 

or more patents for the listed drug might 

be implicated by the change and, if an 

action for patent infringement is brought 

in response to a paragraph IV 

certification to a listed patent, an 

opportunity for 30-month stay would be 

appropriate. Thus, FDA has concluded 

that these modifications to a drug would 

make the drug a ‘‘different drug’’ for 

purposes of section 505(b)(4)(A) of the 

FD&C Act. An applicant seeking 

marketing approval for a drug that has 

been modified in these ways must 

submit a separate marketing application 

for the different drug product, and not 

an amendment or supplement. 

We considered possible alternative 

interpretations of the phrase ‘‘to seek 

approval of a drug that is a different 

drug’’ in section 505(b)(4)(A) of the 

FD&C Act. The narrowest reading of this 

text would preclude the submission of 

an amendment or a supplement to a 

505(b)(2) application for any change 

(including labeling changes and 

manufacturing changes) that would 

arguably render the proposed product a 

‘‘different drug’’ than the drug identified 

in the original submission of the 

application. If labeling changes, for 

example, could not be made through an 

amendment or a supplement to a 

505(b)(2) application, each such change 

would require the submission of a 

separate 505(b)(2) application, with 

related regulatory and administrative 

burdens, and user fee and review cycle 

implications. We did not adopt this 

reading because it would have resulted 

in an unwarranted departure from 

FDA’s previous practice for handling 

such changes. 

In applying section 505(b)(4)(A) of the 

FD&C Act, we initially interpreted the 

phrase ‘‘drug that is a different drug’’ in 

section 505(b)(4)(A) in a manner that 

was influenced by and intended to be 

consistent with the phrase ‘‘drug 

referring to a different listed drug’’ in 

section 505(j)(2)(D)(i) of the FD&C Act. 

Under this interpretation, an applicant 

was not permitted to amend or 

supplement a 505(b)(2) application to 

seek approval of a drug that relied on 

the Agency’s finding of safety and/or 

effectiveness for a listed drug that was 

different from the listed drug(s) 

identified in the original submission of 

the application. This approach assumed 

that the difference in phrasing between 

section 505(b)(4)(A) and (j)(2)(D)(i) of 

the FD&C Act was simply intended to 

reflect the different statutory 

frameworks for 505(b)(2) applications 

and ANDAs. This interpretation also 

was intended to ensure that a 505(b)(2) 

applicant did not circumvent the 30- 

month stay provisions of the FD&C Act 

by amending or supplementing a 

505(b)(2) application to identify a new 

or additional listed drug upon which it 

relied for approval. 

We found our initial approach to be 

overly restrictive in practice, however, 

as this interpretation required 

withdrawal and resubmission of a 

505(b)(2) application to identify a new 

or additional listed drug even where 

there were no patents listed in the 

Orange Book for the new or additional 

listed drug, and thus there was no 

possibility of a 30-month stay. 

Accordingly, we are proposing a 

narrower interpretation that is guided 

by Congress’ expressed view that these 

provisions are intended to ‘‘reflect the 

FDA’s current practice regarding those 

changes and variations to both 

innovator and generic drugs that may be 

approved under amendments and 

supplements to previously filed NDAs 

and ANDAs . . .’’ (see Conference 

Report on H.R. 1, November 20, 2003, at 

H12099). 

Our interpretation of section 

505(b)(4)(A), (b)(4)(B), (j)(2)(D)(i), and 

(j)(2)(D)(ii) of the FD&C Act seeks to 

preserve the legislative balance of the 

Hatch-Waxman Amendments with 

respect to facilitating the availability of 

drug products that meet the statutory 

requirements for approval while 

protecting innovator intellectual 

property rights (and allowing for an 

early resolution of any patent 

infringement litigation). We seek 


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comment on this proposal and potential 

alternatives to maintain the intended 

balance. 

In the Federal Register of November 

4, 2004 (69 FR 64314), FDA announced 

the availability of a draft guidance for 

industry, issued as required by section 

505(j)(2)(D)(iii) of the FD&C Act, that 

defined the term ‘‘listed drug’’ for 

purposes of section 505(j)(2)(D) with 

respect to amendments and 

supplements to an ANDA (see draft 

guidance for industry entitled ‘‘Listed 

Drugs, 30-Month Stays, and Approval of 

ANDAs and 505(b)(2) Applications 

Under Hatch-Waxman, as Amended by 

the Medicare Prescription Drug, 

Improvement, and Modernization Act of 

2003’’ (October 2004), available at 

http://www.fda.gov/downloads/Drugs/

GuidanceComplianceRegulatory

Information/Guidances/UCM072887.

pdf) (Draft Guidance on Listed Drugs). 

In the Draft Guidance on Listed Drugs, 

we advised that our definition of the 

term ‘‘listed drug’’ is set forth in § 314.3, 

and that we did not intend to amend 

that definition to implement section 

505(j)(2)(D) of the FD&C Act. Although 

minor revisions to the definition of 

listed drug are proposed in this 

rulemaking (see section II.A.2.s), these 

proposed revisions do not substantively 

alter the definition for purposes of 

section 505(j)(2)(D) of the FD&C Act. We 

note that different strengths of an 

approved drug product continue to be 

regarded as different listed drugs. 

However, the FD&C Act expressly 

permits an applicant to amend or 

supplement a 505(b)(2) application or 

ANDA to seek approval of a different 

strength (see section 505(b)(4)(B) and 

(j)(2)(D)(ii) of the FD&C Act). 

Table 11 summarizes the proposed 

changes related to amendments or 

supplements to a 505(b)(2) application 

or ANDA: 

TABLE 11—HIGHLIGHTS OF PROPOSED CHANGES REGARDING AMENDMENTS OR SUPPLEMENTS TO A 505(B)(2) 

APPLICATION OR ANDA 1

Current regulations Proposed revisions to regulations 

[No corresponding regulation] ......... Amendments and Supplements—Different drug (§§ 314.60(e) and 314.70(h)) 

• Applicant may not amend a 505(b)(2) application to seek approval of a drug that is a different drug from 

the drug in the original submission of the 505(b)(2) application. 

• Applicant may not supplement a 505(b)(2) application to seek approval of a drug that is a different drug 

from the drug in the approved 505(b)(2) application. 

• For purposes of this section, a drug is a different drug if it has been modified to have a different active 

ingredient, different route of administration, different dosage form, or difference in excipients that requires either a separate clinical study to establish safety or effectiveness or, for topical products, that requires a separate in vivo demonstration of bioequivalence. 

• Approval of a different drug must be requested in a new 505(b)(2) application. 

• Notwithstanding the limitations described above, an applicant may amend or supplement the 505(b)(2) 

application to seek approval of a different strength. 

[No corresponding regulation] ......... Amendments and Supplements—Different listed drug (§§ 314.96(c) and 314.97(b)) 

• Applicant may not amend an ANDA to seek approval of a drug referring to a listed drug that is different 

from the RLD identified in the ANDA. 

—Applies if, at any time before ANDA approval, a different listed drug approved in an NDA is pharmaceutically equivalent to the product in the ANDA and is designated as an RLD. 

—Applies if changes are proposed in an amendment to the ANDA such that the proposed product is a 

pharmaceutical equivalent to a different listed drug than the RLD identified in the ANDA. 

• Applicant may not supplement an ANDA to seek approval of a drug referring to a listed drug that is different from the current RLD identified in the ANDA. 

—Applies if changes are proposed in a supplement to the ANDA such that the proposed product is a 

pharmaceutical equivalent to a different listed drug than the RLD identified in the ANDA. 

• A change of the RLD must be submitted in a new ANDA. 

• Notwithstanding the limitations described above, an applicant may amend or supplement the ANDA to 

seek approval of a different strength. 

1These highlights describe important proposed revisions to our regulations, but should not be relied upon in place of the proposed regulation. 

II.G.1. Amendments to an Unapproved 

ANDA (Proposed § 314.96(c)) 

We are proposing to revise § 314.96 

regarding amendments to an 

unapproved ANDA by adding paragraph 

(c) to implement section 505(j)(2)(D)(i) 

and (ii) of the FD&C Act. Proposed 

§ 314.96(c) states that an applicant may 

not amend an ANDA to seek approval 

of a drug referring to a listed drug that 

is different from the RLD identified in 

the ANDA. Two examples in proposed 

§ 314.96(c) illustrate the application of 

this provision. 

II.G.1.a. Approval of a 

pharmaceutically equivalent drug 

product. Proposed § 314.96(c) states that 

if at any time before approval of the 

ANDA, an NDA is approved for a drug 

product that is pharmaceutically 

equivalent to the product in the pending 

ANDA and that NDA is designated as an 

RLD, the applicant is not permitted to 

amend its pending ANDA to reference 

the new RLD. This change must be 

submitted in a new ANDA. As a 

preliminary matter, we note that the 

drug product designated as an RLD may 

not necessarily be the drug product 

identified in the Orange Book as the 

reference standard for bioequivalence 

studies, for example, for drug product 

lines with multiple strengths. An ANDA 

would not be ineligible for approval 

because it relied upon an RLD that was 

not the reference standard or because it 

relied upon one of two or more potential 

RLDs for a pharmaceutically equivalent 

product. FDA’s policy on designating an 

additional RLD for multiple source 

products is set forth in the preamble to 

the 1992 final rule and also described in 

the preface to the Orange Book. In the 

1992 final rule, we stated in relevant 

part: ‘‘FDA recognizes that, for multiple 

source products, a product not 

designated as the listed drug and not 

shown bioequivalent to the listed drug 

may be shielded from direct generic 

competition. If an applicant believes 

that there are sound reasons for 

designating another drug as a reference 

listed drug, it should consult FDA’’ (57 

FR 17950 at 17958; see also Letter to 

Robert W. Pollock, Lachman Consultant 

Services, Inc., dated April 18, 2005, 

regarding Docket No. FDA–2004–P– 

0466 (requesting designation of DiaBeta 

as a second RLD for glyburide tablets, 5 


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mg), available at http://

www.regulations.gov). 

The scenario described in proposed 

§ 314.96(c) arises, for example, when an 

ANDA is submitted after the grant of a 

suitability petition pursuant to section 

505(j)(2)(C) of the FD&C Act for a new 

dosage form, route of administration, or 

new active ingredient (in a drug product 

containing more than one active 

ingredient) and another applicant 

obtains approval of an NDA (including 

a 505(b)(2) application) for the change 

described in the suitability petition 

before the ANDA is approved. Under 

these circumstances, it is FDA’s 

longstanding position that an ANDA 

(including a tentatively approved 

ANDA) can no longer reference the 

approved suitability petition and the 

listed drug described therein as the 

basis for ANDA submission (see 

§§ 314.94(a)(3) and 314.127(a)(5), (a)(6), 

and (a)(12) and section II.I). Prior to 

enactment of the MMA, an applicant 

with a pending ANDA based upon an 

approved ‘‘suitability petition’’ (a 

petitioned ANDA) could have amended 

its ANDA to change the basis for 

submission (see § 314.94(a)(3)) to a 

pharmaceutically equivalent product 

that subsequently had been approved in 

an NDA and was designated by FDA as 

the RLD. However, the plain language of 

section 505(j)(2)(D)(i) of the FD&C Act 

(added by the MMA) prohibits an 

ANDA applicant from amending its 

ANDA to change the basis for 

submission to a pharmaceutically 

equivalent product subsequently 

approved in an NDA. Accordingly, for 

an ANDA applicant to obtain approval 

for a pharmaceutically equivalent 

product, the applicant would be 

required to submit a new ANDA that 

identifies the pharmaceutically 

equivalent product as its basis for 

ANDA submission under § 314.94 and 

meet applicable statutory and regulatory 

requirements (see, generally, discussion 

in the Letter from Janet Woodcock, 

M.D., Director, CDER, to Mark S. 

Aikman, Pharm.D., Osmotica 

Pharmaceutical Corp., dated November 

25, 2008, regarding Docket No. FDA– 

2008–P–0329, available at http://

www.regulations.gov) (Venlafaxine ER 

Citizen Petition Response). 

FDA’s policy is scientifically justified 

because an NDA (either a ‘‘stand-alone’’ 

NDA or 505(b)(2) application) approved 

for the change described in a suitability 

petition need not be bioequivalent to the 

listed drug identified in the suitability 

petition. For example, a 505(b)(2) 

applicant may develop a different 

dosage form of a drug product that is 

intentionally more bioavailable than a 

previously approved product (see 

§ 314.54(b)). A 505(b)(2) applicant also 

may have relied upon a different listed 

drug in support of its 505(b)(2) 

application than the listed drug 

identified in the suitability petition. By 

ensuring that an ANDA has clearly 

demonstrated bioequivalence to a 

pharmaceutically equivalent drug 

product identified as the RLD, we 

enhance the utility and accuracy of 

FDA’s therapeutic equivalence 

determinations. We previously have 

explained that ‘‘this approach reduces 

the potentially confusing proliferation 

of pharmaceutically equivalent drug 

products that have not demonstrated 

therapeutic equivalence, and ensures 

that ANDAs . . . will be therapeutically 

equivalent and thus substitutable for the 

RLD’’ (Venlafaxine ER Citizen Petition 

Response at 13). 

FDA’s requirement that an applicant 

with a pending ANDA must change its 

basis for ANDA submission upon 

approval of an NDA for the same drug 

product described in the suitability 

petition also is intended to ensure that 

ANDA applicants do not circumvent the 

patent certification requirements of 

section 505(j)(2)(A)(vii) and 

(j)(2)(A)(viii) of the FD&C Act through 

the suitability petition process. 

Otherwise, if a patent were listed for a 

drug product approved in an NDA and 

designated as the RLD and a pending 

ANDA submitted pursuant to an 

approved suitability petition were 

permitted to amend its application to 

refer to the new RLD, even a single 30- 

month stay would not be available 

should the NDA holder or patent owner 

initiate patent infringement litigation 

within the statutory timeframe in 

response to a paragraph IV certification 

for a patent listed after submission of 

the original ANDA that FDA later 

determined to be substantially 

complete. In addition, our policy 

appropriately protects any marketing 

exclusivity that has been granted to the 

newly approved RLD. 

The Agency has rejected the argument 

that a pending ANDA submitted 

pursuant to an approved suitability 

petition may continue to reference the 

listed drug identified in the suitability 

petition after a pharmaceutically 

equivalent product has been approved 

in an NDA (including a 505(b)(2) 

application) and is designated as the 

RLD (see generally Venlafaxine ER 

Citizen Petition Response). This 

‘‘reflects the Agency’s judgment that 

considerations regarding an ANDA’s 

limited reliance on an approved 

suitability petition are outweighed by 

the need for a clear determination of 

therapeutic equivalence for a generic 

drug product and protection of 

intellectual property rights accorded an 

NDA holder’’ (Venlafaxine ER Citizen 

Petition Response at 9). In section II.I, 

we describe our proposed revisions to 

§ 314.93(e) and (f) to codify FDA’s 

policy that the listed drug identified in 

an approved suitability petition can no 

longer be the basis for submission for an 

unapproved ANDA after a drug product 

is approved in an NDA for the change 

described in the petition. 

In the case of a first applicant that had 

been eligible for 180-day exclusivity 

based on a paragraph IV certification to 

a patent listed in the Orange Book for 

the listed drug described in the 

suitability petition, we note that a new 

assessment of first applicant status 

would begin upon submission of a new 

ANDA. This reflects the fact that any 

ANDA that referenced the listed drug 

identified in the suitability petition after 

approval of a pharmaceutically 

equivalent product could not be 

approved. Further, an applicant that 

withdrew its ANDA would not have 

lawfully maintained its paragraph IV 

certification and would no longer be 

eligible for first applicant status. 

II.G.1.b. Changes to the drug product 

proposed in the ANDA. The second 

example in proposed § 314.96(c) that 

illustrates the application of this 

provision involves one or more changes 

proposed in an amendment to an ANDA 

that would result in the proposed 

product being a pharmaceutical 

equivalent to a different listed drug than 

the RLD identified in the ANDA. This 

type of change must be submitted in a 

new ANDA that identifies the 

pharmaceutically equivalent product as 

the new RLD. In the Draft Guidance on 

Listed Drugs, we explained that ‘‘[a]ll 

changes that would have the effect of 

seeking approval for a drug product 

different from the listed drug cited in 

the initial submission (e.g., different 

active ingredient, dosage form, route of 

administration) should be made in a 

new application. When the Orange Book 

identifies as a separate listed drug a 

product with the characteristics (e.g., 

active ingredient, dosage form, route of 

administration) for which the applicant 

is seeking approval, the applicant 

should submit a separate ANDA 

referencing the corresponding listed 

drug’’ (Draft Guidance on Listed Drugs, 

at 3). This generally conforms with 

Agency practice before passage of the 

MMA with respect to certain types of 

changes (e.g., a change in the dosage 

form or a change in the formulation that 

may significantly affect absorption of 

the active drug ingredient or active 

moiety) that should be submitted as a 

separate ANDA (see guidance for 

industry entitled ‘‘Variations in Drug 


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Products that May Be Included in a 

Single ANDA’’ (December 1998), 

available at http://www.fda.gov/

downloads/Drugs/GuidanceCompliance

RegulatoryInformation/Guidances/

UCM072892.pdf) (Guidance on Drug 

Product Variations). For example, we 

noted ‘‘[g]enerally, when there is a 

separate NDA as a RLD for a specific 

drug product there should be a separate 

abbreviated application for that NDA’’ 

(Guidance on Drug Product Variations, 

at 2). 

Proposed § 314.96(c) clarifies that, 

notwithstanding these restrictions on 

amendments to an ANDA, an applicant 

is permitted to amend an ANDA to seek 

approval for a different strength of the 

drug product (see section 505(j)(2)(D)(ii) 

of the FD&C Act). As discussed in 

section II.A.2.bb, we interpret this 

exception for different strengths of the 

drug product to include changes to the 

concentration or to the total drug 

content of a parenteral drug product. We 

note that, unlike original ANDAs, not all 

amendments are subject to a filing 

review by the Office of Generic Drugs to 

determine whether the submission may 

be formally received for substantive 

review. Accordingly, it is possible that 

an ANDA applicant that submits an 

amendment not permitted by statute 

may be informed late in the review 

process that the proposed change to its 

ANDA must be submitted as a new 

ANDA. We encourage ANDA applicants 

with questions about whether a 

proposed amendment to an ANDA 

would be precluded by section 

505(j)(2)(D)(i) of the FD&C Act to 

contact the Office of Generic Drugs for 

further guidance. 

II.G.2. Supplements to an ANDA 

(Proposed § 314.97(b)) 

We are proposing to revise § 314.97 

regarding supplements by designating 

the current text as paragraph (a) and by 

adding proposed paragraph (b) to 

implement section 505(j)(2)(D)(i) and (ii) 

of the FD&C Act. Proposed § 314.97(b) 

explains that an applicant may not 

supplement an ANDA to seek approval 

of a drug referring to a listed drug that 

is different from the current RLD 

identified in the ANDA. This restriction 

applies if changes are proposed in a 

supplement to the ANDA that would 

result in the proposed product being 

pharmaceutically equivalent to a 

different listed drug than the RLD 

identified in the underlying ANDA. 

This type of change must be submitted 

in a new ANDA that identifies the 

pharmaceutically equivalent product as 

the new RLD. 

There are several types of changes 

that may be proposed in a supplement 

to an ANDA that would result in the 

proposed product being 

pharmaceutically equivalent to a 

different listed drug than the RLD 

identified in the underlying ANDA. For 

example, the scenario described in 

proposed § 314.97(b) may arise if the 

RLD for the drug product approved in 

an ANDA is subsequently changed from 

prescription use to OTC status for some 

or all conditions of use of the drug 

product. An ANDA holder for the drug 

product with the ‘‘switched’’ conditions 

of use would be required to seek 

approval of the drug product for OTC 

use because the FD&C Act does not 

permit a drug product to be marketed as 

prescription and OTC for the same 

conditions of use at the same time (see 

section 503(b) of the FD&C Act (21 

U.S.C. 353(b)). However, if the NDA 

holder for the RLD obtained approval of 

the switch from prescription use to OTC 

status in a separate NDA (for example, 

if fewer than all conditions of use were 

switched to OTC status), then the NDA 

for OTC use would be considered a 

different RLD. Section 505(j)(2)(D)(i) of 

the FD&C Act does not permit an ANDA 

holder to refer to a different RLD in a 

supplement (or, with respect to a 

pending ANDA, an amendment) to its 

ANDA. This type of change must be 

submitted in a new ANDA that 

identifies the different NDA for OTC use 

as the RLD. 

We note, however, that an ANDA 

holder may submit a supplement that 

seeks to demonstrate bioequivalence to 

a different listed drug when there are 

multiple RLDs (see, e.g., Orange Book, 

33rd Edition (2013) at xx to xxi 

(Description of Special Situations— 

levothyroxine sodium)). In this case, the 

submission of additional bioequivalence 

data in an ANDA supplement is not for 

the purpose of seeking approval of a 

drug referring to a different RLD, but 

rather to obtain an additional 

therapeutic equivalence rating. This 

type of change may continue to be 

submitted as a supplement to an ANDA. 

Proposed § 314.97(b) clarifies that, 

notwithstanding these restrictions on 

supplements to an ANDA, an applicant 

is permitted to supplement an ANDA to 

seek approval for a different strength of 

the drug product (see section 

505(j)(2)(D)(ii) of the FD&C Act). As 

discussed in section II.G.1.b, we 

interpret this exception for different 

strengths of the drug product to include 

changes to the concentration or to the 

total drug content of a parenteral drug 

product (see also section II.A.2.bb). 

II.G.3. Amendments to an Unapproved 

505(b)(2) Application (Proposed 

§ 314.60(e)) 

We are proposing to revise § 314.60 

regarding amendments to an 

unapproved 505(b)(2) application by 

adding proposed paragraph (e) to 

implement section 505(b)(4)(A) and 

(b)(4)(B) of the FD&C Act. Proposed 

§ 314.60(e) states that an applicant may 

not amend a 505(b)(2) application to 

seek approval of a drug that is a 

different drug from the drug in the 

original submission of the 505(b)(2) 

application. For purposes of this 

section, a drug is a different drug if it 

has been modified to have a different 

active ingredient, different route of 

administration, different dosage form, or 

difference in excipients that requires 

either a separate clinical study to 

establish safety or effectiveness or, for 

topical products, that requires a separate 

in vivo demonstration of 

bioequivalence. 

II.G.3.a. Applications within the scope 

of section 505(b)(4)(A) of the FD&C Act. 

Section 505(b)(4)(A) of the FD&C Act 

restricts certain types of amendments 

and supplements to a 505(b)(2) 

application. We interpret this statutory 

provision to apply to an NDA that was 

submitted as a 505(b)(2) application and 

to an NDA that was submitted as a 

stand-alone 505(b)(1) application but 

was misclassified by the applicant. A 

stand-alone 505(b)(1) application would 

be misclassified if, for example, the 

application relied, at least in part, on 

the Agency’s finding of safety and/or 

effectiveness for one or more listed 

drugs or published literature. Such an 

NDA is considered to be a 505(b)(2) 

application even if the applicant failed 

to identify the listed drug(s) in 

accordance with § 314.54(a)(1)(iii) and 

comply with applicable regulatory 

requirements. It would be inconsistent 

with the statutory scheme, as amended 

by the MMA, to permit an applicant to 

circumvent the restrictions on 

amendments to a 505(b)(2) application 

and the potential implications for the 

availability of a 30-month stay of 

approval pursuant to section 

505(c)(3)(C) of the FD&C Act merely by 

incorrectly characterizing the original 

submission as a stand-alone 505(b)(1) 

application. 

We note, however, that reliance on a 

listed drug pursuant to section 505(b)(2) 

of the FD&C Act generally assumes that 

the drug the applicant is referencing is 

one for which it is not the application 

holder and for which it would not have 

a right of reference or use. Accordingly, 

an applicant that cross-references 

relevant studies in its own previous 


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505(b)(2) application (i.e., studies that 

were conducted by or for the applicant 

or to which the applicant has obtained 

a right of reference or use) would not be 

a 505(b)(2) applicant as to those 

portions of its previous 505(b)(2) 

application. However, an applicant may 

be relying, in part, for approval of its 

current NDA upon the Agency’s finding 

of safety and/or effectiveness for a listed 

drug identified in its previous 505(b)(2) 

application, to which it does not have 

a right of reference or use. In this 

scenario, if an applicant continues to 

rely upon the original listed drug for 

approval of its current NDA, then it is 

a 505(b)(2) application and the 

applicant must identify the original 

listed drug in accordance with § 314.54 

and comply with other applicable 

regulatory requirements. 

An applicant also may not amend a 

literature-based 505(b)(2) application to 

seek approval of a drug that has been 

modified to have a different active 

ingredient, different route of 

administration, different dosage form, or 

difference in excipients that requires 

either a separate clinical study to 

establish safety or effectiveness or, for 

topical products, that requires a separate 

in vivo demonstration of 

bioequivalence. 

II.G.3.b. Proposed amendments 

subject to section 505(b)(4)(A) of the 

FD&C Act. Proposed § 314.60(e) 

provides that the statutory restriction on 

amending a 505(b)(2) application to seek 

approval of a drug that is a different 

drug from the drug in the original 

submission of the 505(b)(2) application 

applies to any proposed amendment, 

even if the amendment is submitted 

prior to the Agency’s decision regarding 

whether the 505(b)(2) application can be 

filed in accordance with § 314.101(a). 

This standard is consistent with the 

MMA’s amendments to section 

505(c)(3)(C) of the FD&C Act to limit the 

availability of a 30-month stay of 

approval to patents for which the NDA 

holder submitted information to FDA 

‘‘before the date on which the 

application (excluding an amendment 

or supplement to the application) was 

submitted.’’ 

Under proposed § 314.60, an 

applicant cannot amend a 505(b)(2) 

application to seek approval for a drug 

that has been modified to have a 

different active ingredient. This 

includes, but is not limited to, a 

different salt, ester, or complex of the 

same active moiety (compare section 

II.F.1.d). A change in the route of 

administration or dosage form also 

cannot be made in an amendment to a 

505(b)(2) application unless the product 

is qualitatively (Q1) the same and 

quantitatively (Q2) essentially the same 

as the proposed drug product in the 

original 505(b)(2) application for all 

routes of administration or dosage 

forms, as applicable. 

An applicant also cannot amend a 

505(b)(2) application to seek approval 

for a drug that has been modified to 

have a difference in excipients that 

requires either a separate clinical study 

to establish safety or effectiveness or, for 

topical products, that requires a separate 

in vivo demonstration of bioequivalence 

(see § 320.24(b)(4)). These proposed 

modifications would result in a different 

drug for which approval must be 

requested in a new 505(b)(2) 

application. 

However, notwithstanding these 

restrictions on amendments to a 

505(b)(2) application, an applicant is 

permitted to amend a 505(b)(2) 

application to identify a new or 

additional listed drug upon which the 

application relies for approval. 

In addition, proposed § 314.60(e) 

clarifies that an applicant is permitted 

to amend a 505(b)(2) application to seek 

approval for a different strength of the 

drug product (see section 505(b)(4)(B) of 

the FD&C Act; see also sections II.A.2.bb 

and II.G.1.b of this document). 

II.G.4. Supplements to a 505(b)(2) 

Application (Proposed § 314.70(h)) 

We are proposing to revise § 314.70 

regarding supplements to an approved 

505(b)(2) application by adding 

proposed paragraph (h) to implement 

section 505(b)(4)(A) and (b)(4)(B) of the 

FD&C Act. Proposed § 314.70(h) states 

that an applicant may not supplement a 

505(b)(2) application to seek approval of 

a drug that is a different drug from the 

drug in the original submission of the 

505(b)(2) application. For purposes of 

this section, a drug is a different drug if 

it has been modified to have a different 

active ingredient, different route of 

administration, different dosage form, or 

difference in excipients that requires 

either a separate clinical study to 

establish safety or effectiveness or, for 

topical products, that requires a separate 

in vivo demonstration of bioequivalence 

(see discussion in section II.G.3.b). 

These proposed modifications would 

result in a different drug for which 

approval must be requested in a new 

505(b)(2) application. 

In addition, proposed § 314.70(h) 

clarifies that, notwithstanding these 

restrictions on supplements to a 

505(b)(2) application, an applicant is 

permitted to supplement a 505(b)(2) 

application to seek approval for a 

different strength of the drug product 

(see section 505(b)(4)(B) of the FD&C 

Act; see also sections II.A.2.bb and 

II.G.1.b of this document). 

We interpret section 505(b)(4)(A) of 

the FD&C Act to apply to the 

submission of a 505(b)(2) supplement to 

an NDA approved through the 505(b)(2) 

pathway, irrespective of whether the 

original 505(b)(2) application relied 

upon published literature or the 

Agency’s finding of safety and/or 

effectiveness for one or more listed 

drugs. However, because the statutory 

text expressly applies to a supplement 

to a 505(b)(2) application, we do not 

interpret the restriction in section 

505(b)(4)(A) to apply to a 505(b)(2) 

supplement to an NDA that received 

approval as a stand-alone 505(b)(1) 

application unless an intervening 

505(b)(2) supplement has been 

approved for that NDA (see § 314.3(b) 

(defining the term ‘‘application’’ to 

include all supplements to the 

application)). 

II.H. Procedure for Submission of an 

Application Requiring Investigations for 

Approval of a New Indication for, or 

Other Change From, a Listed Drug 

(Proposed § 314.54) 

We are proposing to revise 

§§ 314.50(i), 314.54(a), and 314.125(b) to 

establish the requirement that an 

applicant identify a pharmaceutically 

equivalent product, if already approved, 

as a listed drug relied upon to support 

approval of a 505(b)(2) application. 

FDA’s longstanding policy has been 

that a 505(b)(2) applicant may rely on 

FDA’s finding of safety and/or 

effectiveness for a listed drug only to the 

extent that the proposed product in the 

505(b)(2) application shares 

characteristics (e.g., active ingredient, 

dosage form, route of administration, 

strength, indication, conditions of use) 

in common with the listed drug. To the 

extent that the listed drug and the drug 

proposed in the 505(b)(2) application 

differ, the 505(b)(2) application must 

include sufficient data to demonstrate 

that the proposed drug meets the 

statutory approval standard for safety 

and effectiveness. The 505(b)(2) 

approval pathway is not intended for a 

‘‘duplicate’’ of a listed drug that is 

eligible for approval in an ANDA, and 

FDA would refuse to file such a 

505(b)(2) application (see 

§ 314.101(d)(9)). The Hatch-Waxman 

Amendments established a specific 

abbreviated approval pathway for 

duplicates of a listed drug in section 

505(j) of the FD&C Act. 

However, there are circumstances in 

which a proposed drug product that is 

pharmaceutically equivalent to a listed 

drug (i.e., drug products in the same 

dosage form and route(s) of 


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administration that contain the same 

amount of the same active drug 

ingredient and that meet other 

applicable standards) is not eligible for 

approval as an ANDA and must be 

submitted as an NDA. For example, a 

proposed extended-release drug product 

may intentionally differ in its 

pharmacokinetic profile from a listed 

drug that is also an extended-release 

drug product such that the proposed 

product cannot meet the bioequivalence 

requirement for ANDAs (see section 

505(j)(2)(A)(iv) of the FD&C Act; 

compare § 314.54(b)). Certain drug 

products intended for parenteral, 

ophthalmic, otic, or topical use may 

contain differences in excipients that 

render the drug product ineligible for 

submission in an ANDA (see 

§ 314.94(a)(9)(iii) to (a)(9)(v)). For 

certain complex drug products, an 

applicant may be unable to demonstrate 

‘‘sameness’’ of the active ingredient as 

required for submission of an ANDA 

(see section 505(j)(2)(A)(ii) of the FD&C 

Act). A request for approval of a new 

indication for a pharmaceutically 

equivalent drug product also is 

ineligible for submission as an ANDA. 

These changes to a listed drug must be 

submitted in an NDA. 

We have explained that a 505(b)(2) 

applicant may rely on FDA’s finding of 

safety and effectiveness for a listed drug 

‘‘only to the extent that such reliance 

would be allowed under section 505(j) 

of the act’’ (1989 proposed rule, 54 FR 

28872 at 28892). If a pharmaceutically 

equivalent drug product has been 

approved before a 505(b)(2) application 

is submitted, then we consider the 

505(b)(2) applicant to be implicitly 

relying on the approval of such drug 

product. We are proposing to revise 

§ 314.54(a)(1)(iii) to require that the 

listed drug or drugs identified as relied 

upon by a 505(b)(2) applicant must 

include any approved drug product that: 

(1) Is pharmaceutically equivalent to the 

drug product for which the 505(b)(2) 

application is submitted and (2) was 

approved before the 505(b)(2) 

application was submitted. This 

requirement is intended to help ensure 

that the 505(b)(2) pathway is not used 

to circumvent the statutory obligation 

that would have applied if the proposed 

product was submitted as an ANDA— 

namely, submission of a patent 

certification for a listed patent that 

corresponds to the protected aspects of 

the pharmaceutically equivalent listed 

drug (see draft guidance for industry 

entitled ‘‘Applications Covered by 

Section 505(b)(2)’’ (October 1999), 

available at http://www.fda.gov/

downloads/Drugs/GuidanceCompliance

RegulatoryInformation/Guidances/

ucm079345.pdf) (‘‘If there is a listed 

drug that is the pharmaceutical 

equivalent of the drug proposed in the 

505(b)(2) application, the 505(b)(2) 

applicant should provide patent 

certifications for the patents listed for 

the pharmaceutically equivalent drug’’). 

Clarifying revisions in proposed 

§ 314.54(a)(1)(iii) and (a)(1)(vi) replace 

the reference to ‘‘other drugs’’ with 

‘‘listed drug’’ to conform with our 

longstanding policy that an applicant 

may rely upon more than one listed 

drug to support approval of a 505(b)(2) 

application. In addition, we are 

proposing to replace the term ‘‘reference 

listed drug’’ in § 314.54(b) with ‘‘listed 

drug’’ because the descriptor ‘‘reference 

listed drug’’ is a term of art that applies 

to an ANDA. A 505(b)(2) application 

may rely on FDA’s finding of safety and/ 

or effectiveness for one or more listed 

drugs. 

We also are proposing to add 

§ 314.50(i)(1)(i)(C) to require that if, 

before the date of submission of the 

505(b)(2) application, there is an 

approved drug product that is 

pharmaceutically equivalent to the drug 

product for which the 505(b)(2) 

application is submitted, the applicant 

must submit an appropriate patent 

certification under § 314.50(i) with 

respect to each patent listed for the 

pharmaceutically equivalent product 

that claims the drug substance or drug 

product or that claims an approved use 

for such drug. 

We are proposing a conforming 

revision to § 314.125(b) to state that we 

may refuse to approve a 505(b)(2) 

application based on the applicant’s 

failure to submit an appropriate patent 

certification or statement with respect to 

each listed patent for a drug product 

that: (1) Is pharmaceutically equivalent 

to the drug product for which the 

505(b)(2) application is submitted and 

(2) was approved before the 505(b)(2) 

application was submitted. If FDA 

approves a pharmaceutically equivalent 

product within the 60-day filing review 

period after a 505(b)(2) application is 

submitted, the 505(b)(2) applicant is not 

required to identify the product as a 

listed drug relied upon or submit a 

patent certification under § 314.50(i) 

and FDA would not refuse to file the 

application under § 314.101(d)(9) based 

on the new approval. 

It also should be noted that the 

requirement to identify a 

pharmaceutically equivalent product as 

a listed drug relied upon (and to submit 

an appropriate patent certification or 

statement with respect to each listed 

patent) does not apply if a 

pharmaceutically equivalent product is 

approved while the 505(b)(2) 

application is pending. 

We intend to promptly publish on 

FDA’s Web site information regarding 

the approval of new drug products to 

facilitate, among other things, a 

505(b)(2) applicant’s compliance with 

proposed § 314.54(a)(1)(iii) and (a)(1)(vi) 

and § 314.50(i)(1)(i)(C). 

II.I. Petition To Request a Change From 

a Listed Drug (Proposed § 314.93) 

We are proposing to amend § 314.93 

regarding petitioned ANDAs to codify 

FDA’s policy that the listed drug 

identified in an approved suitability 

petition can no longer be the basis for 

submission for an unapproved ANDA 

after a drug product is approved in an 

NDA for the change described in the 

petition (see generally Venlafaxine ER 

Citizen Petition Response). This 

proposed revision is intended to 

facilitate implementation of section 

505(j)(2)(D)(i) and (ii) of the FD&C Act 

and complement proposed revisions to 

§ 314.96(c) regarding amendments to an 

unapproved ANDA (see section II.F.1.a). 

We are proposing to revise § 314.93(f) 

regarding withdrawal of approval of a 

suitability petition by redesignating the 

current text as paragraph (f)(1) and by 

adding paragraph (f)(2). Proposed 

§ 314.93(f)(2) clarifies that if, after 

approval of a petition and before 

approval of an ANDA submitted 

pursuant to the approved petition, a 

drug product is approved in an NDA for 

the change described in the petition, the 

petition and the listed drug identified in 

the petition can no longer be the basis 

for ANDA submission, irrespective of 

whether FDA has withdrawn approval 

of the petition. Because an ANDA 

applicant may not amend its ANDA to 

change the basis for submission to the 

new RLD (see section 505(j)(2)(D)(i) of 

the FD&C Act), a person seeking 

approval for such drug product would 

be required to submit a new ANDA that 

identifies the pharmaceutically 

equivalent RLD as the basis for ANDA 

submission and comply with applicable 

statutory and regulatory requirements. 

We also are proposing to add 

§ 314.93(e)(1)(vi) to codify our 

longstanding policy that FDA will not 

approve a suitability petition if a drug 

product is approved in an NDA for the 

change described in the petition. The 

suitability petition process is intended 

for a proposed ‘‘drug product which is 

not identical to a listed drug in route of 

administration, dosage form, and 

strength, or in which one active 

ingredient is substituted for one of the 

active ingredients in a listed 

combination drug’’ (§ 314.93(b)). If a 

pharmaceutically equivalent drug 


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product has been approved in an NDA, 

the ANDA applicant should refer to the 

approved pharmaceutical equivalent 

designated by the Agency as the RLD as 

its basis for ANDA submission. 

Throughout the pendency of review of 

the ANDA, applicants should confirm 

that an NDA has not been approved for 

the drug product described in the 

suitability petition. 

Although FDA currently has the 

authority to withdraw approval of a 

suitability petition after a drug product 

is approved in an NDA for the change 

described in the petition, we note that 

it has been the Agency’s practice not to 

rescind approval of the petition under 

these circumstances due to the 

administrative burden. We previously 

have explained: ‘‘we need not withdraw 

approval of the suitability petition to 

implement our long-standing practice 

that the intervening approval of an NDA 

for the product described by the 

suitability petition precludes an ANDA 

applicant from referring to the 

suitability petition and listed drug 

described therein as its basis for ANDA 

submission. Any pending ANDA that 

referred to the suitability petition and 

the listed drug described therein would 

not be eligible for approval, and any 

newly submitted ANDA that sought to 

reference the suitability petition instead 

of the RLD identified in the Orange 

Book would not be received by the 

Agency’’ (Venlafaxine ER Citizen 

Petition Response at 25). To ensure that 

our regulations consistently reflect this 

policy, we are proposing to add 

§ 314.127(a)(14) to state that FDA will 

refuse to approve a petitioned ANDA if 

an NDA subsequently has been 

approved for the change described in 

the suitability petition. 

II.J. Filing an NDA and Receiving an 

ANDA (Proposed § 314.101) 

II.J.1. Notification of Filing of a 505(b)(2) 

Application or Receipt of an ANDA 

We are proposing to amend § 314.101, 

with respect to 505(b)(2) applications 

and ANDAs that contain a paragraph IV 

certification, to facilitate 

implementation of the MMA’s timing 

requirements for sending notice of a 

paragraph IV certification and for 

efficient enforcement of the FD&C Act. 

Section 505(b)(3)(B)(i) and 

(j)(2)(B)(ii)(I) of the FD&C Act require a 

505(b)(2) or ANDA applicant, 

respectively, to send notice of a 

paragraph IV certification within 20 

days after the date of the postmark on 

the notice with which FDA informs the 

applicant that the 505(b)(2) application 

has been filed or the ANDA has been 

received (see section II.D.1). Our 

proposed revisions to § 314.101(a)(2) 

and (b)(2) clarify that FDA will notify 

the applicant that the 505(b)(2) 

application is regarded as filed or the 

ANDA is regarded as received, 

respectively, by means of an 

acknowledgment letter or a paragraph 

IV acknowledgment letter (see also 

section II.A.2.c and II.A.2.u). 

We are proposing to revise 

§ 314.101(b)(1) and (b)(2) regarding 

ANDAs to incorporate the statutory 

definition of a ‘‘substantially complete 

application,’’ which was added by the 

MMA for purposes of section 505(j)(5) of 

the FD&C Act (see section 

505(j)(5)(B)(iv)(II)(cc) of the FD&C Act 

and section II.A.2.cc of this document). 

Proposed § 314.101(b)(1) states that 

receipt of an ANDA means that FDA has 

made a threshold determination that the 

ANDA is substantially complete. We 

also are proposing to revise proposed 

§ 314.101(b)(2) to clarify that if an 

ANDA is determined to have been 

substantially complete as of the date on 

which it was submitted, the date of 

submission is considered to be the date 

of receipt. As noted in section II.A.2.cc, 

our proposed replacement of the current 

standard ‘‘sufficiently complete to 

permit a substantive review’’ with the 

phrase ‘‘substantially complete 

application’’ is not intended to alter the 

meaning. Rather, we are seeking to 

consistently use defined terms 

throughout our regulations. 

We are proposing to amend 

§ 314.101(b)(3) to remove the method of 

notification by which FDA will advise 

an ANDA applicant that FDA has 

refused to receive the ANDA under 

§ 314.101(d) or (e). The regulations 

currently state that FDA will ordinarily 

notify an ANDA applicant by telephone; 

however, this does not accurately 

describe FDA’s current practice to 

inform the ANDA applicant in writing 

by issuing a ‘‘refuse to receive’’ letter. 

In proposed § 314.101(b)(4), we 

establish an administrative consequence 

for an ANDA applicant that fails to 

timely provide notice of a paragraph IV 

certification as required by section 

505(j)(2)(B)(ii) of the FD&C Act and 

§ 314.95(b) and (d). If FDA determines 

that an ANDA applicant did not send 

notice of a paragraph IV certification 

within the timeframe described in 

§ 314.95(b) or (d), as applicable, FDA 

will deem the date that the ANDA was 

submitted to be delayed by the number 

of days by which the timeframe for 

sending notice of a paragraph IV 

certification was exceeded. As 

discussed in section II.D.5, an ANDA 

applicant that fails to provide timely 

notice of a paragraph IV certification 

may, based upon the revised date on 

which the ANDA was determined to 

have been received, lose its first 

applicant status and thus its eligibility 

for 180-day exclusivity. In addition, 

such an ANDA may be repositioned in 

the review queue consistent with the 

revised date of ANDA submission. 

II.J.2. Other Proposed Revisions 

We are proposing several clarifying 

revisions to § 314.101. First, we are 

proposing to delete the reference to 

section 507 of the FD&C Act in 

§ 314.101(d)(3). As discussed in section 

II.A.2.b, FDAMA repealed section 507 of 

the FD&C Act under which marketing 

applications, including abbreviated 

applications, for antibiotics had been 

approved (see section 125 of FDAMA). 

Section 125(d) of FDAMA provided that 

abbreviated applications for antibiotics 

previously approved under section 507 

of the FD&C Act would be deemed 

approved under section 505(j) of the 

FD&C Act. 

Second, we are proposing to replace 

the term ‘‘application’’ in 

§ 314.101(d)(6) and (d)(7) with ‘‘NDA 

and ANDA’’ to clarify that these 

provisions apply to ANDAs as well as 

NDAs. As discussed in section II.A.2.b 

and II.A.2.i, we have proposed to 

incorporate the commonly used 

acronyms NDA and ANDA in place of 

the terms application and abbreviated 

application, as appropriate, throughout 

the sections of part 314 and part 320 in 

this rulemaking. Proposed 

§ 314.101(d)(6) states that FDA may 

refuse to file an NDA or may not 

consider an ANDA to be received if the 

NDA or ANDA does not contain a 

statement for each nonclinical 

laboratory study regarding compliance 

with the requirements of part 58 of this 

chapter. This criterion is applicable to 

ANDAs as well as NDAs. Nonclinical 

studies submitted in an ANDA may 

include, but are not limited to, 

dissolution studies and ‘‘dosedumping’’ studies. Proposed 

§ 314.101(d)(7) provides that FDA may 

refuse to file an NDA or may not 

consider an ANDA to be received if the 

NDA or ANDA does not contain a 

statement for each clinical study 

regarding whether it was conducted in 

compliance with the regulations in part 

50 and part 56 of this chapter. Clinical 

studies submitted in an ANDA which 

may be subject to the regulations in part 

50 and part 56 of this chapter include, 

for example, comparative clinical trials 

conducted for the purpose of 

demonstrating bioequivalence (see 

§ 320.24(b)(4); see also 

§ 314.94(a)(7)(iii)). 

Third, we are proposing to replace the 

current text of § 314.101(e)(2) with a 


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statement that FDA will refuse to file a 

505(b)(2) application or will consider an 

ANDA not to have been received if 

submission of a 505(b)(2) application or 

an ANDA for the active moiety is not 

permitted under § 314.108(b)(2). This is 

not a substantive revision, as 

§ 314.108(b)(2) describes the conditions 

set forth in current § 314.101(e)(2)(i) and 

(e)(2)(ii). 

We also propose to add headings to 

certain paragraphs for administrative 

convenience. 

II.K. Approval of an NDA and ANDA 

(Proposed § 314.105) 

We are proposing to revise 

§ 314.105(a) and (d) regarding approval 

of an NDA (including a 505(b)(2) 

application) and an ANDA to remove 

the references to a ‘‘delayed effective 

date’’ and clarify that an application is 

approved on the date of issuance of an 

approval letter. These proposed 

revisions reflect current FDA practice 

and policy with respect to approval 

letters. The Agency does not issue 

approval letters with delayed effective 

dates. Rather, the Agency will issue a 

tentative approval letter when an NDA 

or ANDA that is otherwise eligible for 

approval cannot be approved due to 

unexpired patents, certain 

circumstances related to patent 

litigation (see § 314.107(b)(3) and 

(e)(1)(vi)), or various types of exclusivity 

(see proposed § 314.107(b)(1)(iii), (c) 

and (d)). ‘‘Tentative approval’’ is 

defined in proposed § 314.3. We also 

have made conforming revisions 

throughout this proposed rulemaking to 

replace references to the ‘‘effective date’’ 

of an application with language 

reflecting our current practice. 

A drug product granted tentative 

approval is not an approved drug. Prior 

to obtaining approval of a 505(b)(2) 

application or ANDA, the applicant may 

be requested to submit updated labeling; 

chemistry, manufacturing, and controls 

(CMC) data; a safety update; and any 

other information necessary to ensure 

that the 505(b)(2) application or ANDA 

meets the statutory and regulatory 

requirements for approval. For a 

505(b)(2) application or ANDA to be 

approved, the applicant must receive an 

approval letter from FDA (see proposed 

§ 314.107(b)(4)). 

We note that an applicant with a 

tentatively approved 505(b)(2) 

application or ANDA has a continuing 

obligation to amend its patent 

certification or statement if, at any time 

before approval of the 505(b)(2) 

application or ANDA, the submitted 

certification is no longer accurate (see 

proposed §§ 314.50(i)(6) and 

314.94(a)(12)(viii)). In the context of a 

tentatively approved application, this 

obligation may apply, for example, if the 

NDA holder for the listed drug relied 

upon or RLD timely submits new patent 

information for a patent that claims the 

drug substance, drug product, or a 

method of use after the 505(b)(2) 

application or ANDA has been 

tentatively approved. In this scenario, 

the 505(b)(2) or ANDA applicant would 

be required to submit an amendment to 

its tentatively approved application 

with an appropriate patent certification 

or statement regarding the newly listed 

patent. 

The applicant with a tentatively 

approved application also may need to 

update the draft product labeling to 

incorporate relevant revisions to the 

labeling of the listed drug relied upon 

or RLD made after the tentative approval 

of the 505(b)(2) application or ANDA, 

respectively. This caveat is particularly 

relevant for an ANDA, which is required 

by statute to have, among other things, 

the same labeling and conditions of use 

as the RLD (see section 505(j)(2)(A)(i) 

and (j)(2)(A)(v) of the FD&C Act; 

compare section 505(j)(10) of the FD&C 

Act), unless the ANDA applicant is not 

seeking approval for an indication or 

other aspect of labeling protected by 

patent or accorded exclusivity under 

section 505(j)(4)(D) of the FD&C Act (see 

§ 314.94(a)(8)(iv); see also section 

505(j)(2)(A)(viii) of the FD&C Act). In 

addition, a tentatively approved ANDA 

for a drug product intended for 

parenteral, ophthalmic, otic, or topical 

use that is required to contain the same 

inactive ingredients in the same 

concentration as the RLD, subject to 

exceptions specified in 

§ 314.94(a)(9)(iii) through (a)(9)(v), may 

be required to modify its drug product 

and amend its ANDA to address certain 

changes in the formulation of the RLD 

subsequent to tentative approval unless 

FDA has made a determination that the 

RLD was not withdrawn from sale for 

reasons of safety or effectiveness (see 

§§ 314.122 and 314.161; see also 

discussion in section II.L). 

In addition, we are proposing to 

revise § 314.105(a) and (d) to expressly 

state that FDA’s tentative approval of a 

drug product is based on information 

available to FDA at the time of the 

tentative approval letter (i.e., 

information in the 505(b)(2) application 

or ANDA and the status of current good 

manufacturing practices of the facilities 

used in the manufacturing and testing of 

the drug product) and is therefore 

subject to change on the basis of new 

information that may come to FDA’s 

attention. 

Finally, it should be noted that a 

tentatively approved application is 

subject to any applicable period of 

marketing exclusivity granted to the 

listed drug relied upon (for a 505(b)(2) 

application) or RLD (for an ANDA) after 

tentative approval. For example, 

approval of a tentatively approved 

application may be delayed by the 

intervening grant, pursuant to section 

505A of the FD&C Act, of a period of 

pediatric exclusivity to the NDA holder 

for the listed drug relied upon or RLD 

after tentative approval of the 505(b)(2) 

application or ANDA, respectively (see, 

e.g., Barr Labs., Inc. v. Thompson, 238 

F. Supp. 2d 236 (D.D.C. 2002) 

(upholding FDA’s determination that a 

6-month period of pediatric exclusivity 

that had attached to a listed patent for 

which a paragraph III certification had 

been submitted applied to a tentatively 

approved application)). 

II.L. Refusal to Approve an NDA or 

ANDA (Proposed §§ 314.125 and 

314.127 and Related Provisions in 

Proposed §§ 314.90 and 314.99) 

We are proposing to revise §§ 314.90 

and 314.99 to clarify the effect of FDA’s 

grant of an applicant’s request for 

waiver of a requirement under §§ 314.50 

through 314.81 or §§ 314.92 through 

314.99, respectively. If FDA grants such 

a request, the applicant’s failure to 

comply with the requirement that is the 

subject of the waiver request will not 

constitute a basis for refusal to approve 

the NDA under § 314.125 or the ANDA 

under § 314.127, as applicable. We also 

are proposing corresponding revisions 

to §§ 314.125(b) and 314.127(a), which 

address permissive refusal to approve 

an NDA and mandatory refusal to 

approve an ANDA, respectively. 

Proposed § 314.125(b) states that FDA 

may refuse to approve an NDA for any 

of the following reasons listed, unless 

the requirement has been waived 

pursuant to § 314.90. Proposed 

§ 314.127(a) states that FDA will refuse 

to approve an ANDA for a new drug 

under section 505(j) of the FD&C Act for 

any of the following reasons listed, 

unless the requirement has been waived 

pursuant to § 314.99. 

Sections 314.90 and 314.99 currently 

provide that an NDA or ANDA 

applicant may ask FDA to waive any 

requirement that applies to the 

applicant under §§ 314.50 through 

314.81 or §§ 314.92 through 314.99, 

respectively. FDA has interpreted its 

waiver of a submission requirement 

under these provisions to carry with it 

the implicit waiver of any 

corresponding approval requirement 

under §§ 314.125 or 314.127. Otherwise, 

the waiver of a submission requirement 

for an NDA or ANDA would be 

meaningless if there was a parallel 


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requirement under §§ 314.125 or 

314.127, respectively, for approval of 

the application. 

The proposed revisions to §§ 314.90 

and 314.99, and corresponding 

proposed revisions to proposed 

§§ 314.125 and 314.127, codify FDA’s 

approach to this issue. For example, 

FDA has relied on § 314.99(b) to grant 

a waiver of the requirement that the 

formulation of a drug product intended 

for parenteral use contain the same 

inactive ingredients in the same 

concentration as the RLD, with limited 

exceptions for preservatives, buffers, 

and antioxidants, where the formulation 

proposed by the ANDA applicant had 

previously been approved by FDA as 

safe and effective. We note that FDA 

may not waive a statutory requirement 

(see 1989 Proposed Rule, 54 FR 28872 

at 28889). 

II.M. Date of Approval of a 505(b)(2) 

Application or ANDA (Proposed 

§ 314.107) 

Section 314.107 establishes the 

earliest date on which a 505(b)(2) 

application or ANDA may be approved 

in light of the statutory provisions that 

can delay the approval of an application 

that is otherwise eligible for approval. 

Approval of a 505(b)(2) application or 

ANDA can be delayed by the marketing 

exclusivity granted to another drug 

product under section 505(c)(3)(E) and 

(j)(5)(F) of the FD&C Act (and, with 

respect to ANDAs, section 

505(j)(5)(B)(iv) of the FD&C Act for 180- 

day exclusivity) or pediatric exclusivity 

under section 505A of the FD&C Act 

that may attach to a patent listed for a 

drug product. Approval of a 505(b)(2) 

application or ANDA also can be 

delayed by a 30-month stay of approval 

should the NDA holder or patent owner 

initiate patent infringement litigation 

within the statutory timeframe in 

response to notice of a paragraph IV 

certification (see section 505(c)(3)(C) 

and (j)(5)(B)(iii) of the FD&C Act). The 

MMA amended the FD&C Act to alter 

the circumstances under which a 30- 

month stay of approval can arise. The 

MMA also amended the FD&C Act to 

specify the types of court actions that 

will terminate a 30-month stay of 

approval. In addition, approval of a 

505(b)(2) application or ANDA can be 

delayed by a court order pursuant to 35 

U.S.C. 271(e)(4)(A) ordering that the 

application may be approved no earlier 

than the date specified (irrespective of 

whether the injunction relates to a 

patent described in § 314.107(b)(3) (see 

proposed § 314.107(b)(4) and (e)(1)(vi)). 

Table 12 summarizes the proposed 

changes related to the effect of patent(s) 

on the listed drug with respect to the 

date of approval of a 505(b)(2) 

application or ANDA. 

TABLE 12—HIGHLIGHTS OF PROPOSED CHANGES REGARDING THE EFFECT OF PATENT(S) ON THE LISTED DRUG 1

Current regulations Proposed revisions to regulations 

Effect of patent on the listed drug (§ 314.107(b)) Effect of patent(s) on the listed drug (§ 314.107(b)) 

• Introduction to criteria for determining date on which approval of a 

505(b)(2) application or ANDA will become effective. 

• Introduction to criteria that must be used to determine, for each relevant patent, the date that patent will no longer prevent approval. 

• The first possible date of approval will be calculated for each patent, 

and the 505(b)(2) application or ANDA may be approved on the last 

applicable date. 

Multiple certifications (§ 314.107(b)(4)) 

• If the applicant has submitted certifications for more than one patent, 

the date of approval will be calculated for each certification, and the 

approval will become effective on the last applicable date. 

Date of approval letter (§ 314.107(b)(1)) Timing of approval based on patent certification or statement 

(§ 314.107(b)(1)) 

• Except as provided in § 314.107(b)(3), (b)(4), and (c), approval will 

become effective on the date FDA issues an approval letter if the applicant certifies that: 

(i) there are no relevant patents; or 

(ii) the patent information has not been submitted to FDA; or 

(iii) the relevant patent has expired; or 

(iv) the relevant patent is invalid, unenforceable, or will not be infringed. 

• If none of the reasons in § 314.125 or § 314.127 for refusing to approve the application apply, and none of the reasons in § 314.107(d) 

for delaying approval apply, the 505(b)(2) application or ANDA may 

be approved— 

(i) Immediately, if the applicant certifies that: 

(A) the patent information has not been submitted to FDA; or 

(B) the relevant patent has expired; or 

(C) the relevant patent is invalid, unenforceable, or will not be infringed, except as provided in § 314.107(b)(3) and (c), and the 45- 

day period provided for in section 505(c)(3)(C) and 505(j)(5)(B)(iii) of 

the FD&C Act has expired; or 

(D) there are no relevant patents. 

(ii) Immediately, if the applicant submits an appropriate statement 

explaining that a method-of-use patent does not claim an indication or other condition of use for which it is seeking approval. 

Patent expiration (§ 314.107(b)(2)) Timing of approval based on patent certification or statement 

(§ 314.107(b)(1)(iii)) 

• If the applicant certifies that the relevant patent will expire on a specified date (paragraph III certification), approval will become effective 

on the specified date. 

• If the applicant certifies that the relevant patent will expire on a specified date (paragraph III certification), a 505(b)(2) application or 

ANDA otherwise eligible for approval may be approved on the specified date. 

[No corresponding regulation] Patent information filed after submission of 505(b)(2) application or 

ANDA (§ 314.107(b)(2)) 

• If an NDA holder submits patent information for a listed drug after 

the date on which a 505(b)(2) application or ANDA relying on such 

drug was submitted to FDA, the 505(b)(2) or ANDA applicant must 

submit an amended patent certification or statement in accordance 

with §§ 314.50(i)(4) and (i)(6) and 314.94(a)(12)(vi) and (a)(12)(viii). 


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TABLE 12—HIGHLIGHTS OF PROPOSED CHANGES REGARDING THE EFFECT OF PATENT(S) ON THE LISTED DRUG 1— 

Continued 

Current regulations Proposed revisions to regulations 

• If the applicant submits a paragraph IV certification to the newly-listed patent information and complies with the notice requirements of 

§ 314.52 or § 314.95, the 505(b)(2) application or ANDA may be approved immediately upon submission of documentation of receipt of 

notice of paragraph IV certification. 

• The 45-day period provided for in section 505(c)(3)(C) and 

(j)(5)(B)(iii) of the FD&C Act does not apply. 

Disposition of patent litigation (§ 314.107(b)(3)(i)) Disposition of patent litigation (§ 314.107(b)(3)(i)) 

• (A) Except as provided in § 314.107(b)(3)(ii) through (b)(3)(iv), if 

—applicant submits a paragraph IV certification; and 

—patent owner or its representative or the exclusive patent licensee 

brings suit for patent infringement within 45 days of receipt by the 

patent owner of the notice of paragraph IV certification, 

• (A) Except as provided in § 314.107(b)(3)(ii) through (b)(3)(viii), if, 

with respect to patents for which required information was submitted 

before the date on which the 505(b)(2) application or ANDA was 

submitted to FDA (excluding an amendment or supplement), 

—applicant submits a paragraph IV certification; and 

Approval may be made effective 30 months after the date of the receipt 

of the notice of paragraph IV certification by the patent owner or by 

the exclusive licensee (or their representatives) unless the court has 

extended or reduced the period; or 

• (B) If the patented drug product qualifies for 5-year exclusivity, and 

—patent owner or the exclusive patent licensee brings suit for patent 

infringement within 45 days of receipt of the notice of paragraph IV 

certification, 505(b)(2) application, or ANDA may be approved 30 

months after the later of the date of the receipt of the notice of certification by any owner of the listed patent or by the NDA holder who 

is an exclusive patent licensee (or their representatives) unless the 

court has extended or reduced the period; or 

• (B) If the patented drug product qualifies for 5-year exclusivity, and— 

patent owner or its representative or the exclusive patent licensee 

brings suit for patent infringement during the 1-year period beginning 

4 years after the date the patented drug was approved and within 45 

days of receipt by the patent owner of the notice of paragraph IV 

certification, 

Approval may be made effective at the expiration of 71⁄2 years from the 

date of NDA approval for the patented drug product. 

—patent owner or its representative or the exclusive patent licensee 

brings suit for patent infringement during the 1-year period beginning 

4 years after the date the patented drug was approved and within 45 

days of receipt of the notice of paragraph IV certification, 

the 505(b)(2) application or ANDA may be approved at the expiration 

of 71⁄2 years from the date of NDA approval for the patented drug 

product. 

Disposition of patent litigation (§ 314.107(b)(3)(ii)–(b)(3)(iv)) Disposition of patent litigation (§ 314.107(b)(3)(ii)–(b)(3)(viii) 

If before the expiration of the 30-month period, or 71⁄2 years where applicable: If before the expiration of the 30-month period, or 71⁄2 years where applicable: 

• (ii) the court issues a final order that the patent is invalid, unenforceable, or not infringed, approval may be made effective on: 

—the date the court enters judgment; 

• (iii) the court issues a final order or judgment that the patent has 

been infringed, approval may be made effective on: 

—the date the court determines that the patent will expire or otherwise orders 

• (iv) the court grants a preliminary injunction prohibiting the applicant from engaging in the commercial manufacture or sale of the 

drug product until the court decides the issues of patent validity 

and infringement, and if the court later decides that the patent is 

invalid, unenforceable, or not infringed, approval may be made 

effective on: 

—the date the court enters a final order or judgment that 

the patent is invalid, unenforceable, or not infringed. 

• (ii) the district court decides that the patent is invalid, unenforceable, 

or not infringed (including any substantive determination that there is 

no cause of action for patent infringement or invalidity), the 505(b)(2) 

application or ANDA may be approved on: 

—(A) the date on which the court enters judgment reflecting the decision; or 

—(B) the date of a settlement order or consent decree signed and entered by the court stating that the patent that is the subject of the 

certification is invalid or not infringed. 

• (iii) the district court decides that the patent has been infringed 

and the judgment is appealed, the 505(b)(2) application or 

ANDA may be approved on: 

—(A) the date on which the mandate is issued by the court of 

appeals entering judgment that the patent is invalid or not 

infringed; or 

—(B) the date of a settlement order or consent decree signed 

and entered by the court of appeals stating that the patent 

is invalid or not infringed. 

• (iv) the district court decides that the patent has been infringed 

and the judgment is not appealed or is affirmed, the 505(b)(2) 

application or ANDA may be approved no earlier than the date 

specified by the district court in an order under 35 U.S.C. 

271(e)(4)(A). 

• (v) the district court grants a preliminary injunction prohibiting 

the applicant from engaging in the commercial manufacture or 

sale of the drug product until the court decides the issues of patent validity and infringement: 

— if the court later decides the patent is invalid, unenforceable, or not infringed, the 505(b)(2) application or ANDA 

may be approved per § 314.107(b)(3)(ii). 


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TABLE 12—HIGHLIGHTS OF PROPOSED CHANGES REGARDING THE EFFECT OF PATENT(S) ON THE LISTED DRUG 1— 

Continued 

Current regulations Proposed revisions to regulations 

—if the court decides that the patent has been infringed, the 

505(b)(2) application or ANDA may be approved per 

§ 314.107(b)(3)(iii) or (b)(3)(iv), as applicable. 

• (vi) the patent owner or the exclusive patent licensee (or their 

representatives) agrees in writing that the 505(b)(2) application 

or ANDA may be approved any time on or after the date of the 

consent, approval may be granted on or after that date. 

• (vii) the court enters an order requiring the 30-month or 71⁄2-year 

period to be terminated, the 505(b)(2) application or ANDA may 

be approved in accordance with the court’s order. 

• (viii) the court enters an order of dismissal, with or without prejudice, without a finding of infringement, the 505(b)(2) application 

or ANDA may be approved on or after the date of the order. 

1These highlights describe important proposed revisions to our regulations, but should not be relied upon in place of the proposed regulation. 

II.M.1. General (Proposed § 314.107(a)) 

We are not proposing any substantive 

revisions to § 314.107(a). As noted in 

section II.A.2.dd and II.I, we are 

proposing to amend references to the 

‘‘effective date of approval’’ and the date 

the approval of a 505(b)(2) application 

or ANDA ‘‘becomes effective’’ to simply 

refer to the date the 505(b)(2) 

application or ANDA ‘‘is approved.’’ 

The current text incorrectly suggests 

that FDA might issue an approval letter 

that would become effective at some 

date in the future. The proposed 

revision clarifies that a 505(b)(2) 

application or ANDA is not approved 

until the date the Agency issues its 

approval letter. 

II.M.2. Effect of Patent(s) on the Listed 

Drug (Proposed § 314.107(b)) 

We are proposing to revise the 

introduction to proposed § 314.107(b) to 

clarify that an analysis is required for 

each relevant patent to determine the 

effect of one or more patents listed for 

the listed drug(s) relied upon or the RLD 

on the date of approval of a 505(b)(2) 

application or ANDA, respectively. For 

each relevant patent, the patent 

certification or statement submitted by 

the 505(b)(2) or ANDA applicant is 

reviewed to determine the first possible 

date of approval based upon each 

patent. The 505(b)(2) application or 

ANDA may be approved on the last 

applicable date for all relevant patents. 

This approach to the evaluation of 

multiple patent certifications is 

described in current § 314.107(b)(4), 

which is proposed for deletion because 

the substance of that paragraph is in 

proposed § 314.107(b). 

II.M.2.a. Timing of approval based on 

patent certification or statement 

(proposed § 314.107(b)(1)). We are 

proposing to amend § 314.107(b)(1) to 

describe, in a more comprehensive 

manner, the timing of approval of a 

505(b)(2) application or ANDA based on 

the patent certification(s) or statement(s) 

submitted by the 505(b)(2) or ANDA 

applicant. As explained in proposed 

§ 314.107(b)(1), the timing of approval 

based on an analysis of an applicant’s 

patent certification(s) or statement(s) is 

directed to a 505(b)(2) application or 

ANDA that is otherwise eligible for 

approval. A 505(b)(2) application or 

ANDA is otherwise eligible for approval 

if none of the reasons in § 314.125 or 

§ 314.127 for refusing to approve the 

505(b)(2) application or ANDA applies, 

and if no delay is required by the 

exclusivity provisions of § 314.108, 

§ 316.31, or section 505A of the FD&C 

Act (see section II.I). 

In proposed § 314.107(b)(1)(i) and 

(b)(1)(ii), we describe the types of patent 

certifications or statements that would 

result in an immediate first possible 

date of approval of a 505(b)(2) 

application or ANDA that is otherwise 

eligible for approval. Proposed 

§ 314.107(b)(1)(i) reflects a 

reorganization of the current regulation 

and not a substantive revision. Current 

§ 314.107(b)(i) through (b)(iv) are 

redesignated as proposed 

§ 314.107(b)(1)(i)(A) through (b)(1)(i)(D). 

We have proposed to move the phrase 

‘‘except as provided in paragraphs (b)(3) 

and (c)’’ from the introduction to 

current § 314.107(b)(1) to 

§ 314.107(b)(1)(i)(C) to more closely 

associate this very important and 

common exception to an immediate 

date of approval with the paragraph that 

describes a paragraph IV certification. In 

addition, we are proposing to clarify 

that a 505(b)(2) application or ANDA 

containing a paragraph IV certification 

may be approved immediately only if 

the 45-day period provided for in 

section 505(c)(3)(C) and (j)(5)(B)(iii) of 

the FD&C Act has expired. 

We are proposing to revise 

§ 314.107(b)(1)(ii) (the current text of 

which is proposed for incorporation 

into § 314.107(b)(1)(i)) to clarify that an 

appropriate statement under 

§ 314.50(i)(1)(iii) or § 314.94(a)(12)(iii) 

also could result in an ‘‘immediate’’ first 

possible date of approval. This proposed 

revision addresses an omission in the 

current regulations. A 505(b)(2) or 

ANDA applicant may submit a 

statement under § 314.50(i)(1)(iii) or 

§ 314.94(a)(12)(iii), respectively, 

explaining that a method-of-use patent 

does not claim an indication or other 

condition of use for which the applicant 

is seeking approval (see section 

505(b)(2)(B) and (j)(2)(A)(viii) of the 

FD&C Act). If the patent only claims the 

method of use for which the 505(b)(2) or 

ANDA applicant submitted a statement 

under § 314.50(i)(1)(iii) or 

§ 314.94(a)(12)(iii), respectively, then a 

505(b)(2) application or ANDA 

otherwise eligible for approval may be 

approved immediately. 

As described in section II.B.1.a, a 

listed patent may claim the drug 

substance and/or drug product in 

addition to one or more methods of use, 

and a 505(b)(2) or ANDA applicant 

could submit a statement under 

§ 314.50(i)(1)(iii) or § 314.94(a)(12)(iii) 

with respect to one or more methods of 

use and a paragraph IV certification 

with respect to the remaining drug 

substance and/or drug product claims 

and/or any additional methods of use. 

In this scenario, the applicant’s 

paragraph IV certification and statement 

under § 314.50(i)(1)(iii) or 

§ 314.94(a)(12)(iii) to the patent would 

be analyzed in accordance with 

proposed § 314.107(b)(1)(i)(C) and 

(b)(1)(ii) to determine whether the first 

possible date of approval for the 

505(b)(2) application or ANDA based on 

this patent is ‘‘immediately’’ or whether 


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the exceptions described in 

§ 314.107(b)(3) and (c) apply with 

respect to the paragraph IV certification. 

Approval of a 505(b)(2) application or 

ANDA that contains a statement under 

§ 314.50(i)(1)(iii) or § 314.94(a)(12)(iii) 

with respect to one or more methods of 

use and a paragraph IV certification 

with respect to the remaining patent 

claims may be subject to a 30-month 

stay (or 71⁄2 years where applicable) if 

patent infringement litigation is 

initiated within the statutory timeframe 

with respect to the patent claims that 

were the subject of the paragraph IV 

certification (see § 314.107(b)(3)). It 

should be noted that if the paragraph IV 

certification that gave rise to the 30- 

month stay (or 71⁄2 years where 

applicable) is subsequently amended to 

a statement under § 314.50(i)(1)(iii) or 

§ 314.94(a)(12)(iii) with respect to one or 

more methods of use, the 30-month stay 

(or 71⁄2 years where applicable) will not 

be terminated in the absence of a 

qualifying event under § 314.107(b)(3). 

We are proposing to move 

§ 314.107(b)(2) regarding paragraph III 

certifications, which delay approval 

until the date on which the patent will 

expire, to proposed § 314.107(b)(1)(iii) 

for organizational convenience. An 

analysis of the effect of patents on the 

timing of approval of a 505(b)(2) 

application or ANDA is made when the 

505(b)(2) application or ANDA is 

otherwise eligible for approval. 

II.M.2.b. Patent information filed after 

submission of 505(b)(2) application or 

ANDA (proposed § 314.107(b)(2)). We 

are proposing to revise § 314.107(b)(2) 

(redesignated as proposed 

§ 314.107(b)(1)(iii)) to clarify the effect 

of patent information filed after 

submission of a 505(b)(2) application or 

ANDA on the date of approval of a 

505(b)(2) application or ANDA. If an 

NDA holder submits patent information 

for a listed drug after the date on which 

a 505(b)(2) application or ANDA relying 

upon such drug was submitted to FDA, 

the 505(b)(2) or ANDA applicant must 

comply with the requirements of 

§§ 314.50(i)(4) and (i)(6) and 

314.94(a)(12)(vi) and (a)(12)(viii) 

regarding amendment of its patent 

certification or statement (see section 

II.E.4). Thus, if the patent information 

was timely filed by the NDA holder 

under § 314.53(d)(3), the 505(b)(2) or 

ANDA applicant would be required to 

amend its patent certification or 

statement for the listed drug relied upon 

or RLD, respectively, to address the 

newly listed patent. (A 505(b)(2) or 

ANDA applicant whose pending 

application did not contain an 

appropriate patent certification at the 

time of submission would be required to 

submit a patent certification or 

statement to the newly listed patent 

even if such patent information was 

filed by the NDA holder more than 30 

days after patent issuance (i.e., untimely 

filed).) 

If the 505(b)(2) or ANDA applicant 

submits an amendment containing a 

paragraph IV certification to the newly 

listed patent, proposed § 314.107(b)(2) 

clarifies that the 505(b)(2) application or 

ANDA may be approved immediately 

upon the submission of an amendment 

containing documentation that the NDA 

holder and each patent owner have 

received notice of paragraph IV 

certification under § 314.52(e) or 

§ 314.95(e). There is no need to delay 

approval until the expiration of the 45- 

day period provided for in section 

505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C 

Act. Even if the NDA holder or patent 

owner initiated patent infringement 

litigation within the 45-day period after 

receipt of notice of paragraph IV 

certification, a 30-month stay of 

approval would not be available in 

connection with a paragraph IV 

certification to a patent submitted after 

a 505(b)(2) application or ANDA had 

been submitted to FDA (see section 

505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C 

Act). 

Although a 30-month stay of approval 

is not available in these circumstances, 

a 505(b)(2) or ANDA applicant still must 

comply with the requirements for 

provision of notice of paragraph IV 

certification described in section 

505(b)(3) and (j)(2)(B) of the FD&C Act 

and §§ 314.52 and 314.95. An NDA 

holder or patent owner may assert a 

claim of patent infringement against the 

505(b)(2) or ANDA applicant in 

response to the notice of paragraph IV 

certification and may seek injunctive 

relief during the pendency of the 

litigation despite the absence of a 30- 

month stay. Notice of paragraph IV 

certification in accordance with 

applicable regulations also is necessary 

for an ANDA applicant to be eligible for 

180-day exclusivity based upon a 

paragraph IV certification to a newly 

listed patent (see section II.D.1). 

II.M.2.c. Disposition of patent 

litigation (proposed § 314.107(b)(3)). 

II.M.2.c.i. Approval upon expiration 

of 30-month stay or 71⁄2 years from date 

of reference product approval (proposed 

§ 314.107(b)(3)(i)). We are proposing to 

revise § 314.107(b)(3)(i)(A) to reflect one 

of the central elements of the MMA’s 

amendments to the FD&C Act: The 

limitation on multiple 30-month stays of 

approval of a 505(b)(2) application or an 

ANDA containing a paragraph IV 

certification to certain patents submitted 

to FDA on or after August 18, 2003. 

Proposed § 314.107(b)(3)(i)(A) states that 

a 30-month stay of approval is available 

only when the patent owner or 

exclusive patent licensee initiates a 

patent infringement action within the 

statutory timeframe in response to a 

paragraph IV certification to a patent 

submitted to FDA before the date on 

which the original 505(b)(2) application 

or ANDA was submitted. As discussed 

in section II.E, the MMA expressly 

provides that, for purposes of 

determining the availability of a 30- 

month stay, the date of submission of a 

505(b)(2) application or ANDA does not 

include the date of submission of an 

amendment or supplement to the 

505(b)(2) application or ANDA (see 

section 505(c)(3)(C) and (j)(5)(B)(iii) of 

the FD&C Act). In other words, there 

will be no possibility of a 30-month stay 

with respect to an action for 

infringement of a patent listed after the 

reference product is approved if the 

patent was submitted to FDA on or after 

the date the 505(b)(2) application or 

ANDA was first submitted. Due to this 

limitation, most 505(b)(2) applications 

and ANDAs will be subject to no more 

than one 30-month stay of approval. 

Multiple 30-month stays, however, 

still may be possible in certain cases. 

For example, an original 505(b)(2) 

application or ANDA may contain a 

paragraph IV certification to a patent 

that results in a 30-month stay of 

approval. If the same application also 

contains a paragraph III certification to 

a different patent that was submitted to 

FDA on or after August 18, 2003, and 

before the 505(b)(2) application or 

ANDA was submitted, and the applicant 

subsequently amends the paragraph III 

certification to a paragraph IV 

certification, a second 30-month stay 

would be possible. Two 30-month stays 

are possible in this example because the 

challenged patents that gave rise to 

sequential actions for patent 

infringement were both submitted to 

FDA before submission of the original 

505(b)(2) application or ANDA. It 

should be noted that the relevant 

benchmark for determining whether a 

patent was submitted by the NDA 

holder prior to submission of an original 

505(b)(2) application or prior to 

submission of an ANDA later 

determined to be substantially complete 

is the date of submission of the patent 

to FDA and not the date on which the 

patent information is published in the 

Orange Book (see § 314.53(d)(5)). We 

note, however, that if the original 

submission of an ANDA is not 

determined to be substantially complete 

(i.e., FDA refuses to receive the ANDA 

under § 314.101), then the relevant 


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benchmark is the date of the ANDA 

amendment that results in a subsequent 

determination that the ANDA is 

substantially complete. 

We also are proposing to revise 

§ 314.107(b)(3)(i) to clarify that a 30- 

month stay of approval begins on the 

later of the date of receipt of the notice 

of paragraph IV certification by any 

owner of the listed patent or by the NDA 

holder who is an exclusive patent 

licensee (or their representatives). This 

proposed revision codifies our current 

practice and provides an 

administratively efficient means of 

ensuring that each patent owner or NDA 

holder that is entitled to receive notice 

of paragraph IV certification receives the 

full statutory 30-month stay of approval 

should one of these parties initiate 

patent infringement litigation within 45 

days of its receipt of notice. Even if a 

patent infringement action was initiated 

within 45 days of receipt of notice of 

paragraph IV certification by the first of 

two intended recipients, the 30-month 

stay of approval would begin on the 

later of the dates of receipt of notice of 

paragraph IV certification by any owner 

of the listed patent or by the NDA 

holder. 

Finally, we are proposing to revise 

§ 314.107(b)(3) to supplement the list 

that describes different scenarios related 

to the timing of approval of a 505(b)(2) 

application or ANDA containing a 

paragraph IV certification that was the 

subject of patent litigation. Many of our 

proposed additions to the § 314.107(b) 

list reflect corresponding MMA 

amendments to section 505(c)(3)(C) and 

(j)(5)(B)(iii) of the FD&C Act (see 

sections II.M.3.e to II.M.3.h). It should 

be noted that we are not proposing 

revisions to § 314.107(b)(3) to describe 

the date on which a 505(b)(2) 

application or ANDA may be approved 

when a 30-month stay relates to a patent 

to which pediatric exclusivity has 

attached (see section 505A of the FD&C 

Act). However, a period of pediatric 

exclusivity under section 505A of the 

FD&C Act may affect the approval date 

of a 505(b)(2) application or ANDA in 

the circumstances described in 

§ 314.107(b)(3). 

II.M.2.c.ii. Federal district court 

decision of invalidity, unenforceability, 

or non infringement (proposed 

§ 314.107(b)(3)(ii)). The MMA amended 

section 505(c)(3)(C) and (j)(5)(B)(iii) of 

the FD&C Act for 505(b)(2) applications 

and ANDAs, respectively, to clarify the 

type of court decision in patent 

litigation that will terminate a 30-month 

stay (or 71⁄2 years where applicable) and 

lead to approval of a 505(b)(2) 

application or ANDA that is otherwise 

eligible for approval. Prior to the MMA, 

FDA interpreted the reference to a court 

decision in section 505(c)(3)(C)(i) and 

(j)(5)(B)(iii)(I) of the FD&C Act to mean 

‘‘the court that enters final judgment 

from which no appeal can be or has 

been taken’’ (see guidance for industry 

entitled ‘‘Court Decisions, ANDA 

Approvals, and 180-Day Exclusivity 

Under the Hatch-Waxman Amendments 

to the Federal Food, Drug, and Cosmetic 

Act’’ (March 2000), available at http:// 

www.fda.gov/downloads/Drugs/

GuidanceComplianceRegulatory

Information/Guidances/UCM072868.

pdf) (superseded Guidance on Court 

Decisions). The MMA amended the 

FD&C Act to codify the types of Federal 

district court decisions and, as 

discussed in section II.M.2.c.iii to 

II.M.2.c.iv, the types of Federal 

appellate court decisions that will 

terminate a 30-month stay (or 71⁄2 years 

where applicable). Accordingly, FDA is 

not required to delay approval of an 

otherwise approvable ANDA until there 

has been a court decision from which no 

appeal can be or has been taken. 

The MMA amended section 

505(c)(3)(C)(i) and (j)(5)(B)(iii)(I) of the 

FD&C Act to describe the Federal 

district court decisions in patent 

litigation that will terminate a 30-month 

stay (or 71⁄2 years where applicable) and 

lead to approval of a 505(b)(2) 

application or ANDA that is otherwise 

eligible for approval (see Sanofi-Aventis 

v. FDA, 643 F.Supp.2d 82, 86 (D.D.C.), 

inj. denied, 2009 U.S. Dist. LEXIS 74578 

(D.D.C. 2009) (‘‘The plain language of 

the entry of judgment provision of the 

Hatch-Waxman Act is clear that the 

FDA’s approval of a generic application 

‘shall be made effective on the . . . date 

on which the court enters judgment’ ’’ 

irrespective of whether the 

enforceability of that judgment is 

stayed) (emphasis in original)). We are 

proposing to revise § 314.107(b)(3)(ii) to 

reflect these statutory revisions that 

change the decisive event from court 

issuance of a final order that the patent 

is invalid, unenforceable, or not 

infringed to a district court’s entry of 

judgment pursuant to Federal Rule of 

Civil Procedure (Fed. R. Civ. P.) Rule 58 

that the patent is invalid, unenforceable, 

or not infringed. As with current 

§ 314.107(b)(3)(ii), we are proposing to 

implement section 505(c)(3)(C)(i) and 

(j)(5)(B)(iii)(I) of the FD&C Act to 

include a court decision that the 

applicable patent is unenforceable. 

Thus, a Federal district court’s entry of 

judgment that a patent has been 

infringed by the 505(b)(2) or ANDA 

applicant but is unenforceable (for 

example, due to inequitable conduct in 

patent prosecution) would terminate a 

30-month stay (or 71⁄2 years where 

applicable). Consistent with section 

505(c)(3)(C)(i) and (j)(5)(B)(iii)(I) of the 

FD&C Act, proposed § 314.107(b)(3)(ii) 

also includes cases in which a Federal 

district court has made a substantive 

determination that there is no cause of 

action for patent infringement or 

invalidity. 

We are proposing to further revise 

§ 314.107(b)(3)(ii) to incorporate the text 

of section 505(c)(3)(C)(i) and 

(j)(5)(B)(iii)(I) of the FD&C Act, as 

amended by the MMA, regarding the 

timing of approval of a 505(b)(2) 

application or ANDA in relation to the 

district court decision. Proposed 

§ 314.107(b)(3)(ii) provides that in cases 

in which a district court decides that the 

patent is invalid, unenforceable, or not 

infringed, the 505(b)(2) application or 

ANDA may be approved on the date on 

which the court enters judgment 

reflecting the decision (paragraph (A)); 

or the date of a settlement order or 

consent decree signed and entered by 

the court stating that the patent that is 

the subject of the certification is invalid 

or not infringed (paragraph (B)). 

II.M.2.c.iii. Appeal of Federal district 

court judgment of infringement 

(proposed § 314.107(b)(3)(iii)). The 

MMA amended section 505(c)(3)(C)(ii) 

and (j)(5)(B)(iii)(II) of the FD&C Act for 

505(b)(2) applications and ANDAs, 

respectively, to describe the earliest date 

on which a 30-month stay (or 71⁄2 years 

where applicable) can be terminated 

after a Federal district court has decided 

that the patent has been infringed based 

on whether the judgment is appealed. 

We are proposing to revise 

§ 314.107(b)(3)(iii) and, as discussed in 

section II.M.2.c.iv, § 314.107(b)(3)(iv) to 

reflect these statutory revisions. 

Proposed § 314.107(b)(3)(iii) states 

that if the Federal district court decides 

that the patent has been infringed and 

the district court judgment is appealed, 

the 505(b)(2) application or ANDA may 

be approved on the date on which the 

mandate is issued by the court of 

appeals entering judgment that the 

patent is invalid or not infringed 

(including any substantive 

determination that there is no cause of 

action for patent infringement or 

invalidity) (paragraph (A)); or the date 

of a settlement order or consent decree 

signed and entered by the court of 

appeals stating that the patent that is the 

subject of the certification is invalid or 

not infringed (paragraph (B)). Proposed 

§ 314.107(b)(3)(iii) restates the text of 

section 505(c)(3)(C)(ii) and 

(j)(5)(B)(iii)(II) of the FD&C Act except 

that we are proposing to further specify 

that the date of the court of appeals 

decision is the date on which the 


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mandate is issued by the court of 

appeals (see Federal Rule of Appellate 

Procedure Rule 41). This proposal 

reflects the Agency’s current practice in 

implementing section 505(c)(3)(C)(ii) 

and (j)(5)(B)(iii)(II) of the FD&C Act, 

which recognizes that a party may 

request rehearing by the appellate panel 

or rehearing en banc. In such 

circumstances, it would be premature to 

terminate the 30-month stay and 

possibly approve the 505(b)(2) 

application or ANDA while a decision 

regarding patent noninfringement, 

invalidity, or unenforceability was being 

reheard by the court of appeals. By 

interpreting the ‘‘date on which the 

court of appeals decides that the patent 

is invalid or not infringed’’ (see section 

505(c)(3)(C)(ii) and (j)(5)(B)(iii)(II) of the 

FD&C Act) to mean the date on which 

the mandate issues, we are ensuring that 

the Agency’s action reflects the 

judgment of the court of appeals. We 

seek comment on this interpretation. 

II.M.2.c.iv. Affirmation or non-appeal 

of Federal district court judgment of 

infringement (proposed 

§ 314.107(b)(3)(iv)). The MMA amended 

section 505(c)(3)(C)(ii)(II) and 

(j)(5)(B)(iii)(II)(bb) of the FD&C Act to 

describe the timing of approval of a 

505(b)(2) application or ANDA, 

respectively, that a Federal district court 

has decided infringes a patent that was 

the subject of a paragraph IV 

certification if the district court decision 

was not appealed or was affirmed on 

appeal. In such a case, section 

505(c)(3)(C)(ii)(II) and (j)(5)(B)(iii)(II)(bb) 

of the FD&C Act provide that the 

505(b)(2) application or ANDA will be 

approved on the date specified by the 

district court in an order under 35 

U.S.C. 271(e)(4)(A). We are proposing to 

revise § 314.107(b)(3)(iv) to reflect these 

statutory revisions with certain 

clarifications. 

Proposed § 314.107(b)(3)(iv) provides 

that if the district court decides that the 

patent at issue is infringed and this 

judgment is not appealed or is affirmed 

on appeal, the 505(b)(2) application or 

ANDA may be approved no earlier than 

the date specified by the district court 

in an order under 35 U.S.C. 271(e)(4)(A). 

Although the date specified by the 

district court order would not be earlier 

than the date of expiration of the 

infringed patent (see 35 U.S.C. 

271(e)(4)(A)), the date specified by the 

order may not take into account any 

other unexpired patents or unexpired 

exclusivity (or deficiencies in the 

application) that would delay approval 

of the 505(b)(2) application or ANDA 

beyond the date of expiration of the 

infringed patent. Therefore, proposed 

§ 314.107(b)(3)(iv) states that the 

505(b)(2) application or ANDA may be 

approved no earlier than the date 

specified in a district court’s order 

under 35 U.S.C. 271(e)(4)(A), rather than 

using the statutory phrasing that the 

‘‘approval shall be made effective on the 

date’’ specified by such order (see 

section 505(c)(3)(C)(ii)(II) and 

(j)(5)(B)(iii)(II)(bb) of the FD&C Act and 

section II.I regarding removal of 

references to the effective date of 

approval). 

II.M.2.c.v. Grant of preliminary 

injunction by Federal district court 

(proposed § 314.107(b)(3)(v)). The MMA 

amended section 505(c)(3)(C)(iii), 

(c)(3)(C)(iv), (j)(5)(B)(iii)(III), and 

(j)(5)(B)(iii)(IV) of the FD&C Act to 

clarify that the timing of approval of a 

505(b)(2) application or ANDA, 

respectively, is subject to provisions of 

section 505(c)(3)(C)(i), (c)(3)(C)(ii), 

(j)(5)(B)(iii)(I), and (j)(5)(B)(iii)(II) even if 

preceded by a preliminary injunction 

prohibiting the applicant from engaging 

in the commercial manufacture or sale 

of the drug until the court decides the 

issues of patent validity and 

infringement. We are proposing to 

revise current § 314.107(b)(3)(iv) 

(redesignated as proposed 

§ 314.107(b)(3)(v)) to reflect these 

statutory revisions. Proposed 

§ 314.107(b)(3)(v) cross-references the 

applicable paragraph of § 314.107(b)(3) 

that would address the timing of 

approval of the 505(b)(2) application or 

ANDA based on the court’s decision 

with respect to patent validity and 

infringement. If a preliminary 

injunction is entered before the 

expiration of the 30-month stay, FDA 

interprets section 505(j)(5)(B)(iii) of the 

FD&C Act to require that the stay of 

approval is extended until the court 

decides the issues of patent 

infringement and validity. Once such a 

decision is made, the references to 

section 505(j)(5)(B)(iii)(I) and 

(j)(5)(B)(iii)(II) of the FD&C Act provide 

for the timing of approval (see section 

505(j)(5)(B)(iii)(III) and (j)(5)(B)(iii)(IV) 

of the FD&C Act). We seek comment on 

this approach. 

In addition, proposed 

§ 314.107(b)(3)(v) makes clear that the 

court that grants a preliminary 

injunction pending a decision on the 

issues of patent validity and 

infringement refers to the Federal 

district court hearing the patent 

infringement action. 

II.M.2.c.vi. Written consent to 

approval by patent owner or exclusive 

patent licensee (proposed 

§ 314.107(b)(3)(vi)). We are proposing to 

add § 314.107(b)(3)(vi) to clarify that if 

the patent owner or exclusive patent 

licensee (or their representatives) agrees 

in writing that the 505(b)(2) application 

or ANDA application may be approved, 

the 30-month stay (or 71⁄2 years where 

applicable) will be terminated and the 

approval may be granted on or after the 

date of the consent. Thus, proposed 

§ 314.107(b)(3)(vi) would permit 

termination of the 30-month stay (or 71⁄2

years where applicable) without a court 

order. This scenario may arise, for 

example, if settlement of the patent 

litigation results in a license to the 

505(b)(2) or ANDA applicant. 

II.M.2.c.vii. Court order terminating 

30-month or 71⁄2-year period (proposed 

§ 314.107(b)(3)(vii)). We are proposing 

to add § 314.107(b)(3)(vii) to clarify that 

if a court enters an order requiring the 

termination of the 30-month stay (or 71⁄2

years where applicable), the 505(b)(2) 

application or ANDA, if otherwise ready 

for approval, may be approved in 

accordance with the court order. 

II.M.2.c.viii. Court order of dismissal 

without a finding of infringement 

(proposed § 314.107(b)(3)(viii)). The 

MMA’s amendments to section 

505(c)(3)(C)(i), (c)(3)(C)(ii), 

(j)(5)(B)(iii)(I), and (j)(5)(B)(iii)(II) of the 

FD&C Act clarify the timing of approval 

of a 505(b)(2) application or ANDA, 

respectively, in relation to a settlement 

order or consent decree stating that the 

patent that is the subject of the 

paragraph IV certification is invalid or 

not infringed. However, the statute does 

not address whether a 30-month stay 

may be terminated and a 505(b)(2) 

application or ANDA approved if the 

court enters an order of dismissal 

without a finding of patent 

infringement—a scenario that FDA 

encounters frequently. We are proposing 

to add § 314.107(b)(3)(viii) to codify 

FDA’s policy that court entry of an order 

of dismissal, with or without prejudice, 

of patent infringement litigation that 

was timely initiated in response to 

notice of a paragraph IV certification 

will terminate the 30-month period (or 

71⁄2 years where applicable) if such 

order does not state a finding of patent 

infringement. It is appropriate that a 30- 

month stay terminates under these 

circumstances because the statutory 

purpose of the stay is to allow time for 

claims of patent infringement to be 

litigated prior to approval of the 

potentially infringing drug product. If 

the patent owner or exclusive patent 

licensee dismisses the patent 

infringement action on terms that the 

court considers proper (see Fed. R. Civ. 

P. Rule 41(a)(2)), then there should be 

no further delay of approval of a 

505(b)(2) application or ANDA 

otherwise eligible for approval. 

II.M.2.d. Tentative approval 

(proposed § 314.107(b)(4)). We are 


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proposing to redesignate current 

§ 314.107(b)(3)(v) as proposed 

§ 314.107(b)(4) for organizational 

convenience. Proposed § 314.107(b)(4) 

describes tentative approval of a 

505(b)(2) application or ANDA as 

appropriate in accordance with 

§ 314.107(b)(3). In addition, we are 

proposing to revise § 314.107(b)(4) to 

state that FDA will issue a tentative 

approval letter when tentative approval 

is appropriate in accordance with a 

court order pursuant to 35 U.S.C. 

271(e)(4)(A) that a 505(b)(2) application 

or ANDA may be approved no earlier 

than the date specified, irrespective of 

whether the injunction relates to a 

patent described in § 314.107(b)(3) (see 

proposed § 314.107(e)(1)(vi)). This 

proposed revision is intended to 

complement proposed § 314.107(g), 

which clarifies that if a court enters an 

order requiring that the date of approval 

be delayed for an already approved 

505(b)(2) application or ANDA, FDA 

will convert the approval to a tentative 

approval, if appropriate. This scenario 

may occur, for example, if a patent 

infringement action is initiated after the 

45-day period described in section 

505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C 

Act and results in a judgment of patent 

infringement. Proposed § 314.107(b)(4) 

would expressly describe FDA’s 

practice of giving effect to the court 

order under 35 U.S.C. 271(e)(4)(A), 

irrespective of whether the order relates 

to a patent associated with a 30-month 

stay of approval (see, e.g., Mylan Labs., 

Inc. v. Thompson, 389 F.3d 1272 (D.C. 

Cir. 2004)). 

We also are proposing to amend 

references to ‘‘receiv[ing] final 

approval’’ and making an approval 

‘‘effective’’ to refer instead to receipt of 

an approval letter (see sections II.A.2.dd 

and II.I). 

II.M.3. Subsequent ANDA Submission 

(Proposed § 314.107(c)) 

Section 1102 of the MMA amended 

section 505(j)(5) of the FD&C Act to 

modify the conditions under which a 

180-day period of exclusivity is granted 

and to establish conditions under which 

a first applicant would forfeit the 180- 

day exclusivity period. As noted in 

section I.D, we are currently 

implementing the 180-day exclusivity 

provisions of the MMA directly from the 

statute and will determine if additional 

rulemaking is necessary in the future. At 

this time, we are proposing to revise 

§ 314.107(c) to remove provisions that 

have been superseded by the statute, as 

revised by the MMA, and to generally 

conform with the statute. 

Table 13 summarizes the proposed 

changes related to submission of an 

ANDA containing a paragraph IV 

certification by a subsequent ANDA 

applicant. 

TABLE 13—HIGHLIGHTS OF PROPOSED CHANGES REGARDING SUBSEQUENT ANDA SUBMISSION 1

Current regulations Proposed revisions to regulations 

Subsequent ANDA submission (§ 314.107(c)(1),(3)) Subsequent ANDA submission (§ 314.107(c)(1)) 

• If an ANDA contains a paragraph IV certification and the ANDA is for 

a generic copy of the same listed drug for which one or more substantially complete ANDAs were previously submitted containing a 

paragraph IV certification to the same patent, approval of the subsequent ANDA will be made effective no sooner than 180 days from 

whichever of the following dates is earlier: 

—(i) The date the applicant submitting the first application first 

commences commercial marketing of its drug product; or 

—(ii) The date of a decision of the court holding the relevant patent invalid, unenforceable, or not infringed. 

• If an ANDA contains a paragraph IV certification for a relevant patent 

and the ANDA is not that of a first applicant, the ANDA is regarded 

as that of a subsequent applicant. 

• The ANDA of a subsequent applicant will not be approved during the 

period when any first applicant for the drug product is eligible for 

180-day exclusivity or during the 180-day exclusivity period of a first 

applicant. 

• Any applicable 180-day exclusivity period can not extend beyond the 

expiration of the patent upon which the 180-day exclusivity period 

was based. 

• For purposes of § 314.107(c)(1), if FDA concludes that the applicant 

submitting the first ANDA is not actively pursuing approval, FDA will 

make the approval of subsequent ANDAs immediately effective if 

they are otherwise eligible for an immediately effective approval. 

Subsequent ANDA submission (§ 314.107(c)(2)) Definitions (§ 314.3(b)) 

• For purposes of § 314.107(c)(1), the ‘applicant submitting the first application’ is the applicant that submits an ANDA that is both substantially complete and contains a certification that the patent was invalid, 

unenforceable, or not infringed prior to the submission of any other 

application for the same listed drug that is both substantially complete and contains the same certification. 

• A ‘substantially complete’ application must contain the results of any 

required bioequivalence studies, or, if applicable, a request for a 

waiver of such studies. 

• First applicant is an applicant that, on the first day on which a substantially complete ANDA containing a paragraph IV certification is 

submitted for approval of a drug, submits a substantially complete 

ANDA that contains, and for which the applicant lawfully maintains, a 

paragraph IV certification for the drug. 

• Substantially complete application is an ANDA that on its face is sufficiently complete to permit a substantive review and contains all the 

information required under section 505(j)(2)(A) of the FD&C Act and 

§ 314.94. 

Subsequent ANDA submission (§ 314.107(c)(4)) Subsequent ANDA submission (§ 314.107(c)(2)) 

• For purposes of § 314.107(c)(1)(i), the applicant submitting the 

first ANDA shall notify FDA of the date that it commences commercial marketing of its drug product. 

• For purposes of § 314.107(c)(1), a first applicant must submit a supplement to its ANDA notifying FDA within 30 days of the date of first 

commercial marketing of its drug product. 

• If an applicant does not promptly notify FDA of such date, the 

effective date of approval shall be deemed to be the date of the 

commencement of first commercial marketing. 

• If an applicant does not notify FDA, as required above, of this date, 

the date of first commercial marketing will be deemed to be the date 

of the drug product’s approval. 

• Commercial marketing commences with the first date of introduction or delivery for introduction into interstate commerce outside the control of the manufacturer of a drug product, except for 

investigational use under part 312 of this chapter, but does not 

include transfer of the drug product for reasons other than sale 

within the control of the manufacturer or application holder. 

Definitions (§ 314.3(b)) 

• Commercial marketing is the introduction or delivery for introduction 

into interstate commerce of a drug product described in an approved 

ANDA, outside the control of the ANDA holder, except for investigational use under part 312 of this chapter, but does not include transfer of the drug product for reasons other than sale to parties identified in the approved ANDA. 

1These highlights describe important proposed revisions to our regulations, but should not be relied upon in place of the proposed regulation. 


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We are proposing to revise 

§ 314.107(c)(1) to incorporate the term 

‘‘first applicant,’’ as defined by section 

505(j)(5)(B)(iv)(II)(bb) of the FD&C Act 

and in proposed § 314.3(b) (see section 

II.A.2.q), and to distinguish a ‘‘first 

applicant’’ from a ‘‘subsequent 

applicant.’’ An ANDA has been 

submitted by a subsequent applicant if 

the ANDA has not been submitted by a 

first applicant and contains a paragraph 

IV certification to a relevant patent that 

has been listed for the drug product for 

which a first applicant has submitted an 

ANDA. A subsequent applicant’s ANDA 

will not be approved during the period 

when any first applicant for the drug 

product is eligible for 180-day 

exclusivity or during the 180-day 

exclusivity period of a first applicant 

(see section 505(j)(5)(B)(iv)(I) of the 

FD&C Act). By including the period 

during which any first applicant is 

eligible for 180-day exclusivity, 

proposed § 314.107(c)(1) clarifies that a 

subsequent ANDA for the drug product 

may not be approved while a first 

applicant is eligible for 180-day 

exclusivity as long as a forfeiture event 

has not occurred with respect to that 

first applicant (see section 

505(j)(2)(D)(ii) of the FD&C Act). These 

proposed revisions replace the current 

text of § 314.107(c)(1), superseded by 

statute, which describe a patent-bypatent analysis to determine eligibility 

for 180-day exclusivity and events that 

would trigger the start of the 180-day 

period under the pre-MMA statutory 

scheme. 

We are proposing to delete the 

definition of the ‘‘applicant submitting 

the first application’’ in current 

§ 314.107(c)(2) because it has been 

superseded by the statutory definition 

added by the MMA. We are proposing 

to incorporate the MMA’s definition of 

the term ‘‘first applicant,’’ with minor 

editorial changes and additional 

clarifying text, into § 314.3(b) (see 

section 505(j)(5)(B)(iv)(II)(bb) of the 

FD&C Act and section II.A.2.q). We also 

are proposing to delete § 314.107(c)(3), 

which described the potential 

consequences of a first applicant’s 

failure to actively pursue approval of its 

ANDA because this regulation has been 

superseded by the statutory provisions 

that specify events that will result in 

forfeiture of the 180-day exclusivity 

period by a first applicant (see section 

505(j)(5)(D) of the FD&C Act). 

The MMA amended the FD&C Act to 

modify the types of events that can 

trigger the start of the 180-day 

exclusivity period for a first applicant 

(see section 505(j)(5)(B)(iv)(I) of the 

FD&C Act; see also section 1102(b)(3) of 

the MMA). Section 505(j)(5)(B)(iv)(I) of 

the FD&C Act provides that the period 

of 180-day exclusivity will begin on the 

‘‘date of the first commercial marketing 

of the drug (including the commercial 

marketing of the listed drug) by any first 

applicant.’’ This commercial marketing 

trigger differs from the version of 

section 505(j)(5)(B)(iv)(I) in effect prior 

to enactment of the MMA, which 

provided that the 180-day exclusivity 

period will begin on the earlier of two 

events, one of which was the date the 

Secretary receives notice from the 

applicant of the first commercial 

marketing of the drug eligible for 180- 

day exclusivity. We are proposing to 

revise § 314.107(c)(4) to conform with 

these changes to the FD&C Act and 

redesignate this provision as 

§ 314.107(c)(2) (‘‘redesignated 

§ 314.107(c)(2)’’). 

In light of the change in the 

commercial marketing trigger from the 

date on which FDA receives notice from 

the applicant of the first commercial 

marketing to the date of the first 

commercial marketing of the drug, we 

are proposing to revise redesignated 

§ 314.107(c)(2) to require a first 

applicant to submit correspondence to 

its ANDA notifying FDA within 30 days 

of the date of first commercial marketing 

of the drug product (see current 

§ 314.107(c)(4)). This proposal to require 

notification within 30 days of the date 

of first commercial marketing is 

intended to facilitate the efficient 

enforcement of the FD&C Act and 

provide adequate notice to subsequent 

applicants that have received tentative 

approval and are awaiting expiration of 

the period of 180-day exclusivity. If the 

first applicant does not notify FDA 

within this timeframe, we are proposing 

to deem the date of first commercial 

marketing to be the date of the drug 

product’s approval. This may have the 

effect of shortening the 180-day period 

of exclusivity in a manner similar to 

current § 314.107(c)(4). 

We also are proposing to revise 

redesignated § 314.107(c)(2) to remove 

the description of ‘‘commercial 

marketing.’’ As explained in section 

II.A.2.l, we are proposing to define 

‘‘commercial marketing’’ in § 314.3(b) 

with certain modifications, as compared 

to current § 314.107(c)(4), to the scope 

of the exclusion for transfer of the drug 

product for reasons other than sale. 

II.M.4. Delay of Approval Due to 

Exclusivity (Proposed § 314.107(d)) 

We are proposing to revise 

§ 314.107(d) to clarify that approval of a 

505(b)(2) application or ANDA may be 

delayed by orphan drug exclusivity and 

pediatric exclusivity in addition to the 

exclusivities described in § 314.108. 

Proposed § 314.107(d) explains that 

when approval of a 505(b)(2) 

application or ANDA is delayed under 

§ 314.107 and § 314.108, 21 CFR 316.31 

(orphan drug exclusivity), or section 

505A of the FD&C Act (pediatric 

exclusivity), the 505(b)(2) application or 

ANDA will be approved on the latest of 

the dates specified under these 

provisions. We also have made 

conforming revisions to proposed 

§ 314.107(d) that are described 

elsewhere in section II.M. 

II.M.5. Notification of Court Actions or 

Documented Agreement (Proposed 

§ 314.107(e)) 

We are proposing to revise 

§ 314.107(e) to expand the scope of 

documentation that an applicant must 

submit to FDA regarding court actions 

and settlements related to patents. 

These changes are intended to ensure 

that FDA is promptly advised of court 

actions and documented agreements 

that may affect the timing of approval of 

a 505(b)(2) application or ANDA for the 

efficient administration of the FD&C 

Act. FDA does not have the resources to 

monitor the numerous court actions that 

are pending at any given time which 

may affect the date of approval of a 

505(b)(2) application or ANDA that is 

otherwise eligible for approval. 

Table 14 summarizes the proposed 

changes related to notification of court 

actions or documented agreements. 

TABLE 14—HIGHLIGHTS OF PROPOSED CHANGES REGARDING NOTIFICATION OF COURT ACTIONS OR DOCUMENTED

AGREEMENTS1

Current regulations Proposed revisions to regulations 

Notification of court actions (§ 314.107(e)) Notification of court actions or documented agreements 

(§ 314.107(e)(1) and (e)(2)) 


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TABLE 14—HIGHLIGHTS OF PROPOSED CHANGES REGARDING NOTIFICATION OF COURT ACTIONS OR DOCUMENTED

AGREEMENTS1—Continued 

Current regulations Proposed revisions to regulations 

• Applicant must submit a copy of the entry of the order or judgment to 

the Office of Generic Drugs or to the appropriate division in the Office of New Drugs, as applicable, within 10 working days of a final 

judgment.

• Applicant must submit the following information to FDA, as applicable: 

—a copy of any judgment by the court (district court or mandate of 

the court of appeals) or settlement order or consent decree 

signed and entered by the court (district court or court of appeals) finding a patent described in § 314.107(b)(3) invalid, unenforceable, or not infringed, or finding the patent valid and infringed, and written notification of whether any such court action 

has been appealed; 

—A copy of any order entered by the court terminating the 30- 

month or 71⁄2-year period described in § 314.107(b)(3)(i) and 

(b)(3)(ii); 

—A copy of any documented agreement described in 

§ 314.107(b)(3)(vi); 

—A copy of any preliminary injunction described in 

§ 314.107(b)(3)(v), and a copy of any subsequent court order lifting the injunction; and 

—A copy of any court order pursuant to 35 U.S.C. 271(e)(4)(A) ordering that a 505(b)(2) application or ANDA may be approved 

no earlier than the date specified (irrespective of whether the injunction relates to a patent described in § 314.107(b)(3)). 

• All required information must be sent to the Office of Generic Drugs 

or to the appropriate division in the Office of New Drugs, as applicable, within 14 days of: 

—the date of entry by the court, 

—the date of appeal or expiration of the time for appeal, or 

—the date of documented agreement, as applicable. 

1These highlights describe important proposed revisions to our regulations, but should not be relied upon in place of the proposed regulation. 

Proposed § 314.107(e)(1)(i) would 

require a 505(b)(2) or ANDA applicant 

to submit a copy of any judgment by the 

court (district court or mandate of the 

court of appeals) finding a patent 

described in § 314.107(b)(3) invalid, 

unenforceable, or not infringed, or 

finding the patent valid and infringed. 

This proposed requirement imposes a 

duty on 505(b)(2) and ANDA applicants 

to notify FDA regarding any court 

judgment regardless of whether or not 

the action for patent infringement has 

resulted in a substantive determination 

by the court regarding validity, 

enforceability, and/or infringement of 

the patent. 

In addition, we are proposing to 

require 505(b)(2) and ANDA applicants 

to submit to FDA a copy of certain 

documented agreements and court 

actions other than judgments to 

facilitate FDA’s administration of the 

FD&C Act. Proposed § 314.107(e)(1)(i) 

would require a 505(b)(2) or ANDA 

applicant to submit a copy of a 

settlement order or consent decree 

signed and entered by the court (district 

court or court of appeals) finding a 

patent described in proposed 

§ 314.107(b)(3) invalid, unenforceable, 

or not infringed, or finding the patent 

valid and infringed. It should be noted 

that this proposal would require 

submission of written documentation 

that the parties have entered into a 

settlement that has terminated the 

patent infringement litigation, but does 

not require applicants to send copies of 

the actual settlement agreement to FDA 

(compare section 1112 of the MMA 

(requiring that generic drug applicants 

file certain agreements with the FTC)). 

Proposed § 314.107(e)(1)(ii) would 

require a 505(b)(2) or ANDA applicant 

to submit written notification of 

whether or not any action by the court 

described in § 314.107(e)(1)(i) has been 

appealed within the time permitted for 

an appeal. Proposed § 314.107(e)(1)(iii) 

and (e)(1)(iv) would require a 505(b)(2) 

or ANDA applicant to submit a copy of 

any order entered by the court 

terminating the 30-month or 71⁄2-year 

period described in proposed 

§ 314.107(b)(3)(i) and (b)(3)(ii), and any 

documented agreement described in 

proposed § 314.107(b)(3)(vi). Proposed 

§ 314.107(e)(1)(v) would require a 

505(b)(2) or ANDA applicant to submit 

a copy of any preliminary injunction 

described in § 314.107(b)(3)(v), and a 

copy of any subsequent court order 

lifting the injunction. Proposed 

§ 314.107(e)(1)(vi) would require a 

505(b)(2) or ANDA applicant to submit 

a copy of any court order pursuant to 35 

U.S.C. 271(e)(4)(A) ordering that a 

505(b)(2) application or ANDA may be 

approved no earlier than the date 

specified (irrespective of whether the 

injunction relates to a patent described 

in § 314.107(b)(3)). This revision is 

intended to conform with proposed 

§ 314.107(b)(4) (see section II.M.2.d). 

These court actions and documented 

agreements also may affect the timing of 

approval of a 505(b)(2) application or 

ANDA and frequently are unpublished. 

If an applicant is unsure whether a 

particular court action or documented 

agreement requires notification to FDA 

under proposed § 314.107(e), we 

recommend submission. 

We also are proposing to modify the 

timeframe for a 505(b)(2) or ANDA 

applicant to submit the required 

information to the appropriate division 

in OND or to OGD, as applicable, to 

ensure timely notification to FDA. 

Proposed § 314.107(e)(2) would require 

submission of all required information 

within 14 calendar days of entry by the 

court, the date of appeal or expiration of 

the time for appeal, or the date of 

written agreement, as applicable. We are 

proposing to change the timeframe for 

submission of required information 

from 10 working days to 14 calendar 

days for clarity and consistency with 

other counting conventions used in part 

314. 

II.M.6. Computation of the 45-Day Time 

Clock (Proposed § 314.107(f)) 

We are proposing to revise 

§ 314.107(f) to clarify the computation 

of the 45-day period after receipt of 

notice of paragraph IV certification and 

to enhance the requirements for 

notifying FDA of any legal action filed 


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within this timeframe. Table 15 

summarizes the proposed changes 

related to the 45-day period after receipt 

of notice of paragraph IV certification. 

We seek comment on the proposed 

notification requirement and alternative 

ways for FDA to monitor compliance 

with the FD&C Act. 

TABLE 15—HIGHLIGHTS OF PROPOSED CHANGES REGARDING THE 45-DAY PERIOD AFTER RECEIPT OF NOTICE OF

PARAGRAPH IV CERTIFICATION 1

Current regulations Proposed revisions to regulations 

Computation of 45-day time clock (§ 314.107(f)(1)) Computation of 45-day time clock (§ 314.107(f)(1)) 

• The 45-day clock described in § 314.107(b)(3) begins on the day 

after the date of receipt of the applicant’s notice of certification by the 

patent owner or its representative, and by the approved application 

holder. 

• The 45-day clock described in § 314.107(b)(3) as to each recipient 

required to receive notice of paragraph IV certification under 

§§ 314.52 or 314.95 begins on the day after the date of receipt of the 

applicant’s notice of certification by each recipient. 

Computation of 45-day time clock (§ 314.107(f)(2)) Notification of filing of legal action (§ 314.107(f)(2)(i) to (f)(2)(ii)) 

• The 505(b)(2) or ANDA applicant must notify FDA immediately of the 

filing of any legal action filed within 45 days of receipt of the notice of 

certification. 

• The 505(b)(2) or ANDA applicant must notify FDA in writing within 14 

days of the filing of any legal action filed within 45 days of receipt of 

the notice of certification by any recipient. 

• The notification to FDA of the legal action must include, among other 

things: (iv) A certification that an action for patent infringement identified by number, has been filed in an appropriate court on a specified 

date. 

• A patent owner or its representative may also notify FDA of the filing 

of any legal action for patent infringement. 

• The notification to FDA of the legal action must include, among other 

things: (iv) A statement that an action for patent infringement, identified by the court, case number and the patent number(s) of the patent(s) at issue in the action, has been filed in an appropriate court 

on a specified date. 

• A patent owner or NDA holder (or their representatives) may also 

notify FDA of the filing of any legal action for patent infringement. 

Computation of 45-day time clock (§ 314.107(f)(2)) Notification of filing of legal action (§ 314.107(f)(2)(iii)) 

• If the 505(b)(2) or ANDA applicant or the patent owner or its representative does not notify FDA in writing before the expiration of the 

45-day time period or the completion of the Agency’s review of the 

application, whichever occurs later, that a legal action for patent infringement was filed within 45 days of receipt of the notice of certification, approval of the 505(b)(2) application or ANDA will be made 

effective immediately upon expiration of the 45 days or upon completion of FDA’s review and approval of the application, whichever is 

later. 

• If the 505(b)(2) or ANDA applicant, the patent owner(s), the NDA 

holder, or their representatives do not notify FDA in writing before 

the expiration of the 45-day time period or the completion of the 

Agency’s review of the 505(b)(2) application or ANDA, whichever occurs later, that a legal action for patent infringement was filed within 

45 days of receipt of the notice of paragraph IV certification, the 

505(b)(2) application or ANDA may be approved upon expiration of 

the 45-day period (if the 505(b)(2) or ANDA applicant confirms that a 

legal action for patent infringement has not been filed) or upon completion of FDA’s review of the 505(b)(2) application or ANDA, whichever is later. 

Computation of 45-day time clock (§ 314.107(f)(3)) Waiver (§ 314.107(f)(3)) 

• If the patent owner or approved application holder who is an exclusive patent licensee waives its opportunity to file a legal action for 

patent infringement within 45 days of a receipt of the notice of certification and the patent owner or approved application holder who is 

an exclusive patent licensee submits to FDA a valid waiver before 

the 45 days elapse, approval of the ANDA or the 505(b)(2) application will be made effective upon completion of FDA’s review and approval of the application. FDA will only accept a waiver in the form 

specified in § 314.107(f)(3)). 

• If the patent owner or NDA holder who is an exclusive patent licensee (or their representatives) waives its opportunity to file a legal 

action for patent infringement within 45 days of a receipt of the notice of certification and the patent owner or NDA holder who is an 

exclusive patent licensee (or their representatives) submits to FDA a 

valid waiver before the 45 days elapse, the 505(b)(2) application or 

ANDA may be approved upon completion of the Agency’s review of 

the application. FDA will only accept a waiver in the form specified in 

§ 314.107(f)(3), as proposed for revision. 

1These highlights describe important proposed revisions to our regulations, but should not be relied upon in place of the proposed regulation. 

We are proposing to revise 

§ 314.107(f)(1) to clarify that the 45-day 

period after receipt of notice of 

paragraph IV certification is calculated 

for each recipient required to be notified 

under §§ 314.52(a) and 314.95(a). This 

proposed revision would codify FDA’s 

longstanding interpretation of section 

505(b)(3) and (j)(2)(B) of the FD&C Act, 

as amended by the MMA. This 

interpretation ensures that each person 

required to receive notice under 

§ 314.52 or § 314.95, as applicable, also 

receives the full 45-day period in order 

to evaluate whether to initiate an action 

for patent infringement and obtain a 30- 

month (or 71⁄2-year) stay of approval 

while litigation is pending. Accordingly, 

a 505(b)(2) or ANDA applicant’s notice 

of paragraph IV certification may result 

in more than one ‘‘45-day clock’’ if the 

NDA holder and patent owners(s) are 

different entities and receive notice of 

paragraph IV certification on different 

days. 

Proposed § 314.107(f)(2) would 

require that a 505(b)(2) or ANDA 

applicant notify FDA in writing within 

14 calendar days of the filing of any 

legal action filed within 45 days of 

receipt of the notice of certification. We 

are proposing to replace the current 

requirement for ‘‘immediate’’ 

notification to establish a date certain by 

which the applicant must send written 

notification to FDA. This revision is 

intended to enhance compliance and 

conform with proposed § 314.107(e), 

which would require a 505(b)(2) or 

ANDA applicant to submit notification 

of court actions and documented 

agreements (and a copy of certain court 

actions) to FDA within 14 calendar days 

of entry by the court, the date of appeal 

or expiration of the time for appeal, or 

the date of documented agreement, as 

applicable (see section II.M.5). 

We also are proposing to revise 

§ 314.107(f)(2)(iv) (redesignated as 

§ 314.107(f)(2)(i)(D)) to eliminate the 

requirement that the notification to the 

Agency include a ‘‘certification’’ that an 

action has been filed. This requirement 

has resulted in confusion, and the 

Agency has concluded that a written 

‘‘statement’’ containing the necessary 

information is adequate. We are 

proposing to require that this statement 

contain the patent number(s) of the 

listed patent(s) at issue in the patent 

infringement action, in addition to the 

court and case number. The patent 

number(s) of the listed patent(s) at issue 

in the litigation will assist FDA in its 

administration of the approval 


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requirements for 505(b)(2) applications 

and ANDAs. 

We are proposing to expressly state 

that an NDA holder or its representative 

also may notify FDA of the filing of any 

legal action for patent infringement, 

irrespective of whether the NDA holder 

is an exclusive patent licensee and 

initiated the patent infringement action. 

The notification must be sent to the 

appropriate office or division and 

contain the information described in 

proposed § 314.107(f)(2)(i). 

Proposed § 314.107(f)(2)(iii) clarifies 

that a 505(b)(2) application or ANDA 

may be approved upon expiration of the 

45-day period (if the 505(b)(2) or ANDA 

applicant confirms that a legal action for 

patent infringement has not been filed 

within the 45-day period) or upon 

completion of FDA’s review of the 

505(b)(2) application or ANDA, 

whichever is later. This provision 

would apply, for example, if an 

applicant changed a paragraph III 

certification or a statement pursuant to 

section 505(b)(2)(B) or 505(j)(2)(A)(viii), 

as applicable, to a paragraph IV 

certification during review of the 

505(b)(2) application or ANDA and the 

45-day period had not elapsed by the 

time the office or division was ready to 

take an action on the application. It is 

unlikely that this provision would be 

implicated in most cases, however, 

because a 505(b)(2) or ANDA applicant 

is required by statute to provide notice 

of paragraph IV certification not later 

than 20 days after the date of the 

postmark on the acknowledgment letter 

or paragraph IV acknowledgment letter, 

and review of an application would not 

be expected to be completed before the 

45-day period for each recipient had 

ended. The proposed revisions to 

§ 314.107(f)(2)(iii) and (f)(3) would 

replace the current references to the 

approval of a 505(b)(2) application or 

ANDA being made effective because this 

text incorrectly suggests that FDA might 

issue an approval letter that would 

become effective at some date in the 

future (see section II.A.2.dd and II.I). In 

addition, proposed § 314.107(f)(2)(iii) 

clarifies that FDA would not approve a 

505(b)(2) application or ANDA upon 

expiration of the 45-day period unless 

the 505(b)(2) or ANDA applicant had 

confirmed that a legal action for patent 

infringement had not been filed. 

Proposed § 314.107(f)(3) would permit 

a representative of the patent owner or 

NDA holder who is an exclusive patent 

licensee to waive the opportunity to file 

a patent infringement action within the 

45-day period. This revision is intended 

to conform with other sections of part 

314, including §§ 314.52 and 314.95 

which permit notice of paragraph IV 

certification to be sent to a 

representative designated by the patent 

owner to receive notice and the NDA 

holder’s attorney, agent, or other 

authorized official. 

Finally, we are proposing to revise the 

title to § 314.107(f) and add titles to 

paragraphs (f)(1), (f)(2), and (f)(3) of that 

section for administrative convenience. 

II.M.7. Conversion of Approval to 

Tentative Approval (Proposed 

§ 314.107(g)) 

We are proposing to add § 314.107(g) 

to clarify that if FDA issues an approval 

letter in error or a court enters an order 

requiring that the date of approval be 

delayed for an already approved 

505(b)(2) application or ANDA, FDA 

will convert the approval to a tentative 

approval if appropriate. 

An approved application may be 

converted to tentatively approved status 

if a court determines that a listed patent 

has been infringed by a 505(b)(2) or 

ANDA applicant and issues an order 

pursuant to 35 U.S.C. 271(e)(4) requiring 

that the effective date of approval shall 

not be earlier than the date on which the 

infringed patent will expire, including 

any pediatric exclusivity that may 

attach to that patent (see, e.g., Mylan 

Labs., Inc. v. Thompson, 389 F.3d 1272 

(D.C. Cir. 2004)). In addition, FDA will 

convert an approval to tentatively 

approved status if the approval letter 

was issued in error (for example, if an 

ANDA applicant failed to notify FDA of 

an adverse decision in patent 

infringement litigation). 

II.N. Assessing Bioavailability and 

Bioequivalence for Drugs Not Intended 

To Be Absorbed Into the Bloodstream 

(Proposed § 320.23) 

The MMA amends section 505(j)(8) of 

the FD&C Act to explicitly authorize 

FDA to establish methods for assessing 

bioavailability and bioequivalence for 

drugs that are not absorbed into the 

bloodstream (see section 505(j)(8)(A)(ii) 

and (j)(8)(C) of the FD&C Act). These 

amendments essentially codify our 

existing practice of establishing such 

methods, as reflected in current 

§§ 320.23(a)(1) and 320.24 and in our 

implementation of these regulations. 

Our proposal would revise the text of 

§ 320.23 to more precisely reflect the 

text of section 505(j)(8) of the FD&C Act. 

However, these proposed revisions are 

not intended to change our current 

interpretation of § 320.23, as the 

amendments to section 505(j)(8) of the 

FD&C Act are intended to codify our 

existing interpretation (see section 

1103(b) of the MMA, which specifically 

states that the amendments made to 

section 505(j)(8) of the FD&C Act ‘‘do[] 

not alter the standards for approval of 

[ANDAs].’’). 

II.O. Miscellaneous 

II.O.1. Clarifying Revisions and Editorial 

Changes 

We are proposing several clarifying 

revisions and editorial changes 

throughout the sections of parts 314 and 

320 that are the subject of this 

rulemaking. These changes are intended 

to promote consistency throughout our 

regulations, incorporate ‘‘plain 

language,’’ employ grammatically 

correct phrasing, and otherwise clarify 

the text of these regulations. Examples 

of proposed revisions that are not 

otherwise described in this document 

are provided below. 

• Change ‘‘means’’ to ‘‘is’’ after each 

term described in the definitions section 

(see proposed § 314.3(b)); 

• change ‘‘shall’’ to ‘‘must’’ as 

appropriate (see generally part 314); 

• change ‘‘are required’’ to ‘‘must’’ 

because an applicant is always required 

to comply with applicable regulations 

(see proposed § 314.50(d)(5)); 

• change ‘‘prior to the submission of’’ 

to ‘‘before submitting’’ for clarity (see 

proposed § 314.50(d)(5)); 

• change ‘‘claims no uses’’ to ‘‘does 

not claim a use’’ to correct grammar (see 

proposed §§ 314.52(a) and 314.95(a)); 

and 

• change ‘‘each amendment to 

§ 314.50(d)(1)’’ to ‘‘each amendment to 

a section of the NDA described in 

§ 314.50(d)(1)’’ for clarity (see proposed 

§ 314.60(d)). 

In the codified section of this 

proposed rule, we have indicated 

proposed editorial changes as 

amendatory instructions to remove and 

add text. In some instances, however, it 

was necessary to print an entire 

paragraph to indicate proposed changes 

that are only editorial changes and 

would not affect substantive portions of 

the proposed rule. 

We also are proposing to correct 

statutory citations in part 314 that have 

changed due to a series of amendments 

to the FD&C Act (see, e.g., proposed 

§§ 314.52(c), 314.60(c), and 314.95(c) 

and (f)). 

II.O.2. Effect of Other Rulemaking 

In anticipation of the Agency’s 

business process efforts to move all 

submissions to FDA to electronic 

submission, we are proposing certain 

revisions to provisions that clearly 

contemplate submission of paper to 

facilitate the transition to electronic 

submissions and reduce the volume of 

conforming revisions that may be 

needed in the future. Examples of these 

proposed revisions are provided below: 


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• Change ‘‘in a form other than hard 

copy, for example, on microfiche or 

computer tapes’’ to ‘‘in an alternate 

form’’ to reflect advances in technology 

and facilitate the transition to electronic 

submissions (see proposed 

§ 314.50(f)(4)); 

• delete references to ‘‘mailing cover’’ 

(see proposed §§ 314.53(d)(6) and 

314.70(b)(4)); and 

• change ‘‘cover letter’’ to 

‘‘submission’’ (see proposed 

§ 314.70(a)(6)). 

FDA is committed to adapting its 

business practices to evolving 

technology, including using the 

significant advancements in Web-based, 

electronic systems. We anticipate that 

Web-based filing of most submissions 

eventually will be required. We 

anticipate that when such a change to 

an electronic submission system is 

implemented, future guidance will 

address any technical questions related 

to such submissions. Until such time, 

the sponsor or applicant must submit 

them in the manner described in the 

regulations and to the appropriate FDA 

location identified in the regulations. 

III. Legal Authority 

The MMA and sections 505, 505A, 

527, and 701 (21 U.S.C. 360cc and 371) 

of the FD&C Act provide the principal 

legal authority for this proposed rule. 

Section 505(b) of the FD&C Act 

describes the contents of an NDA and 

505(b)(2) application, including patent 

listing and patent certification 

requirements. Section 505(j) of the 

FD&C Act describes the contents of an 

ANDA, including bioequivalence 

information, patent certification 

requirements, and criteria for a 

petitioned ANDA. Section 505(b) and (j) 

of the FD&C Act restrict certain 

amendments and supplements to a 

505(b)(2) application or an ANDA. 

Section 505(b), (c), and (j) of the FD&C 

Act describe the timing of approval for 

505(b)(2) applications and ANDAs that 

are subject to the patent and marketing 

exclusivity protections accorded the 

listed drug(s) relied upon and the RLD, 

respectively. Section 505(j) also 

describes the availability of 180-day 

exclusivity for a first ANDA applicant. 

Section 505A of the FD&C Act 

describes the availability of pediatric 

exclusivity and describes the effect of 

such exclusivity on approval of 

505(b)(2) applications and ANDAs. 

Section 527 of the FD&C Act describes 

the effect of orphan exclusivity on 

approval of 505(b)(2) applications and 

ANDAs. 

Thus, sections 505, 505A, and 527 of 

the FD&C Act, in conjunction with our 

general rulemaking authority in section 

701(a) of the FD&C Act, serve as our 

principal legal authority for this 

proposal. 

IV. Analysis of Impacts 

FDA has examined the impacts of the 

proposed rule under Executive Order 

12866, Executive Order 13563, the 

Regulatory Flexibility Act (5 U.S.C. 

601–612), and the Unfunded Mandates 

Reform Act of 1995 (Pub. L. 104–4). 

Executive Orders 12866 and 13563 

direct Agencies to assess all costs and 

benefits of available regulatory 

alternatives and, when regulation is 

necessary, to select regulatory 

approaches that maximize net benefits 

(including potential economic, 

environmental, public health and safety, 

and other advantages; distributive 

impacts; and equity). 

The Regulatory Flexibility Act 

requires Agencies to analyze regulatory 

options that would minimize any 

significant impact of a rule on small 

entities. We do not believe this 

proposed rule would result in a 

significant impact on a substantial 

number of small entities, but the 

impacts are uncertain. Because we are 

uncertain whether the proposed rule 

would have a significant economic 

impact on a substantial number of small 

entities, this and other sections of the 

preamble and the full preliminary 

regulatory impact analysis constitute the 

Agency’s regulatory flexibility analysis. 

Section 202(a) of the Unfunded 

Mandates Reform Act of 1995 requires 

that Agencies prepare a written 

statement, which includes an 

assessment of anticipated costs and 

benefits, before proposing ‘‘any rule that 

includes any Federal mandate that may 

result in the expenditure by State, local, 

and tribal governments, in the aggregate, 

or by the private sector, of $100,000,000 

or more (adjusted annually for inflation) 

in any one year.’’ The current threshold 

after adjustment for inflation is $141 

million, using the most current (20132) 

Implicit Price Deflator for the Gross 

Domestic Product. FDA does not expect 

this proposed rule to result in any 1- 

year expenditure that would meet or 

exceed this amount. 

This proposed rule would implement 

portions of the MMA in a manner that 

preserves the balance struck in the 1984 

Hatch-Waxman Amendments between 

encouraging the availability of less 

expensive generic drugs and bringing 

innovative new drugs to market. This 

rule would also revise and clarify 

procedures related to the approval of 

505(b)(2) applications and ANDAs to 

reduce uncertainty among drug firms, 

reduce costs to industry, and reduce 

demands on FDA resources responding 

to industry inquiries. 

FDA has been implementing the 

MMA directly from the statute for 

several years and based on this 

experience has identified opportunities 

to clarify MMA provisions through the 

adoption of codified language. To the 

extent that clarified regulatory language 

improves certainty among regulated 

entities, this proposal, if promulgated, 

would reduce industry compliance costs 

and Agency enforcement costs. The full 

discussion of economic impacts is 

available in docket FDA–2011–N–0830 

and at http://www.fda.gov/AboutFDA/

ReportsManualsForms/Reports/

EconomicAnalyses/default.htm (Ref. 1). 

IV.A. Summary of the Benefits and 

Costs of the Proposed Rule 

Although many provisions of this 

proposed rule would codify current 

practice, elements of this proposal 

would lead to changes that generate 

additional benefits and costs. This 

proposed rule would affect applicants 

and application holders for NDAs 

(including 505(b)(2) applications) and 

ANDAs. Provisions of this rule would 

affect the submission of patent 

information by NDA holders for listing 

in the Orange Book and the submission 

by 505(b)(2) and ANDA applicants of a 

patent certification or statement 

addressing the listed patent(s) for the 

listed drug(s) relied upon or RLD, 

respectively. This proposed rule would 

also affect, for those certifying that a 

listed patent is invalid, unenforceable, 

or not infringed (paragraph IV 

certification), the requirements for the 

provision of notice of the paragraph IV 

certification to each patent owner and 

the NDA holder for the listed drug. The 

proposed rule would also affect other 

requirements associated with 505(b)(2) 

applications and ANDAs. 

This proposed rule would revise 

certain aspects of the regulations on 

listing of patent information, patent 

certification requirements, and a 30- 

month stay of approval. It would also 

update regulations pertaining to the 

type of bioavailability and 

bioequivalence data that can be used to 

support 505(b)(2) applications and 

ANDAs. These proposed revisions to the 

Agency’s regulations in parts 314 and 

320 would implement portions of Title 

XI of the MMA and facilitate 

compliance with and enforcement of the 

FD&C Act. 

We present a summary of benefits and 

costs in Table 16. The estimated annual 

monetized benefits of this proposed rule 

are $194,314, and estimated annual 

monetized costs are $91,371. We have 

also identified, but are unable to 


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quantify, impacts from proposed 

changes to submitted patent information 

and the implementation of an 

administrative consequence for failing 

to provide notice within the timeframe 

specified by the MMA. 

TABLE 16—ECONOMIC DATA: COSTS AND BENEFITS STATEMENT

Category Primary 

estimate 

Low 

estimate 

High 

estimate 

Units 

Notes 

Year dollars Discount 

rate 

Period 

covered 

Benefits 

Annualized Monetized $millions/year ........... $0.19 $0.19 $0.19 .................... 7% Annual ....................

$0.19 $0.19 $0.19 .................... 3% Annual ....................

Annualized Quantified ................................... ................ ................ ................ .................... 7% Annual ....................

....................

Qualitative ..................................................... ................ ................ ................ .................... 3% Annual ....................

Costs 

Annualized Monetized $millions/year ........... $0.09 $0.09 $0.09 2012 7% Annual ....................

$0.09 $0.09 $0.09 2012 3% Annual ....................

Annualized Quantified ................................... ................ ................ ................ .................... 7% .................... ....................

Qualitative ..................................................... ................ ................ ................ .................... 3% ....................

Transfers 

Federal Annualized Monetized $millions/

year ........................................................... ................ ................ ................ .................... 7% .................... None. 

................ ................ ................ .................... 3% ....................

From/To ........................................................ From: To: 

Other Annualized Monetized $millions/year ................ ................ ................ .................... 7% .................... None. 

From/To ........................................................ From: To: 3% 

Effects 

State, Local, or Tribal Government: Not applicable 

Small Business: For firms with 25 to 49 employees, which is a more likely lower bound for firms submitting 505(b)(2) applications, the unit cost 

of this provision would be less than 0.05 percent of average shipments. 

Wages: No estimated effect 

Growth: No estimated effect 

IV.B. Summary of Regulatory Flexibility 

Analysis 

FDA conducted a regulatory 

flexibility analysis of the impact of the 

proposed rule on small entities. 

Statistics on the classification of firms 

by employment size from the U.S. 

Bureau of the Census show that in 2005, 

at least 85 percent of pharmaceutical 

manufacturing entities had fewer than 

500 employees and would have been 

considered small by the U.S. Small 

Business Administration (Ref. 2). 

We have provided monetized 

estimates for $194,314 in benefits and 

$91,371 in costs. These costs of this 

proposed rule are generally small unit 

costs incurred across many entities. Our 

estimated unit costs for all but one item 

are less than $190 per unit. In table 17, 

we express the unit cost of an 

amendment to a patent certification in 

terms of hundredths of a percent of 

average establishment shipments. 

Excluding one item (505(b)(2) 

applicants providing a patent 

certification to a pharmaceutically 

equivalent drug product), there are costs 

of $83,146 attributable to about 1,200 

units. Some affected entities would face 

multiple unit costs of some type in a 

year, but even this circumstance would 

not approach a significant impact on a 

substantial number of small entities. For 

a unit cost of $190 to amount to 1 

percent of average shipments among 

establishment with fewer than 5 

employees, the entity would have to 

incur that cost more than 40 times. 

TABLE 17—SMALL ENTITY CHARACTERISTICS AND THE IMPACT OF UNIT COSTS ATTRIBUTABLE TO THIS PROPOSED RULE

Pharmaceutical Preparation 

Manufacturing 

(NAICS 325412) 

No. of Employees ............................................................................................................................................ <5 20–49 

Total Value of Shipments ($1,000) .................................................................................................................. 187,933 978,494 

No. of Establishments ...................................................................................................................................... 228 109 

Average Value of Shipments ($) ..................................................................................................................... 824,268 8,977,009 

Unit Costs of Identifying a Pharmaceutically Equivalent Drug Product as a Listed Drug Relied Upon per 

§ 314.50(i)(1)(i)(C) as a Percentage of the Average Value of Shipments .................................................. 0.50% 0.046% 

V. Paperwork Reduction Act of 1995 

This proposed rule contains 

information collection requirements that 

are subject to public comment and 

review by the Office of Management and 

Budget (OMB) under the Paperwork 

Reduction Act of 1995 (44 U.S.C. 3501– 

3520). We describe these provisions 

below in this section of the document 

with an estimate of the annual reporting 

burden. Our estimate includes the time 

for reviewing instructions, searching 

existing data sources, gathering and 

maintaining the data needed, and 

completing and reviewing each 

collection of information. 


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We invite comments on these topics: 

(1) Whether the proposed collection of 

information is necessary for the proper 

performance of FDA’s functions, 

including whether the information will 

have practical utility; (2) the accuracy of 

FDA’s estimate of the burden of the 

proposed collection of information, 

including the validity of the 

methodology and assumptions used; (3) 

ways to enhance the quality, utility, and 

clarity of the information to be 

collected; and (4) ways to minimize the 

burden of the collection of information 

on respondents, including through the 

use of automated collection techniques, 

when appropriate, and other forms of 

information technology. 

Title: Abbreviated New Drug 

Applications and 505(b)(2) 

Applications; Proposed Revisions to 

Implement Portions of the Medicare 

Prescription Drug, Improvement, and 

Modernization Act of 2003 and Other 

Changes. 

Description of Respondents: 

Respondents to this collection of 

information are NDA applicants 

(including 505(b)(2) applicants) and 

ANDA applicants, patent owners, and 

their representatives. 

Burden Estimate: This proposed rule 

would implement portions of Title XI of 

the MMA that pertain to a 505(b)(2) or 

ANDA applicant’s provision of notice of 

paragraph IV certification to each patent 

owner and the NDA holder; the 

availability of 30-month stays of 

approval on 505(b)(2) applications and 

ANDAs that are otherwise ready to be 

approved; submission of amendments 

and supplements to 505(b)(2) 

applications and ANDAs; and the types 

of bioavailability and bioequivalence 

data that can be used to support these 

applications. This proposed rule also 

would amend certain regulations 

regarding 505(b)(2) applications and 

ANDAs to facilitate compliance with 

and efficient enforcement of the FD&C 

Act. 

FDA currently has OMB approval for 

the collection of information entitled 

‘‘Application for Food and Drug 

Administration Approval to Market a 

New Drug’’ (OMB control number 0910– 

0001). This collection of information 

includes, among other things: 

• The requirements in §§ 314.50(i) 

and 314.94(a)(12) for submission of an 

appropriate patent certification or 

statement in a 505(b)(2) application or 

ANDA; 

• the requirements in §§ 314.52 and 

314.95 for a 505(b)(2) or ANDA 

applicant to send notice of any 

paragraph IV certification to each patent 

owner and the NDA holder and amend 

its 505(b)(2) application or ANDA to 

certify that notice has been provided 

and to document receipt of the notice; 

• the content requirements in 

§ 314.54 for a 505(b)(2) application; 

• the requirements in §§ 314.60 and 

314.96 for applicants that amend an 

unapproved 505(b)(2) application or 

ANDA, respectively; 

• the requirements in §§ 314.70 and 

314.97 for supplements submitted to 

FDA for certain changes to an approved 

505(b)(2) application or ANDA; 

• the requirements in §§ 314.90 and 

314.99 for applicants that request 

waivers from FDA for compliance with 

§§ 314.50 through 314.81 or §§ 314.92 

through 314.99, respectively; 

• the procedures in § 314.107(c) by 

which a first applicant notifies FDA of 

the date of first commercial marketing; 

• the requirement in § 314.107(e) for 

an applicant to submit to FDA a copy 

of certain court decisions related to a 

patent that is the subject of a paragraph 

IV certification; 

• the requirement in § 314.107(f) for a 

505(b)(2) or ANDA applicant to notify 

FDA immediately of the filing of any 

legal action within 45 days of receipt of 

the notice of paragraph IV certification 

by each patent owner or the NDA 

holder; and 

• the requirement in § 314.107(f) for a 

patent owner or NDA holder who is an 

exclusive patent licensee that waives its 

opportunity to file a legal action for 

patent infringement within the 45-day 

period to submit to FDA a waiver in the 

specified format. 

FDA has OMB approval for the 

collection of information entitled 

‘‘General Administrative Procedures: 

Citizen Petitions; Petition for 

Reconsideration or Stay of Action; 

Advisory Opinions’’ (OMB control 

number 0910–0183). This collection of 

information includes, among other 

things, the requirements in § 314.93 for 

submitting a suitability petition in 

accordance with 21 CFR 10.20 and 

10.30. 

FDA also has received OMB approval 

for the collection of information entitled 

‘‘Applications for Food and Drug 

Administration Approval to Market a 

New Drug: Patent Submission and 

Listing Requirements and Application 

of 30-Month Stays on Approval of 

Abbreviated New Drug Applications 

Certifying That a Patent Claiming a Drug 

is Invalid or Will Not Be Infringed’’ 

(OMB control number 0910–0513). This 

collection of information includes the 

requirements in § 314.50(h) for 

submission of patent information in an 

NDA, an amendment, or a supplement, 

as described in § 314.53. Section 314.53 

requires that an applicant submitting an 

NDA, an amendment, or a supplement, 

except as provided in § 314.53(d)(2), 

submit on Forms FDA 3542a and 3542 

the required patent information 

described in this section. 

We are not reestimating these 

approved burdens. Only the reporting 

burdens associated with the MMA’s 

amendments to the FD&C Act and the 

proposed changes to parts 314 and 320 

are estimated. 

Under section 505(b), (c), and (j) of 

the FD&C Act and this proposed rule, 

the following information would be 

submitted to FDA but is not currently 

approved by OMB under the PRA: 

Proposed § 314.50(i)(1)(i)(C) would 

require a 505(b)(2) applicant to submit 

an appropriate patent certification or 

statement for each patent listed in the 

Orange Book for a drug product(s) that 

is pharmaceutically equivalent to the 

proposed drug product for which the 

505(b)(2) application is submitted. 

Proposed § 314.54 would require a 

505(b)(2) applicant to identify a 

pharmaceutically equivalent product as 

a listed drug relied upon and to comply 

with applicable regulatory 

requirements. Generally, 505(b)(2) 

applications submitted for a proposed 

drug product for which there is an 

approved pharmaceutical equivalent 

already cite the pharmaceutically 

equivalent product as a listed drug 

relied upon to support approval. 

Therefore, we are not estimating a new 

burden for proposed § 314.54 at this 

time. Based on our experience 

reviewing 505(b)(2) applications, we 

estimate that proposed 

§ 314.50(i)(1)(i)(C) may result in 

approximately two instances per year in 

which an applicant is required to 

identify a pharmaceutically equivalent 

drug product as a listed drug relied 

upon and comply with applicable 

regulatory requirements (including 

submission of an appropriate patent 

certification or statement for each patent 

listed in the Orange Book for the 

pharmaceutically equivalent listed drug 

relied upon). Based on an estimated 

average of 2.6 patents by each NDA 

holder for listing in the Orange Book, 

we estimate that there will be 5.2 

responses per year, and the burden 

hours associated with this requirement 

in proposed § 314.50(i)(1)(i)(C) will be 

approximately 2 hours per response. If 

the patent certification submitted 

pursuant to proposed § 314.50(i)(1)(i)(C) 

is a paragraph IV certification, the 

applicant also must comply with the 

requirements in § 314.52 for notice of 

paragraph IV certification, which add 


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approximately 80 hours (15.33 hours 

per response) to the currently approved 

burden hours. This estimate reflects 

other proposals described in this section 

of the document that would reduce the 

currently approved burden for § 314.52 

from 16 hours per response to 15 hours 

per response, and the additional content 

requirement in proposed § 314.52(c) that 

would increase the estimated burden by 

0.33 hours per response. As previously 

noted, we are not reestimating approved 

burdens in this document. Accordingly, 

the estimate provided for § 314.52(a), 

(b), (c), and (e) reflects the additional 

burden that may arise from the 

requirement in proposed 

§ 314.50(i)(1)(i)(C) if the 505(b)(2) 

applicant submits a paragraph IV 

certification. We separately describe and 

estimate the burden of the additional 

content requirement in proposed 

§ 314.52(c) for the estimated average of 

seven 505(b)(2) applications filed per 

year that contain one or more paragraph 

IV certification. 

Proposed §§ 314.50(i)(6) and 

314.94(a)(12)(viii) would require a 

505(b)(2) or ANDA applicant to amend 

its patent certification from a paragraph 

IV certification to a paragraph III 

certification after the court enters a final 

decision from which no appeal has been 

or can be taken, or signs a settlement 

order or consent decree with a finding 

of infringement (unless the patent also 

is found invalid). Proposed 

§§ 314.50(i)(6) and 314.94(a)(12)(viii) 

also would require a 505(b)(2) or ANDA 

applicant to submit an amended patent 

certification in certain circumstances 

after the NDA holder has requested to 

remove a patent or patent information 

from the list. Based on our experience 

and review of selected court decisions, 

we estimate that there are 

approximately 12 instances per year in 

which a party has submitted a court 

decision or order with a finding of 

infringement. In addition, there are 

approximately 24 instances per year in 

which the NDA holder has requested to 

remove a patent or patent information 

from the list and the patent or patent 

information has been removed. Based 

on our experience, we estimate that this 

requirement may result in 

approximately 36 and 108 instances per 

year in which an applicant amends its 

505(b)(2) application or ANDA, 

respectively, to submit a revised patent 

certification, and the burden hours 

associated with this requirement will be 

approximately 2 hours per response. 

Proposed §§ 314.50(i)(6)(iii)(A)(2) and 

314.94(a)(12)(vi)(C)(1)(ii) would 

expressly codify the current 

requirement for a 505(b)(2) or ANDA 

applicant to submit a patent 

certification or statement if, after 

submission of the application, a new 

patent is issued by the PTO that in the 

opinion of the applicant and to the best 

of its knowledge, claims the listed drug 

or an approved use for such listed drug 

and for which information is required to 

be filed by the NDA holder. The burden 

hours associated with compliance with 

current provisions of §§ 314.50(i)(1) 

through (i)(6) and 314.94(a)(12)(i) 

through (a)(12)(viii) are described in the 

burden hours estimate currently 

approved under OMB control number 

0910–0001. 

Proposed §§ 314.52(a) and 314.95(a) 

would expand the list of acceptable 

delivery methods that may be used to 

send notice of paragraph IV certification 

to the NDA holder and each patent 

owner, and thereby reduce the burden 

on applicants to submit, under current 

§§ 314.52(a) and (e), a request to FDA to 

use common alternate delivery methods. 

We receive approximately 205 written 

inquiries per year from 505(b)(2) or 

ANDA applicants requesting permission 

to send notice of paragraph IV 

certification by an overnight delivery 

service. Proposed §§ 314.52(a) and 

314.95(a) would eliminate the 

requirement to submit a request to use 

a designated delivery service, as defined 

in proposed §§ 314.52(f) and 314.95(f). 

We estimate that approximately 95 

percent of these written inquiries will 

no longer be required because the 

alternate delivery method would fall 

within the definition of a ‘‘designated 

delivery service’’ in proposed 

§§ 314.52(g) and 314.95(g). 

Proposed §§ 314.52(c) and 314.95(c) 

would require that notice of paragraph 

IV certification contain a statement that 

the applicant has received the 

acknowledgment letter or the paragraph 

IV acknowledgment letter, as applicable. 

In addition, proposed § 314.52(c) would 

require that the notice of paragraph IV 

certification contain a statement that a 

505(b)(2) application that contains any 

required bioavailability or 

bioequivalence data has been submitted 

by the applicant and filed by FDA, as 

required by section 505(b)(3)(D)(i) of the 

FD&C Act. We estimate that these 

additional content requirements for the 

notice of paragraph IV certification 

would increase the burden of providing 

notice of paragraph IV certification by 

approximately 20 minutes. Based on an 

estimated average of 7 505(b)(2) 

applications filed per year that contain 

one or more paragraph IV certifications 

and 209 ANDAs received per year that 

contain one or more paragraph IV 

certifications, we estimate that there 

will be 21 and 627 responses per year, 

and the burden hours associated with 

this requirement will be approximately 

20 minutes per response. 

Proposed §§ 314.52(d)(1) and 

314.95(d)(1) would require notice of 

paragraph IV certification regardless of 

whether notice has already been 

provided for another paragraph IV 

certification contained in the 505(b)(2) 

application or ANDA or an amendment 

or supplement to the 505(b)(2) 

application or ANDA, as required by 

section 505(b)(3)(B)(ii) and 

(j)(2)(B)(ii)(II) of the FD&C Act. Since 

enactment of the MMA, FDA has 

regulated directly from the statute and 

required notice of paragraph IV 

certification in these circumstances. 

Thus, the burden associated with this 

statutory requirement is reflected in the 

burden hours estimate for §§ 314.52 and 

314.95 currently approved under OMB 

control number 0910–0001. 

Proposed §§ 314.52(e) and 314.95(e) 

would permit a 505(b)(2) or ANDA 

applicant to submit a single amendment 

containing documentation of timely 

sending and receipt of notice of 

paragraph IV certification. Currently, an 

applicant is required to amend its 

505(b)(2) application or ANDA both at 

the time of sending notice of paragraph 

IV certification and after the notice was 

received by each patent owner and the 

NDA holder (see current §§ 314.52(b) 

and (e) and 314.95(b) and (e)). Proposed 

§ 314.95(e) also would require an ANDA 

applicant to include in its amendment 

a dated printout of the Orange Book 

entry for the RLD. FDA has OMB 

approval for the burden hours estimate 

of 16 hours per response for the 

estimated 260 responses submitted 

annually to comply with §§ 314.52 and 

314.95 (see OMB control number 0910– 

0001). We estimate that 2 hours of the 

16 hours per response are attributable to 

compliance with current §§ 314.52(b) 

and (e) and 314.95(b) and (e). We 

estimate that the burden hours 

associated with the requirement in 

proposed §§ 314.52(e) and 314.95(e) 

(including submission of the dated 

printout of the Orange Book entry) 

would be approximately 1 hour per 

response for each of the estimated 7 and 

209 responses per year by our updated 

estimate of 7 505(b)(2) applicants and 

209 ANDA applicants whose 

applications were filed or received, as 

applicable, by FDA and contained one 

or more paragraph IV certifications. 

Therefore, the proposal would reduce 

the currently approved burden for 

§§ 314.52 and 314.95 by 1 hour. 

Proposed § 314.53(c)(2) would 

decrease the patent information that 

NDA applicants are currently required 

to submit for listing in the Orange Book. 


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Proposed § 314.53(c)(2) would require 

an NDA applicant to submit information 

on a previously submitted patent only if 

a patent is a reissued patent of a patent 

previously submitted for listing for the 

NDA or supplement. Proposed 

§ 314.53(c)(2) would require submission 

of patent information on whether a drug 

substance patent claims a polymorph 

only if such patent claims only a 

polymorph that is the same active 

ingredient described in the NDA or 

supplement. Proposed § 314.53(c)(2) 

also would provide that an applicant 

that submits information for a patent 

that claims either the drug substance or 

drug product and meets the 

requirements for patent listing on that 

basis is not required to provide 

information on whether that patent also 

claims the drug product or drug 

substance, respectively. The information 

collection resulting from current 

§ 314.50(h) (citing § 314.53) and Form 

FDA 3542a has been approved by OMB 

under control number 0910–0153 for 

FDA’s estimate of 20 hours per 

response. We estimate the proposed 

revisions to our regulations will reduce 

the time needed to complete Form FDA 

3542a by approximately 3 hours per 

response. 

Proposed § 314.53(d)(2) would enable 

FDA to reduce duplicative submission 

of patent information and require such 

information only for a supplement to 

change the dosage form or route of 

administration, to change the strength, 

to change the drug product from 

prescription to OTC use, or to correct 

previously submitted patent information 

that differently or no longer claims the 

changed product. 

Proposed § 314.53(f)(2) would 

expressly require correction or change 

of patent information if the NDA holder 

determines that a patent or patent claim 

no longer meets the statutory 

requirements for listing, if the NDA 

holder is required by court order to 

amend patent information or withdraw 

a patent from the list, or if the term of 

a listed patent is extended under 35 

U.S.C. 156(e). We estimate that these 

corrections and changes of patent 

information would result in 

approximately 62 submissions of Form 

FDA 3542 or other written submission, 

as provided in proposed 

§ 314.53(f)(2)(iv), by approximately 39 

NDA holders. We further estimate that 

the burden hours associated with the 

requirement in proposed § 314.53(f)(2) 

would be approximately 1 hour per 

response. 

Section 505(b)(4)(A) and (j)(2)(D)(i) of 

the FD&C Act generally prohibit the 

submission of certain types of changes 

in an amendment or a supplement to a 

505(b)(2) application or an ANDA, 

respectively. Proposed §§ 314.60(e) and 

314.70(h) would prohibit an applicant 

from amending or supplementing a 

505(b)(2) application to seek approval of 

a drug that has been modified to have 

a different active ingredient, different 

route of administration, different dosage 

form, or certain differences in excipients 

that the drug proposed in the original 

submission of the 505(b)(2) application. 

These changes must be requested in a 

new 505(b)(2) application. This 

proposed requirement conforms with 

FDA’s current policy regarding the types 

of proposed changes to a drug product 

that should be submitted as a separate 

application (see Separate Marketing 

Application Guidance). Accordingly, 

the burden associated with this 

statutory requirement is reflected in the 

burden hours estimate for §§ 314.50 and 

314.94 currently approved under OMB 

control number 0910–0001 for 505(b)(2) 

applications and ANDAs, respectively. 

Proposed §§ 314.60(f), 314.70(i), 

314.96(d), and 314.97(c) would require 

an applicant to submit a patent 

certification if approval is sought for 

either of the following types of 

amendments or supplements to a 

505(b)(2) application or ANDA: (1) To 

add a new indication or other condition 

of use or (2) to add a new strength. 

Proposed §§ 314.60(f) and 314.96(d) also 

would require an applicant to submit a 

patent certification if approval is sought 

for either of the following types of 

amendments to a 505(b)(2) application 

or ANDA: (1) To make other than minor 

changes in product formulation or (2) to 

change the physical form or crystalline 

structure of the active ingredient. 

Although currently the submission of a 

patent certification is required if, at any 

time before approval, the applicant 

learns that the previously submitted 

patent certification is no longer accurate 

with respect to the pending application 

or supplement, as amended (thus the 

burden hours are currently approved 

under OMB control number 0910–0001), 

the patent certification requirements 

would be broadened under this 

proposed rule. We estimate that this 

requirement may result in 

approximately six and four instances 

per year in which an applicant is 

required to submit a patent certification 

with an amendment or supplement, 

respectively, to its 505(b)(2) application. 

We further estimate that this 

requirement may result in 

approximately 95 and 16 instances per 

year in which an applicant is required 

to submit a patent certification with an 

amendment or supplement, 

respectively, to its ANDA. The burden 

hours associated with these 

requirements are estimated to be 

approximately 2 hours per response. 

Proposed §§ 314.96(c) and 314.97(b) 

would prohibit an ANDA applicant 

from amending or supplementing an 

ANDA to seek approval of a drug 

referring to a listed drug that is different 

from the RLD identified in the ANDA. 

An applicant must submit a change of 

the RLD in a new ANDA. We estimate 

that approximately one ANDA applicant 

per year will be required to submit a 

new ANDA instead of submitting an 

amendment for a change of the RLD. We 

also estimate that approximately one 

ANDA applicant per year will be 

required to submit a new ANDA instead 

of submitting a supplement for a change 

of the RLD. We further estimate that the 

burden of submitting an ANDA and 

complying with applicable regulatory 

requirements, including any required 

study to demonstrate bioequivalence to 

the new RLD, will be approximately 288 

hours for each of the estimated two 

responses per year. 

Proposed § 314.107(e) would expand 

the scope of the court actions and 

documented agreements related to a 

patent described in § 314.107(b)(3) that 

are required to be submitted to FDA. 

Proposed § 314.107(e) also would 

require submission of any court order 

pursuant to 35 U.S.C. 271(e)(4)(A) 

ordering that a 505(b)(2) application or 

ANDA may be approved no earlier than 

the date specified. FDA has OMB 

approval for the burden hours estimate 

of 30 minutes per response for the 

estimated 98 responses submitted 

annually by 25 505(b)(2) or ANDA 

applicants to comply with § 314.107(e) 

(see OMB control number 0910–0001). 

Based on our experience, we estimate 

that 140 505(b)(2) and ANDA applicants 

will be required to submit a copy of a 

court action, documented agreement, or 

written notification of appeal in 

approximately 310 instances per year. 

We continue to estimate that the burden 

associated with submitting a copy of 

these documents to FDA is 

approximately 30 minutes per response. 

The estimated burden of the burden of 

this collection of information is 

described in Table 18. 


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TABLE 18—ESTIMATED ANNUAL REPORTING BURDEN 1

21 CFR section Number of 

respondents 

Number of 

responses per 

respondent 

Total annual 

responses 

Average 

burden per 

response 

(in hours) 

Total hours 

314.50(i)(1) ........................................................................... 2 2.6 5.2 2. ................... 10.4 

314.50(i)(6) ........................................................................... 36 1 36 2. ................... 72 

314.52(a), (b), (c), and (e) ................................................... 2 2.6 5.2 15.33. ............ 79.7 

314.52(c) .............................................................................. 7 3 21 0.33 (20 minutes)..7 

314.53(f) ............................................................................... 39 1.5 62 1. ................... 62 

314.60(f) ............................................................................... 6 1 6 2. ................... 12 

314.70(i) ............................................................................... 4 1 4 2. ................... 8 

314.94(a)(12) ....................................................................... 108 1 108 2. ................... 216 

314.95(c) .............................................................................. 209 3 627 0.33 (20 minutes)..209 

314.96(c) .............................................................................. 1 1 1 288. ............... 288 

314.96(d) .............................................................................. 95 1 95 2. ................... 190 

314.97(b) .............................................................................. 1 1 1 288. ............... 288 

314.97(c) .............................................................................. 16 1 16 2. ................... 32 

314.107(e) ............................................................................ 140 2.2 310 0.5 (30 minutes)..155 

Total Reporting Burden Hours ...................................... ........................ ........................ ........................ ........................ 1629.1 

1There are no capital costs or operating and maintenance costs associated with this collection of information. 

We have submitted the information 

collection requirements of this rule to 

OMB for review. Interested persons are 

requested to send comments regarding 

information collection to the Office of 

Information and Regulatory Affairs, 

OMB (see ADDRESSES). 

VI. Environmental Impact 

The Agency has determined under 21 

CFR 25.30(h) and 25.31(a) and (g) that 

this action is of a type that does not 

individually or cumulatively have a 

significant effect on the human 

environment. Therefore, neither an 

environmental assessment nor an 

environmental impact statement is 

required. 

VII. Effective Date 

FDA proposes that any final rule 

based on this proposal become effective 

60 days after publication in the Federal 

Register. 

We intend to apply this rule, if 

finalized, to any new submission 

received by FDA on or after the effective 

date. This proposed rule provides 

sufficient notice to all interested parties, 

including NDA holders, NDA applicants 

(including 505(b)(2) applicants), and 

ANDA applicants to adjust their 

submissions and actions by the time we 

issue any final rule. However, we invite 

comments on how a final rule should be 

implemented. 

VIII. Federalism 

FDA has analyzed this proposed rule 

in accordance with the principles set 

forth in Executive Order 13132. FDA 

has determined that the proposed rule, 

if finalized, would not contain policies 

that would have substantial direct 

effects on the States, on the relationship 

between the National Government and 

the States, or on the distribution of 

power and responsibilities among the 

various levels of government. 

Accordingly, the Agency tentatively 

concludes that the proposed rule does 

not contain policies that have 

federalism implications as defined in 

the Executive order and, consequently, 

a federalism summary impact statement 

is not required. 

IX. Request for Comments 

Interested persons may submit to the 

Division of Dockets Management (see 

ADDRESSES) either electronic or written 

comments regarding this document. It is 

only necessary to send one set of 

comments. Identify comments with the 

docket number found in brackets in the 

heading of this document. Received 

comments may be seen in the Division 

of Dockets Management between 9 a.m. 

and 4 p.m., Monday through Friday, and 

will be posted to the docket at http://

www.regulations.gov. 

X. References 

The following references have been 

placed on display in the Division of 

Dockets Management (see ADDRESSES), 

and may be seen by interested persons 

between 9 a.m. and 4 p.m., Monday 

through Friday. (FDA has verified the 

Web site addresses, but we are not 

responsible for any subsequent changes 

to the Web sites after this document 

publishes in the Federal Register.) 

1. Preliminary Regulatory Impact Analysis, 

Initial Regulatory Flexibility Analysis, and 

Unfunded Mandates Reform Act Analysis for 

Abbreviated New Drug Applications and 

505(b)(2) Applications; Proposed Rule, 

available at http://www.fda.gov/AboutFDA/

ReportsManualsForms/Reports/

EconomicAnalyses/default.htm. 

2. U.S. Department of Commerce, Bureau 

of the Census, Economic Census, 

Manufacturing Industry Series, 

Pharmaceutical Preparation Manufacturing, 

Table 4, EC02–311–325412 (RV), 2002. 

List of Subjects 

21 CFR Part 314 

Administrative practice and 

procedure, Confidential business 

information, Drugs, Reporting and 

recordkeeping requirements. 

21 CFR Part 320 

Drugs, Reporting and recordkeeping 

requirements. 

Therefore, under the Federal Food, 

Drug, and Cosmetic Act and under 

authority delegated to the Commissioner 

of Food and Drugs, FDA proposes to 

amend 21 CFR parts 314 and 320 as 

follows: 

PART 314—APPLICATIONS FOR FDA 

APPROVAL TO MARKET A NEW DRUG 

■ 1. The authority citation for 21 CFR 

part 314 is revised to read as follows: 

Authority: 21 U.S.C. 321, 331, 351, 352, 

353, 355, 355a, 356, 356a, 356b, 356c, 360cc, 

371, 374, 379e. 

■ 2. Section 314.3 is revised to read as 

follows: 

§ 314.3 Definitions. 

(a) The definitions and interpretations 

contained in section 201 of the Federal 

Food, Drug, and Cosmetic Act apply to 


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those terms when used in this part and 

part 320 of this chapter. 

(b) The following definitions of terms 

apply to this part and part 320 of this 

chapter: 

180-day exclusivity period is the 180- 

day period beginning on the date of the 

first commercial marketing of the drug 

(including the commercial marketing of 

the reference listed drug) by any first 

applicant. The 180-day period ends on 

the day before the date on which an 

ANDA submitted by an applicant other 

than a first applicant could be approved. 

Abbreviated application, abbreviated 

new drug application, or ANDA is the 

application described under § 314.94, 

including all amendments and 

supplements to the application. 

Acknowledgment letter is a written, 

postmarked communication from FDA 

to an applicant stating that the Agency 

has determined that a 505(b)(2) 

application or ANDA is sufficiently 

complete to permit a substantive review. 

An acknowledgment letter indicates that 

the 505(b)(2) application is regarded as 

filed or the ANDA is regarded as 

received. 

Act is the Federal Food, Drug, and 

Cosmetic Act (section 201 et seq. (21 

U.S.C. 301 et seq.)). 

Active ingredient is any component 

that is intended to furnish 

pharmacological activity or other direct 

effect in the diagnosis, cure, mitigation, 

treatment, or prevention of disease, or to 

affect the structure or any function of 

the body of man or other animals. The 

term includes those components that 

may undergo chemical change in the 

manufacture of the drug product and be 

present in the drug product in a 

modified form intended to furnish the 

specified activity or effect. 

Active moiety is the molecule or ion, 

excluding those appended portions of 

the molecule that cause the drug to be 

an ester, salt (including a salt with 

hydrogen or coordination bonds), or 

other noncovalent derivative (such as a 

complex, chelate, or clathrate) of the 

molecule, responsible for the 

physiological or pharmacological action 

of the drug substance. 

ANDA holder is the applicant that 

owns an approved ANDA. 

Applicant is any person who submits 

an NDA (including a 505(b)(2) 

application) or ANDA or an amendment 

or supplement to an NDA or ANDA 

under this part to obtain FDA approval 

of a new drug and any person who owns 

an approved NDA (including a 505(b)(2) 

application) or ANDA. 

Application, new drug application, or 

NDA is the application described under 

§ 314.50, including all amendments and 

supplements to the application. An 

NDA refers to ‘‘stand-alone’’ 

applications submitted under section 

505(b)(1) of the Federal Food, Drug, and 

Cosmetic Act and to 505(b)(2) 

applications. 

505(b)(2) application is an NDA 

submitted under section 505(b)(1) of the 

Federal Food, Drug, and Cosmetic Act 

for a drug for which the investigations 

described in section 505(b)(1)(A) of the 

Federal Food, Drug, and Cosmetic Act 

and relied upon by the applicant for 

approval of the NDA were not 

conducted by or for the applicant and 

for which the applicant has not obtained 

a right of reference or use from the 

person by or for whom the 

investigations were conducted. 

Approval letter is a written 

communication to an applicant from 

FDA approving an NDA or an ANDA. 

Assess the effects of the change is to 

evaluate the effects of a manufacturing 

change on the identity, strength, quality, 

purity, and potency of a drug product as 

these factors may relate to the safety or 

effectiveness of the drug product. 

Authorized generic drug is a listed 

drug, as defined in this section, that has 

been approved under section 505(c) of 

the Federal Food, Drug, and Cosmetic 

Act and is marketed, sold, or distributed 

directly or indirectly to the retail class 

of trade with labeling, packaging (other 

than repackaging as the listed drug in 

blister packs, unit doses, or similar 

packaging for use in institutions), 

product code, labeler code, trade name, 

or trademark that differs from that of the 

listed drug. 

Bioavailability is the rate and extent 

to which the active ingredient or active 

moiety is absorbed from a drug product 

and becomes available at the site of drug 

action. For drug products that are not 

intended to be absorbed into the 

bloodstream, bioavailability may be 

assessed by scientifically valid 

measurements intended to reflect the 

rate and extent to which the active 

ingredient or active moiety becomes 

available at the site of drug action. 

Bioequivalence is the absence of a 

significant difference in the rate and 

extent to which the active ingredient or 

active moiety in pharmaceutical 

equivalents or pharmaceutical 

alternatives becomes available at the site 

of drug action when administered at the 

same molar dose under similar 

conditions in an appropriately designed 

study. Where there is an intentional 

difference in rate (e.g., in certain 

extended release dosage forms), certain 

pharmaceutical equivalents or 

alternatives may be considered 

bioequivalent if there is no significant 

difference in the extent to which the 

active ingredient or moiety from each 

product becomes available at the site of 

drug action. This applies only if the 

difference in the rate at which the active 

ingredient or moiety becomes available 

at the site of drug action is intentional 

and is reflected in the proposed 

labeling, is not essential to the 

attainment of effective body drug 

concentrations on chronic use, and is 

considered medically insignificant for 

the drug. For drug products that are not 

intended to be absorbed into the 

bloodstream, bioequivalence may be 

assessed by scientifically valid 

measurements intended to reflect the 

rate and extent to which the active 

ingredient or active moiety becomes 

available at the site of drug action. 

Bioequivalence requirement is a 

requirement imposed by FDA for in 

vitro and/or in vivo testing of specified 

drug products that must be satisfied as 

a condition of marketing. 

Class 1 resubmission is the 

resubmission of an NDA or efficacy 

supplement, following receipt of a 

complete response letter, that contains 

one or more of the following: Final 

printed labeling, draft labeling, certain 

safety updates, stability updates to 

support provisional or final dating 

periods, commitments to perform 

postmarketing studies (including 

proposals for such studies), assay 

validation data, final release testing on 

the last lots used to support approval, 

minor reanalyses of previously 

submitted data, and other comparatively 

minor information. 

Class 2 resubmission is the 

resubmission of an NDA or efficacy 

supplement, following receipt of a 

complete response letter, that includes 

any item not specified in the definition 

of ‘‘Class 1 resubmission,’’ including 

any item that would require 

presentation to an advisory committee. 

Commercial marketing is the 

introduction or delivery for introduction 

into interstate commerce of a drug 

product described in an approved 

ANDA, outside the control of the ANDA 

holder, except for investigational use 

under part 312 of this chapter, but does 

not include transfer of the drug product 

for reasons other than sale to parties 

identified in the approved ANDA. 

Complete response letter is a written 

communication to an applicant from 

FDA usually describing all of the 

deficiencies that the Agency has 

identified in an NDA or ANDA that 

must be satisfactorily addressed before 

it can be approved. 

Component is any ingredient 

intended for use in the manufacture of 

a drug product, including those that 

may not appear in such drug product. 


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Date of approval is the date on the 

approval letter from FDA stating that the 

NDA or ANDA is approved. ‘‘Date of 

approval’’ refers only to a final approval 

and not to a tentative approval. 

Dosage form is the physical 

manifestation containing the active and 

inactive ingredients that delivers a dose 

of the drug product. This includes such 

factors as: 

(1) The physical appearance of the 

drug product, 

(2) The physical form of the drug 

product prior to dispensing to the 

patient, 

(3) The way the product is 

administered, and 

(4) The design features that affect 

frequency of dosing. 

Drug product is a finished dosage 

form, e.g., tablet, capsule, or solution 

that contains a drug substance, 

generally, but not necessarily, in 

association with one or more other 

ingredients. 

Drug substance is an active ingredient 

that is intended to furnish 

pharmacological activity or other direct 

effect in the diagnosis, cure, mitigation, 

treatment, or prevention of disease or to 

affect the structure or any function of 

the human body, but does not include 

intermediates used in the synthesis of 

such ingredient. 

Efficacy supplement is a supplement 

to an approved NDA proposing to make 

one or more related changes from among 

the following changes to product 

labeling: 

(1) Add or modify an indication or 

claim; 

(2) Revise the dose or dose regimen; 

(3) Provide for a new route of 

administration; 

(4) Make a comparative efficacy claim 

naming another drug product; 

(5) Significantly alter the intended 

patient population; 

(6) Change the marketing status from 

prescription to over-the-counter use; 

(7) Provide for, or provide evidence of 

effectiveness necessary for, the 

traditional approval of a product 

originally approved under subpart H of 

part 314; or 

(8) Incorporate other information 

based on at least one adequate and wellcontrolled clinical study. 

FDA is the Food and Drug 

Administration. 

First applicant is an applicant that, on 

the first day on which a substantially 

complete ANDA containing a paragraph 

IV certification is submitted for 

approval of a drug, submits a 

substantially complete ANDA that 

contains, and for which the applicant 

lawfully maintains, a paragraph IV 

certification for the drug. 

Inactive ingredient is any component 

other than an active ingredient. 

Listed drug is a new drug product that 

has been approved under section 505(c) 

of the Federal Food, Drug, and Cosmetic 

Act for safety and effectiveness or under 

section 505(j) of the Federal Food, Drug, 

and Cosmetic Act, which has not been 

withdrawn or suspended under section 

505(e)(1) through (e)(5) or section 

505(j)(6) of the Federal Food, Drug, and 

Cosmetic Act, and which has not been 

withdrawn from sale for what FDA has 

determined are reasons of safety or 

effectiveness. Listed drug status is 

evidenced by the drug product’s 

identification in the current edition of 

FDA’s ‘‘Approved Drug Products With 

Therapeutic Equivalence Evaluations’’ 

(the list) as an approved drug. A drug 

product is deemed to be a listed drug on 

the date of the approval letter for the 

NDA or ANDA for that drug product. 

NDA holder is the applicant that owns 

an approved NDA. 

Newly acquired information is data, 

analyses, or other information not 

previously submitted to the Agency, 

which may include (but is not limited 

to) data derived from new clinical 

studies, reports of adverse events, or 

new analyses of previously submitted 

data (e.g., meta-analyses) if the studies, 

events, or analyses reveal risks of a 

different type or greater severity or 

frequency than previously included in 

submissions to FDA. 

Original application, original NDA is 

a pending NDA for which FDA has 

never issued a complete response letter 

or approval letter, or an NDA that was 

submitted again after FDA had refused 

to file it or after it was withdrawn 

without being approved. 

Paragraph IV acknowledgment letter 

is a written, postmarked communication 

from FDA to an applicant stating that 

the Agency has determined that a 

505(b)(2) application or ANDA 

containing a paragraph IV certification 

is sufficiently complete to permit a 

substantive review. A paragraph IV 

acknowledgment letter indicates that 

the 505(b)(2) application is regarded as 

filed or the ANDA is regarded as 

received. 

Paragraph IV certification is a patent 

certification of invalidity, 

unenforceability, or noninfringement 

described in § 314.50(i)(1)(i)(A)(4) or 

§ 314.94(a)(12)(i)(A)(4). 

Patent owner is the owner of the 

patent for which information is 

submitted for an NDA. 

Pharmaceutical alternatives are drug 

products that contain the identical 

therapeutic moiety, or its precursor, but 

not necessarily in the same amount or 

dosage form or as the same salt or ester. 

Each such drug product individually 

meets either the identical or its own 

respective compendial or other 

applicable standard of identity, strength, 

quality, and purity, including potency 

and, where applicable, content 

uniformity, disintegration times, and/or 

dissolution rates. 

Pharmaceutical equivalents are drug 

products in identical dosage forms and 

route(s) of administration that contain 

identical amounts of the identical active 

drug ingredient, i.e., the same salt or 

ester of the same therapeutic moiety, or, 

in the case of modified release dosage 

forms that require a reservoir or overage 

or such forms as prefilled syringes 

where residual volume may vary, that 

deliver identical amounts of the active 

drug ingredient over the identical 

dosing period; do not necessarily 

contain the same inactive ingredients; 

and meet the identical compendial or 

other applicable standard of identity, 

strength, quality, and purity, including 

potency and, where applicable, content 

uniformity, disintegration times, and/or 

dissolution rates. 

Postmark is an independently 

verifiable evidentiary record of the date 

on which a document is transmitted, in 

an unmodifiable format, to another 

party. For postmarks made by the U.S. 

Postal Service or a designated delivery 

service, the date of transmission is the 

date on which the document is received 

by the domestic mail service of the U.S. 

Postal Service or by a designated 

delivery service. For postmarks 

documenting an electronic event, the 

date of transmission is the date (in a 

particular time zone) that FDA sends the 

electronic transmission on its host 

system as evidenced by a verifiable 

record. If the sender and the intended 

recipient are located in different time 

zones, it is the sender’s time zone that 

provides the controlling date of 

electronic transmission. 

Reference listed drug is the listed drug 

identified by FDA as the drug product 

upon which an applicant relies in 

seeking approval of its ANDA. 

Reference standard is the drug 

product selected by FDA that an 

applicant seeking approval of an ANDA 

must use in conducting an in vivo 

bioequivalence study required for 

approval. 

Resubmission is submission by the 

applicant of all materials needed to fully 

address all deficiencies identified in the 

complete response letter. An NDA or 

ANDA for which FDA issued a complete 

response letter, but which was 

withdrawn before approval and later 

submitted again, is not a resubmission. 

Right of reference or use is the 

authority to rely upon, and otherwise 


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use, an investigation for the purpose of 

obtaining approval of an NDA, 

including the ability to make available 

the underlying raw data from the 

investigation for FDA audit, if 

necessary. 

Same drug product formulation is the 

formulation of the drug product 

submitted for approval and any 

formulations that have minor 

differences in composition or method of 

manufacture from the formulation 

submitted for approval, but are similar 

enough to be relevant to the Agency’s 

determination of bioequivalence. 

Specification is the quality standard 

(i.e., tests, analytical procedures, and 

acceptance criteria) provided in an 

approved NDA or ANDA to confirm the 

quality of drug substances, drug 

products, intermediates, raw materials, 

reagents, components, in-process 

materials, container closure systems, 

and other materials used in the 

production of a drug substance or drug 

product. For the purpose of this 

definition, acceptance criteria means 

numerical limits, ranges, or other 

criteria for the tests described. 

Strength is the amount of drug 

substance contained in, delivered, or 

deliverable from a drug product, which 

includes: 

(1)(i) The total quantity of drug 

substance in mass or units of activity in 

a dosage unit or container closure (e.g., 

weight/unit dose, weight/volume or 

weight/weight in a container closure, or 

units/volume or units/weight in a 

container closure); and/or, as 

applicable. 

(ii) The concentration of the drug 

substance in mass or units of activity 

per unit volume or mass (e.g., weight/ 

weight, weight/volume, or units/

volume); or 

(2) Such other criteria the Agency 

establishes for determining the amount 

of drug substance contained in, 

delivered, or deliverable from a drug 

product if the weights and measures 

described in paragraph (i) of this 

definition do not apply (e.g., certain 

drug-device combination products for 

which the amount of drug substance is 

emitted per use or unit time). 

Substantially complete application is 

an ANDA that on its face is sufficiently 

complete to permit a substantive review 

and contains all the information 

required under section 505(j)(2)(A) of 

the Federal Food, Drug, and Cosmetic 

Act and § 314.94. 

Tentative approval is notification that 

an NDA or ANDA otherwise meets the 

requirements for approval under the 

Federal Food, Drug, and Cosmetic Act, 

but cannot be approved because there is 

a 7-year period of orphan exclusivity for 

a listed drug under section 527 of the 

Federal Food, Drug, and Cosmetic Act 

and § 316.31 of this chapter, or that a 

505(b)(2) application or ANDA 

otherwise meets the requirements for 

approval under the Federal Food, Drug, 

and Cosmetic Act, but cannot be 

approved until the conditions in 

§ 314.107(b)(1)(iii), (b)(3), or (c) are met; 

because there is a period of exclusivity 

for the listed drug under § 314.108; 

because there is a period of pediatric 

exclusivity for the listed drug under 

section 505A of the Federal Food, Drug, 

and Cosmetic Act, or because a court 

order pursuant to 35 U.S.C. 271(e)(4)(A) 

orders that the application may be 

approved no earlier than the date 

specified. A drug product that is granted 

tentative approval is not an approved 

drug and will not be approved until 

FDA issues an approval letter after any 

necessary additional review of the NDA 

or ANDA. 

The list is the list of approved drug 

products published in FDA’s current 

‘‘Approved Drug Products With 

Therapeutic Equivalence Evaluations,’’ 

available electronically on FDA’s Web 

site at http://www.fda.gov/cder. 

Therapeutic equivalents are approved 

drug products that are pharmaceutical 

equivalents and for which 

bioequivalence has been demonstrated. 

Therapeutic equivalents can be 

expected to have the same clinical effect 

and safety profile when administered to 

patients under the conditions specified 

in the labeling. 

■ 3. Section 314.50 is amended by: 

■ a. Removing from paragraph (a) 

introductory text, paragraphs (a)(5), 

(d)(1)(v), (d)(5)(v), and (d)(5)(vi)(a), 

paragraph (e)(2) introductory text, and 

paragraphs (f)(3), (g)(2), and (k) the word 

‘‘shall’’ each time it appears and adding 

in its place the word ‘‘must’’; 

■ b. Removing from paragraphs (a)(5), 

(b), (c)(1), (c)(2)(i), and (c)(2)(iv) through 

(c)(2)(viii), paragraph (d) introductory 

text, paragraphs (d)(1)(i), (d)(1)(ii)(a), 

(d)(1)(iii) through (d)(1)(v), (d)(3)(ii), 

and (d)(5)(iv), paragraph (e)(1)(i) 

introductory text, paragraph (e)(2), 

paragraph (f) introductory text, 

paragraphs (f)(1) through (f)(3), (g)(2), 

(j)(4)(i), (j)(4)(ii), and (k), paragraph (l) 

heading, paragraph (l)(1) introductory 

text, and paragraphs (l)(2) and (l)(4) the 

word ‘‘application’’ each time it appears 

and adding in its place ‘‘NDA’’; 

■ c. Removing from paragraph (j) 

introductory text the word ‘‘shall’’ and 

adding in its place the word ‘‘must’’ and 

removing the phrase ‘‘new drug 

application’’ and adding in its place 

‘‘NDA’’; and 

■ d. Revising the section heading and 

section introductory text, paragraphs 

(a)(1) and (d)(5)(vi)(b), paragraph (e)(1) 

introductory text, paragraphs (f)(4), 

(g)(3), and (i), paragraph (j)(4) 

introductory text, the first two sentences 

of paragraph (j)(4)(iii), and paragraph 

(l)(3). 

The revisions read as follows: 

§ 314.50 Content and format of an NDA. 

NDAs and supplements to approved 

NDAs are required to be submitted in 

the form and contain the information, as 

appropriate for the particular 

submission, required under this section. 

Three copies of the NDA are required: 

An archival copy, a review copy, and a 

field copy. An NDA for a new chemical 

entity will generally contain an 

application form, an index, a summary, 

five or six technical sections, case report 

tabulations of patient data, case report 

forms, drug samples, and labeling, 

including, if applicable, any Medication 

Guide required under part 208 of this 

chapter. Other NDAs will generally 

contain only some of those items, and 

information will be limited to that 

needed to support the particular 

submission. These include an NDA of 

the type described in section 505(b)(2) 

of the Federal Food, Drug, and Cosmetic 

Act, an amendment, and a supplement. 

The NDA is required to contain reports 

of all investigations of the drug product 

sponsored by the applicant, and all 

other information about the drug 

pertinent to an evaluation of the NDA 

that is received or otherwise obtained by 

the applicant from any source. FDA will 

maintain guidance documents on the 

format and content of NDAs to assist 

applicants in their preparation. 

(a) * * * 

(1) The name and address of the 

applicant; the date of the NDA; the NDA 

number if previously issued (for 

example, if the NDA is a resubmission 

or an amendment or supplement); the 

name of the drug product, including its 

established, proprietary, code, and 

chemical names; the dosage form and 

strength; the route of administration; the 

identification numbers of all INDs (as 

defined in § 312.3(b) of this chapter) 

that are referenced in the NDA; the 

identification numbers of all drug 

master files and other applications 

under this part that are referenced in the 

NDA; and the drug product’s proposed 

indications for use. 

* * * * * 

(d) * * * 

(5) * * * 

(vi) * * * 

(b) The applicant must, under section 

505(i) of the Federal Food, Drug, and 

Cosmetic Act, update periodically its 

pending NDA with new safety 

information learned about the drug that 


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may reasonably affect the statement of 

contraindications, warnings, 

precautions, and adverse reactions in 

the draft labeling and, if applicable, any 

Medication Guide required under part 

208 of this chapter. These ‘‘safety 

update reports’’ must include the same 

kinds of information (from clinical 

studies, animal studies, and other 

sources) and must be submitted in the 

same format as the integrated summary 

in paragraph (d)(5)(vi)(a) of this section. 

In addition, the reports must include the 

case report forms for each patient who 

died during a clinical study or who did 

not complete the study because of an 

adverse event (unless this requirement 

is waived). The applicant must submit 

these reports: 

(1) 4 months after the initial 

submission; 

(2) In a resubmission following 

receipt of a complete response letter; 

and 

(3) At other times as requested by 

FDA. Before submitting the first such 

report, applicants are encouraged to 

consult with FDA regarding further 

details on its form and content. 

* * * * * 

(e) * * * (1) Upon request from FDA, 

the applicant must submit the samples 

described below to the places identified 

in the Agency’s request. FDA generally 

will ask applicants to submit samples 

directly to two or more Agency 

laboratories that will perform all 

necessary tests on the samples and 

validate the applicant’s analytical 

procedures. 

* * * * * 

(f) * * * 

(4) Applicants are invited to meet 

with FDA before submitting an NDA to 

discuss the presentation and format of 

supporting information. If the applicant 

and FDA agree, the applicant may 

submit tabulations of patient data and 

case report forms in an alternate form. 

(g) * * * 

(3) If an applicant who submits an 

NDA under section 505(b) of the Federal 

Food, Drug, and Cosmetic Act obtains a 

‘‘right of reference or use,’’ as defined 

under § 314.3(b), to an investigation 

described in clause (A) of section 

505(b)(1) of the Federal Food, Drug, and 

Cosmetic Act, the applicant must 

include in its NDA a written statement 

signed by the owner of the data from 

each such investigation that the 

applicant may rely on in support of the 

approval of its NDA, and provide FDA 

access to, the underlying raw data that 

provide the basis for the report of the 

investigation submitted in its NDA. 

* * * * * 

(i) Patent certification—(1) Contents. 

A 505(b)(2) application is required to 

contain the following: 

(i) Patents claiming drug substance, 

drug product, or method of use. (A) A 

certification with respect to each patent 

issued by the U.S. Patent and 

Trademark Office that, in the opinion of 

the applicant and to the best of its 

knowledge, claims the drug substance or 

drug product on which investigations 

that are relied upon by the applicant for 

approval of its 505(b)(2) application 

were conducted or that claims an 

approved use for such drug and for 

which information is required to be 

filed under section 505(b) and (c) of the 

Federal Food, Drug, and Cosmetic Act 

and § 314.53. For each such patent, the 

applicant must provide the patent 

number and certify, in its opinion and 

to the best of its knowledge, one of the 

following circumstances: 

(1) That the patent information has 

not been submitted to FDA. The 

applicant must entitle such a 

certification ‘‘Paragraph I Certification’’; 

(2) That the patent has expired. The 

applicant must entitle such a 

certification ‘‘Paragraph II 

Certification’’; 

(3) The date on which the patent will 

expire. The applicant must entitle such 

a certification ‘‘Paragraph III 

Certification’’; or 

(4) That the patent is invalid, 

unenforceable, or will not be infringed 

by the manufacture, use, or sale of the 

drug product for which the 505(b)(2) 

application is submitted. The applicant 

must entitle such a certification 

‘‘Paragraph IV Certification’’. This 

certification must be submitted in the 

following form: 

I, (name of applicant), certify that Patent 

No. ______ (is invalid, unenforceable, or will 

not be infringed by the manufacture, use, or 

sale of) (name of proposed drug product) for 

which this 505(b)(2) application is submitted. 

The certification must be 

accompanied by a statement that the 

applicant will comply with the 

requirements under § 314.52(a) with 

respect to providing a notice to each 

owner of the patent or its representative 

and to the holder of the approved NDA 

for the drug product which is claimed 

by the patent or a use of which is 

claimed by the patent and with the 

requirements under § 314.52(b) with 

respect to sending the notice and under 

§ 314.52(c) with respect to the content of 

the notice. 

(B) If the drug on which investigations 

that are relied upon by the applicant 

were conducted is itself a licensed 

generic drug of a patented drug first 

approved under section 505(b) of the 

Federal Food, Drug, and Cosmetic Act, 

the appropriate patent certification 

under this section with respect to each 

patent that claims the first-approved 

patented drug or that claims an 

approved use for such a drug. 

(C) If, before the date of submission of 

the 505(b)(2) application, there is an 

approved drug product that is 

pharmaceutically equivalent to the drug 

product for which the 505(b)(2) 

application is submitted, an appropriate 

patent certification under this section 

with respect to each patent that claims 

the drug substance or drug product or 

that claims an approved use for such 

drug. 

(ii) No relevant patents. If, in the 

opinion of the applicant and to the best 

of its knowledge, there are no patents 

described in paragraph (i)(1)(i) of this 

section, a certification in the following 

form: 

In the opinion and to the best knowledge 

of (name of applicant), there are no patents 

that claim the drug or drugs on which 

investigations that are relied upon in this 

505(b)(2) application were conducted or that 

claim a use of such drug or drugs. 

(iii) Method-of-use patent. (A) If 

information that is submitted under 

section 505(b) or (c) of the Federal Food, 

Drug, and Cosmetic Act and § 314.53 is 

for a method-of-use patent, and the 

labeling for the drug product for which 

the applicant is seeking approval does 

not include any indications or other 

conditions of use that are covered by the 

use patent, a statement explaining that 

the method-of-use patent does not claim 

any of the proposed indications or other 

conditions of use. 

(B) If the labeling of the drug product 

for which the applicant is seeking 

approval includes an indication or other 

condition of use that, according to the 

patent information submitted under 

section 505(b) or (c) of the Federal Food, 

Drug, and Cosmetic Act and § 314.53 or 

in the opinion of the applicant, is 

claimed by a use patent, the applicant 

must submit an applicable certification 

under paragraph (i)(1)(i) of this section. 

(2) [Reserved] 

(3) Licensing agreements. If a 

505(b)(2) application is for a drug or 

method of using a drug claimed by a 

patent and the applicant has a licensing 

agreement with the patent owner, the 

applicant must submit a certification 

under paragraph (i)(1)(i)(A)(4) of this 

section (‘‘Paragraph IV Certification’’) as 

to that patent and a statement that it has 

been granted a patent license. If the 

patent owner consents to approval of 

the 505(b)(2) application (if otherwise 

justified) as of a specific date, the 

505(b)(2) application must contain a 

written statement from the patent owner 

that it has a licensing agreement with 


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the applicant and that it consents to 

approval of the 505(b)(2) application as 

of a specific date. 

(4) Untimely filing of patent 

information. If a patent described in 

paragraph (i)(1)(i) of this section is 

issued and the holder of the approved 

NDA for the patented drug does not file 

with FDA the required information on 

the patent within 30 days of issuance of 

the patent, an applicant who submitted 

a 505(b)(2) application that, before the 

submission of the patent information, 

contained an appropriate patent 

certification is not required to submit an 

amended certification to address the 

patent that is late-listed with respect to 

the pending 505(b)(2) application. 

Except as provided in § 314.53(f)(1), an 

NDA holder’s amendment to the 

description of the approved method(s) 

of use claimed by the patent will be 

considered untimely filing of patent 

information if: 

(i) The amendment is submitted more 

than 30 days after patent issuance and 

it is not related to a corresponding 

change in approved product labeling; or 

(ii) The amendment is submitted more 

than 30 days after a corresponding 

change in approved product labeling. 

An applicant whose 505(b)(2) 

application is filed after the NDA 

holder’s untimely filing of patent 

information or whose 505(b)(2) 

application was previously filed but did 

not contain an appropriate patent 

certification at the time of the patent 

submission must submit a certification 

under paragraph (i)(1)(i) of this section 

or a statement under paragraph (i)(1)(iii) 

of this section as to that patent. 

(5) Disputed patent information. If an 

applicant disputes the accuracy or 

relevance of patent information 

submitted to FDA, the applicant may 

seek a confirmation of the correctness of 

the patent information in accordance 

with the procedures under § 314.53(f). 

Unless the patent information is 

withdrawn or changed, the applicant 

must submit an appropriate certification 

for each relevant patent. 

(6) Amended certifications. A 

certification submitted under 

paragraphs (i)(1)(i) through (i)(1)(iii) of 

this section may be amended at any 

time before the approval of the 505(b)(2) 

application. An applicant must submit 

an amended certification as an 

amendment to a pending 505(b)(2) 

application. If an applicant with a 

pending 505(b)(2) application 

voluntarily makes a patent certification 

for an untimely filed patent, the 

applicant may withdraw the patent 

certification for the untimely filed 

patent. Once an amendment for the 

change in certification has been 

submitted, the 505(b)(2) application will 

no longer be considered to be one 

containing the prior certification. 

(i) After finding of infringement. An 

applicant who has submitted a 

paragraph IV certification and is sued 

for patent infringement must submit an 

amendment to change its certification if 

a court enters a final decision from 

which no appeal has been or can be 

taken, or signs a settlement order or 

consent decree in the action that 

includes a finding that the patent is 

infringed, unless the final decision, 

settlement order, or consent decree also 

finds the patent to be invalid. In its 

amendment, the applicant must certify 

under paragraph (i)(1)(i)(A)(3) of this 

section that the patent will expire on a 

specific date or, with respect to a patent 

claiming a method of use, the applicant 

may instead provide a statement under 

paragraph (i)(1)(iii) of this section if the 

applicant amends its 505(b)(2) 

application such that the applicant is no 

longer seeking approval for a method of 

use claimed by the patent. 

(ii) After request to remove a patent 

or patent information from the list. If the 

list reflects that an NDA holder has 

requested that a patent be removed from 

the list and no ANDA applicant is 

eligible for 180-day exclusivity based on 

a paragraph IV certification to that 

patent, the patent will be removed and 

any applicant with a pending 505(b)(2) 

application (including a tentatively 

approved 505(b)(2) application) who has 

made a certification with respect to such 

patent must submit an amendment to 

withdraw its certification. In the 

amendment, the applicant must state 

the reason for withdrawing the 

certification (that the patent has been 

removed from the list). If the list reflects 

that an NDA holder has requested that 

a patent be removed from the list and 

one or more first applicants are eligible 

for 180-day exclusivity based on a 

paragraph IV certification to that patent, 

the patent shall remain listed until any 

180-day exclusivity is extinguished. A 

505(b)(2) applicant is not required to 

provide or maintain a certification to a 

patent that remains listed only for 

purposes of a first applicant’s 180-day 

exclusivity for its ANDA. Once an 

amendment to withdraw the 

certification has been submitted, the 

505(b)(2) application will no longer be 

considered to be one containing a 

paragraph IV certification to the patent. 

If removal of a patent from the list 

results in there being no patents listed 

for the listed drug(s) identified in the 

505(b)(2) application, the applicant 

must submit an amended certification 

reflecting that there are no listed 

patents. 

(iii) Other amendments. (A) Except as 

provided in paragraphs (i)(4) and 

(i)(6)(iii)(B) of this section: 

(1) An applicant must amend a 

submitted certification if, at any time 

before the approval of the 505(b)(2) 

application, the applicant learns that the 

submitted certification is no longer 

accurate; and 

(2) An applicant must submit a 

certification or statement under 

paragraph (i)(1) of this section if, after 

submission of the 505(b)(2) application, 

a new patent is issued by the U.S. Patent 

and Trademark Office that, in the 

opinion of the applicant and to the best 

of its knowledge, claims a listed drug 

relied upon or that claims an approved 

use for such listed drug for which 

information is required to be filed under 

section 505(b) and (c) of the Federal 

Food, Drug, and Cosmetic Act and 

§ 314.53. 

(B) An applicant is not required to 

submit a supplement to change a 

submitted certification when 

information on an otherwise applicable 

patent is submitted after the approval of 

the 505(b)(2) application, except as 

provided in § 314.70(i). 

(j) * * * 

(4) If the applicant claims exclusivity 

under § 314.108(b)(4) or (b)(5), the 

following information to show that the 

NDA contains ‘‘new clinical 

investigations’’ that are ‘‘essential to 

approval of the application or 

supplement’’ and ‘‘were conducted or 

sponsored by the applicant’’: 

* * * * * 

(iii) * * * If the applicant was the 

sponsor named in the Form FDA 1571 

for an IND under which the new clinical 

investigation(s) that is essential to the 

approval of its NDA was conducted, 

identification of the IND by number. If 

the applicant was not the sponsor of the 

IND under which the clinical 

investigation(s) was conducted, a 

certification that the applicant or its 

predecessor in interest provided 

substantial support for the clinical 

investigation(s) that is essential to the 

approval of its NDA, and information 

supporting the certification. * * * 

* * * * * 

(l) * * * 

(3) Field copy. The applicant must 

submit a field copy of the NDA that 

contains the technical section described 

in paragraph (d)(1) of this section, a 

copy of the application form required 

under paragraph (a) of this section, a 

copy of the summary required under 

paragraph (c) of this section, and a 

certification that the field copy is a true 

copy of the technical section described 

in paragraph (d)(1) of this section 


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contained in the archival and review 

copies of the NDA. 

* * * * * 

■ 4. Section 314.52 is revised to read as 

follows: 

§ 314.52 Notice of certification of invalidity 

or noninfringement of a patent. 

(a) Notice of certification. For each 

patent that claims the listed drug or 

drugs relied upon or that claims a use 

for such listed drug or drugs and for 

which the applicant submits a 

paragraph IV certification, the applicant 

must send notice of such certification by 

registered or certified mail, return 

receipt requested, or by a designated 

delivery service, as defined in paragraph 

(g) of this section to each of the 

following persons: 

(1) Each owner of the patent that is 

the subject of the certification or the 

representative designated by the owner 

to receive the notice. The name and 

address of the patent owner or its 

representative may be obtained from the 

U.S. Patent and Trademark Office; and 

(2) The holder of the approved NDA 

under section 505(b) of the Federal 

Food, Drug, and Cosmetic Act for each 

drug product which is claimed by the 

patent or a use of which is claimed by 

the patent and for which the applicant 

is seeking approval, or, if the NDA 

holder does not reside or maintain a 

place of business within the U.S., the 

NDA holder’s attorney, agent, or other 

authorized official. The name and 

address of the NDA holder or its 

attorney, agent, or authorized official 

may be obtained from the Orange Book 

Staff, Office of Generic Drugs, 7620 

Standish Pl., Rockville, MD 20855. 

(3) This paragraph does not apply to 

a use patent that does not claim a use 

for which the applicant is seeking 

approval. 

(4) An applicant may send notice by 

an alternative method only if FDA has 

agreed in advance that the method will 

produce an acceptable form of 

documentation. 

(b) Sending the notice. (1) Except as 

provided under paragraph (d) of this 

section, the applicant must send the 

notice required by paragraph (a) of this 

section on or after the date it receives a 

paragraph IV acknowledgment letter 

from FDA, but not later than 20 days 

after the date of the postmark on the 

paragraph IV acknowledgment letter. 

The 20-day clock described in this 

paragraph begins on the day after the 

date of the postmark on the paragraph 

IV acknowledgment letter. When the 

20th day falls on Saturday, Sunday, or 

a Federal holiday, the 20th day will be 

the next day that is not a Saturday, 

Sunday, or Federal holiday. 

(2) Any notice required by paragraph 

(a) of this section is invalid if it is sent 

before the applicant’s receipt of a 

paragraph IV acknowledgment letter. 

The applicant will not have complied 

with this paragraph until it sends valid 

notice. 

(3) At the same time it sends the 

notice required by paragraph (a) of this 

section, the applicant must submit to 

FDA an amendment to its 505(b)(2) 

application that includes a statement 

certifying that the notice has been 

provided to each person identified 

under paragraph (a) of this section and 

that the notice met the content 

requirement under paragraph (c) of this 

section. A copy of the notice itself need 

not be submitted to the Agency. 

(c) Content of a notice. In the notice, 

the applicant must cite section 

505(b)(3)(D) of the Federal Food, Drug, 

and Cosmetic Act and must include, but 

is not limited to, the following 

information: 

(1) A statement that a 505(b)(2) 

application that contains any required 

bioavailability or bioequivalence studies 

has been submitted by the applicant and 

filed by FDA. 

(2) The NDA number. 

(3) A statement that the applicant has 

received the paragraph IV 

acknowledgment letter for the 505(b)(2) 

application. 

(4) The established name, if any, as 

defined in section 502(e)(3) of the 

Federal Food, Drug, and Cosmetic Act, 

of the proposed drug product. 

(5) The active ingredient, strength, 

and dosage form of the proposed drug 

product. 

(6) The patent number and expiration 

date of each patent on the list alleged to 

be invalid, unenforceable, or not 

infringed. 

(7) A detailed statement of the factual 

and legal basis of the applicant’s 

opinion that the patent is not valid, 

unenforceable, or will not be infringed. 

The applicant must include in the 

detailed statement: 

(i) For each claim of a patent alleged 

not to be infringed, a full and detailed 

explanation of why the claim is not 

infringed. 

(ii) For each claim of a patent alleged 

to be invalid or unenforceable, a full 

and detailed explanation of the grounds 

supporting the allegation. 

(8) If the applicant alleges that the 

patent will not be infringed and the 

applicant may later decide to file a civil 

action for declaratory judgment in 

accordance with section 505(c)(3)(D) of 

the Federal Food, Drug, and Cosmetic 

Act, then the notice must be 

accompanied by an offer of confidential 

access to the 505(b)(2) application for 

the sole and limited purpose of 

evaluating possible infringement of the 

patent that is the subject of the 

paragraph IV certification. 

(9) If the applicant does not reside or 

have a place of business in the United 

States, the name and address of an agent 

in the United States authorized to 

accept service of process for the 

applicant. 

(d) Amendment or supplement to a 

505(b)(2) application. (1) If, after receipt 

of an acknowledgment letter or 

paragraph IV acknowledgment letter, an 

applicant submits an amendment or 

supplement to its 505(b)(2) application 

that includes a paragraph IV 

certification, the applicant must send 

the notice required by paragraph (a) of 

this section at the same time that the 

amendment or supplement to the 

505(b)(2) application is submitted to 

FDA, regardless of whether the 

applicant has already given notice with 

respect to another such certification 

contained in the 505(b)(2) application or 

in an amendment or supplement to the 

505(b)(2) application. 

(2) If, before receipt of a paragraph IV 

acknowledgment letter, an applicant 

submits a paragraph IV certification in 

an amendment, the applicant must send 

the notice required by paragraph (a) of 

this section in accordance with the 

procedures in paragraph (b) of this 

section. 

(3) An applicant that submits an 

amendment or supplement to seek 

approval of a different strength must 

provide notice of any paragraph IV 

certification in accordance with 

paragraphs (d)(1) or (d)(2) of this 

section, as applicable. 

(e) Documentation of timely sending 

and receipt of notice. The applicant 

must amend its 505(b)(2) application to 

provide documentation of the date of 

receipt of the notice required under 

paragraph (a) of this section by each 

person provided the notice. The 

amendment must be submitted to FDA 

within 30 days after the last date on 

which notice was received by a person 

described in paragraph (a) of this 

section. The applicant’s amendment 

also must include documentation that 

its notice was sent on a date that 

complies with the timeframe required 

by paragraph (b) or paragraph (d) of this 

section, as applicable. FDA will accept, 

as adequate documentation of the date 

the notice was sent, a copy of the 

registered mail receipt, certified mail 

receipt, or receipt from a designated 

delivery service, as defined in paragraph 

(g) of this section. FDA will accept as 

adequate documentation of the date of 

receipt a return receipt, a signature 

proof of delivery by a designated 


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delivery service, or a letter 

acknowledging receipt by the person 

provided the notice. An applicant may 

rely on another form of documentation 

only if FDA has agreed to such 

documentation in advance. A copy of 

the notice itself need not be submitted 

to the Agency. 

(f) Approval. If the requirements of 

this section are met, the Agency will 

presume the notice to be complete and 

sufficient and will count the day 

following the date of receipt of the 

notice by the patent owner or its 

representative and by the approved 

NDA holder as the first day of the 45- 

day period provided for in section 

505(c)(3)(C) of the Federal Food, Drug, 

and Cosmetic Act. FDA may, if the 

applicant amends its 505(b)(2) 

application with a written statement 

that a later date should be used, count 

from such later date. 

(g) Designated delivery services. (1) 

For purposes of this section, the term 

‘‘designated delivery service’’ is any 

delivery service provided by a trade or 

business that the Agency determines: 

(i) Is available to the general public 

throughout the United States; 

(ii) Records electronically to its 

database, kept in the regular course of 

its business, or marks on the cover in 

which any item referred to in this 

section is to be delivered, the date on 

which such item was given to such 

trade or business for delivery; and 

(iii) Provides overnight or 2-day 

delivery service throughout the United 

States. 

(2) FDA will periodically issue 

guidance regarding designated delivery 

services that meet these criteria. 

■ 5. Section 314.53 is revised to read as 

follows: 

§ 314.53 Submission of patent information. 

(a) Who must submit patent 

information. This section applies to any 

applicant who submits to FDA an NDA 

or an amendment to it under section 

505(b) of the Federal Food, Drug, and 

Cosmetic Act and § 314.50 or a 

supplement to an approved NDA under 

§ 314.70, except as provided in 

paragraph (d)(2) of this section. 

(b) Patents for which information 

must be submitted and patents for 

which information must not be 

submitted—(1) General requirements. 

An applicant described in paragraph (a) 

of this section must submit the required 

information, on the required FDA 

declaration form, set forth in paragraph 

(c) of this section for each patent that 

claims the drug or a method of using the 

drug that is the subject of the NDA or 

amendment or supplement to it and 

with respect to which a claim of patent 

infringement could reasonably be 

asserted if a person not licensed by the 

owner of the patent engaged in the 

manufacture, use, or sale of the drug 

product. For purposes of this part, such 

patents consist of drug substance (active 

ingredient) patents, drug product 

(formulation and composition) patents, 

and method-of-use patents. For patents 

that claim the drug substance, the 

applicant must submit information only 

on those patents that claim the drug 

substance that is the subject of the 

pending or approved NDA or that claim 

a drug substance that is the same as the 

active ingredient that is the subject of 

the approved or pending NDA. For 

patents that claim only a polymorph 

that is the same as the active ingredient 

described in the approved or pending 

NDA, the applicant must certify in the 

required FDA declaration form that the 

applicant has test data, as set forth in 

paragraph (b)(2) of this section, 

demonstrating that a drug product 

containing the polymorph will perform 

the same as the drug product described 

in the NDA. For patents that claim a 

drug product, the applicant must submit 

information only on those patents that 

claim a drug product, as is defined in 

§ 314.3, that is described in the pending 

or approved application. For patents 

that claim a method of use, the 

applicant must submit information only 

on those patents that claim indications 

or other conditions of use for which 

approval is sought or has been granted 

in the NDA. The applicant must 

separately identify each pending or 

approved method of use and related 

patent claim(s). For approved NDAs, the 

applicant submitting the method-of-use 

patent must identify with specificity the 

section of the approved labeling that 

corresponds to the method of use 

claimed by the patent submitted. If the 

scope of the method-of-use claim(s) of 

the patent does not cover every use of 

the drug, the applicant must only 

identify the specific portion(s) of the 

indication or other condition of use 

claimed by the patent. Process patents, 

patents claiming packaging, patents 

claiming metabolites, and patents 

claiming intermediates are not covered 

by this section, and information on 

these patents must not be submitted to 

FDA. 

(2) Test data for submission of patent 

information for patents that claim only 

a polymorph. The test data, referenced 

in paragraph (b)(1) of this section, must 

include the following: 

(i) A full description of the 

polymorphic form of the drug 

substance, including its physical and 

chemical characteristics and stability; 

the method of synthesis (or isolation) 

and purification of the drug substance; 

the process controls used during 

manufacture and packaging; and such 

specifications and analytical methods as 

are necessary to assure the identity, 

strength, quality, and purity of the 

polymorphic form of the drug 

substance; 

(ii) The executed batch record for a 

drug product containing the 

polymorphic form of the drug substance 

and documentation that the batch was 

manufactured under current good 

manufacturing practice requirements; 

(iii) Demonstration of bioequivalence 

between the executed batch of the drug 

product that contains the polymorphic 

form of the drug substance and the drug 

product as described in the NDA; 

(iv) A list of all components used in 

the manufacture of the drug product 

containing the polymorphic form and a 

statement of the composition of the drug 

product; a statement of the 

specifications and analytical methods 

for each component; a description of the 

manufacturing and packaging 

procedures and in-process controls for 

the drug product; such specifications 

and analytical methods as are necessary 

to assure the identity, strength, quality, 

purity, and bioavailability of the drug 

product, including release and stability 

data complying with the approved 

product specifications to demonstrate 

pharmaceutical equivalence and 

comparable product stability; and 

(v) Comparative in vitro dissolution 

testing on 12 dosage units each of the 

executed test batch and the NDA 

product. 

(c) Reporting requirements—(1) 

General requirements. An applicant 

described in paragraph (a) of this 

section must submit the required patent 

information described in paragraph 

(c)(2) of this section for each patent that 

meets the requirements described in 

paragraph (b) of this section. We will 

not accept the patent information unless 

it is submitted on the appropriate form, 

Form FDA 3542 or 3542a, and contains 

the information required in paragraph 

(c)(2) of this section. These forms may 

be obtained on the Internet at http://

www.fda.gov by searching for ‘‘forms’’. 

(2) Drug substance (active ingredient), 

drug product (formulation or 

composition), and method-of-use 

patents—(i) Original declaration. For 

each patent that claims a drug substance 

(active ingredient), drug product 

(formulation and composition), or 

method of use, the applicant must 

submit Form FDA 3542a. The following 

information and verification is required, 

subject to the exceptions listed in 

paragraph (c)(2)(i)(S) of this section: 

(A) NDA number; 


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(B) Name of NDA sponsor; 

(C) Trade name (or proposed trade 

name) of new drug; 

(D) Active ingredient(s) of new drug; 

(E) Strength(s) of new drug; 

(F) Dosage form of new drug; 

(G) U.S. patent number, issue date, 

and expiration date of patent submitted; 

(H) The patent owner’s name, full 

address, phone number and, if available, 

fax number and email address; 

(I) The name, full address, phone 

number and, if available, fax number 

and email address of an agent or 

representative who resides or maintains 

a place of business within the United 

States authorized to receive notice of 

patent certification under section 

505(b)(3) and (j)(2)(B) of the Federal 

Food, Drug, and Cosmetic Act and 

§§ 314.52 and 314.95 (if patent owner or 

NDA applicant or holder does not reside 

or have a place of business within the 

United States); 

(J) Information on whether the patent 

is a reissued patent of a patent 

submitted previously for listing for the 

NDA or supplement; 

(K) Information on whether the 

expiration date is a new expiration date 

if the patent had been submitted 

previously for listing; 

(L) Information on whether the patent 

is a product-by-process patent in which 

the product claimed is novel; 

(M) Information on the drug substance 

(active ingredient) patent, including the 

following: 

(1) Whether the patent claims the 

drug substance that is the active 

ingredient in the drug product described 

in the NDA or supplement; 

(2) Whether the patent claims only a 

polymorph that is the same active 

ingredient that is described in the 

pending NDA or supplement; 

(3) Whether the applicant has test 

data, described in paragraph (b)(2) of 

this section, demonstrating that a drug 

product containing only the polymorph 

will perform the same as the drug 

product described in the NDA or 

supplement, and a description of the 

polymorphic form(s) claimed by the 

patent for which such test data exist; 

(4) Whether the patent claims only a 

metabolite of the active ingredient; and 

(5) Whether the patent claims only an 

intermediate; 

(N) Information on the drug product 

(composition/formulation) patent, 

including the following: 

(1) Whether the patent claims the 

drug product for which approval is 

being sought, as defined in § 314.3; and 

(2) Whether the patent claims only an 

intermediate; 

(O) Information on each method-ofuse patent, including the following: 

(1) Whether the patent claims one or 

more methods of using the drug product 

for which use approval is being sought 

and a description of each pending 

method of use or related indication and 

related patent claim of the patent being 

submitted; 

(2) Identification of the specific 

section(s) of the proposed labeling for 

the drug product that corresponds to the 

method of use claimed by the patent 

submitted (if the scope of the methodof-use claim(s) of the patent does not 

cover every use of the drug, the 

applicant must only identify the specific 

portion(s) of the indication or other 

condition of use claimed by the patent); 

and 

(3) An applicant that submits 

information for a patent that claims one 

or more methods of using the drug 

product must also submit information 

described in either paragraph 

(c)(2)(i)(M) or (c)(2)(i)(N) of this section, 

regarding whether that patent also 

claims either the drug substance (active 

ingredient) or the drug product 

(composition/formulation). 

(P) Whether there are no relevant 

patents that claim the drug substance 

(active ingredient), drug product 

(formulation or composition), or 

method(s) of use, for which the 

applicant is seeking approval and with 

respect to which a claim of patent 

infringement could reasonably be 

asserted if a person not licensed by the 

owner of the patent engaged in the 

manufacture, use, or sale of the drug 

product; 

(Q) A signed verification that states: 

The undersigned declares that this is an 

accurate and complete submission of patent 

information for the NDA, amendment, or 

supplement pending under section 505 of the 

Federal Food, Drug, and Cosmetic Act. This 

time-sensitive patent information is 

submitted pursuant to 21 CFR 314.53. I attest 

that I am familiar with 21 CFR 314.53 and 

this submission complies with the 

requirements of the regulation. I verify under 

penalty of perjury that the foregoing is true 

and correct.; 

and 

(R) Information on whether the 

applicant, patent owner or attorney, 

agent, representative, or other 

authorized official signed the form; the 

name of the person; and the full 

address, phone number and, if available, 

the fax number and email address. 

(S) Exceptions to required submission 

of patent information: 

(1) If an applicant submits the 

information described in paragraph 

(c)(2)(i)(M) of this section for a patent 

that claims the drug substance (active 

ingredient) and meets the requirements 

for listing on that basis, then the 

applicant is not required to provide the 

information described in paragraph 

(c)(2)(i)(N) of this section on whether 

that patent also claims the drug product 

(composition/formulation). 

(2) If an applicant submits the 

information described in paragraph 

(c)(2)(i)(N) of this section for a patent 

that claims the drug product 

(composition/formulation) and meets 

the requirements for listing on that 

basis, then the applicant is not required 

to provide the information described in 

paragraph (c)(2)(i)(M) of this section on 

whether that patent also claims the drug 

substance (active ingredient). 

(ii) Submission of patent information 

upon and after approval. Within 30 

days after the date of approval of its 

NDA or supplement, the applicant must 

submit Form FDA 3542 for each patent 

that claims the drug substance (active 

ingredient), drug product (formulation 

and composition), or approved method 

of use. FDA will rely only on the 

information submitted on this form and 

will not list or publish patent 

information if the patent declaration is 

incomplete or indicates the patent is not 

eligible for listing. Patent information 

must also be submitted for patents 

issued after the date of approval of the 

NDA as required in paragraph (c)(2)(ii) 

of this section. As described in 

paragraph (d)(3) of this section, to be 

timely filed, patent information for 

patents issued after the date of approval 

of the NDA must be submitted to FDA 

within 30 days of the date of issuance 

of the patent. If the applicant submits 

the required patent information within 

the 30 days, but we notify an applicant 

that a declaration form is incomplete or 

shows that the patent is not eligible for 

listing, the applicant must submit an 

acceptable declaration form within 15 

days of FDA notification to be 

considered timely filed. The following 

information and verification statement 

is required, subject to the exceptions 

listed in paragraph (c)(2)(ii)(T) of this 

section: 

(A) NDA number; 

(B) Name of NDA sponsor; 

(C) Trade name of new drug; 

(D) Active ingredient(s) of new drug; 

(E) Strength(s) of new drug; 

(F) Dosage form of new drug; 

(G) Approval date of NDA or 

supplement; 

(H) U.S. patent number, issue date, 

and expiration date of patent submitted; 

(I) The patent owner’s name, full 

address, phone number and, if available, 

fax number and email address; 

(J) The name, full address, phone 

number and, if available, fax number 

and email address of an agent or 

representative who resides or maintains 


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a place of business within the United 

States authorized to receive notice of 

patent certification under section 

505(b)(3) and (j)(2)(B) of the Federal 

Food, Drug, and Cosmetic Act and 

§§ 314.52 and 314.95 (if patent owner or 

NDA applicant or holder does not reside 

or have a place of business within the 

United States); 

(K) Information on whether the patent 

is a reissued patent of a patent 

submitted previously for listing for the 

NDA or supplement; 

(L) Information on whether the 

expiration date is a new expiration date 

if the patent had been submitted 

previously for listing; 

(M) Information on whether the 

patent is a product-by-process patent in 

which the product claimed is novel; 

(N) Information on the drug substance 

(active ingredient) patent, including the 

following: 

(1) Whether the patent claims the 

drug substance that is the active 

ingredient in the drug product described 

in the approved NDA; 

(2) Whether the patent claims only a 

polymorph that is the same as the active 

ingredient that is described in the 

approved NDA; 

(3) Whether the applicant has test 

data, described in paragraph (b)(2) of 

this section, demonstrating that a drug 

product containing only the polymorph 

will perform the same as the drug 

product described in the approved NDA 

and a description of the polymorphic 

form(s) claimed by the patent for which 

such test data exist; 

(4) Whether the patent claims only a 

metabolite of the active ingredient; and 

(5) Whether the patent claims only an 

intermediate; 

(O) Information on the drug product 

(composition/formulation) patent, 

including the following: 

(1) Whether the patent claims the 

approved drug product as defined in 

§ 314.3; and 

(2) Whether the patent claims only an 

intermediate; 

(P) Information on each method-ofuse patent, including the following: 

(1) Whether the patent claims one or 

more approved methods of using the 

approved drug product and a 

description of each approved method of 

use or indication and related patent 

claim of the patent being submitted; 

(2) Identification of the specific 

section(s) of the approved labeling for 

the drug product that corresponds to the 

method of use claimed by the patent 

submitted (if the scope of the methodof-use claim(s) of the patent does not 

cover every use of the drug, the 

applicant must only identify the specific 

portion(s) of the indication or other 

condition of use claimed by the patent); 

(3) The description of the patented 

method of use as required for 

publication (which must contain 

adequate information to assist 505(b)(2) 

and ANDA applicants in determining 

whether a listed method-of-use patent 

claims a use for which the 505(b)(2) or 

ANDA applicant is not seeking 

approval; for example, if the scope of 

the method-of-use claim(s) of the patent 

does not cover every approved use of 

the drug, then the description of the 

patented method of use must contain 

only the specific portion(s) of the 

indication or other method of use 

claimed by the patent); and 

(4) An applicant that submits 

information for a patent that claims one 

or more methods of using the drug 

product must also submit information 

described in either paragraph 

(c)(2)(ii)(N) or (c)(2)(ii)(O) of this 

section, regarding whether that patent 

also claims either the drug substance 

(active ingredient) or the drug product 

(composition/formulation). 

(Q) Whether there are no relevant 

patents that claim the approved drug 

substance (active ingredient), the 

approved drug product (formulation or 

composition), or approved method(s) of 

use and with respect to which a claim 

of patent infringement could reasonably 

be asserted if a person not licensed by 

the owner of the patent engaged in the 

manufacture, use, or sale of the drug 

product; 

(R) A signed verification that states: 

The undersigned declares that this is an 

accurate and complete submission of patent 

information for the NDA, amendment, or 

supplement approved under section 505 of 

the Federal Food, Drug, and Cosmetic Act. 

This time-sensitive patent information is 

submitted pursuant to 21 CFR 314.53. I attest 

that I am familiar with 21 CFR 314.53 and 

this submission complies with the 

requirements of the regulation. I verify under 

penalty of perjury that the foregoing is true 

and correct.; 

and 

(S) Information on whether the 

applicant, patent owner or attorney, 

agent, representative, or other 

authorized official signed the form; the 

name of the person; and the full 

address, phone number and, if available, 

the fax number and email address. 

(T) Exceptions to required submission 

of patent information: 

(1) If an applicant submits the 

information described in paragraph 

(c)(2)(ii)(N) of this section for a patent 

that claims the drug substance (active 

ingredient) and meets the requirements 

for listing on that basis, then the 

applicant is not required to provide the 

information described in paragraph 

(c)(2)(ii)(O) of this section on whether 

that patent also claims the drug product 

(composition/formulation). 

(2) If an applicant submits the 

information described in paragraph 

(c)(2)(ii)(O) of this section for a patent 

that claims the drug product 

(composition/formulation) and meets 

the requirements for listing on that 

basis, then the applicant is not required 

to provide the information described in 

paragraph (c)(2)(ii)(N) of this section on 

whether that patent also claims the drug 

substance (active ingredient). 

(3) No relevant patents. If the 

applicant believes that there are no 

relevant patents that claim the drug 

substance (active ingredient), drug 

product (formulation or composition), 

or the method(s) of use for which the 

applicant has received approval, and 

with respect to which a claim of patent 

infringement could reasonably be 

asserted if a person not licensed by the 

owner of the patent engaged in the 

manufacture, use, or sale of the drug 

product, the applicant will verify this 

information in the appropriate forms, 

Form FDA 3542 or 3542a. 

(4) Authorized signature. The 

declarations required by this section 

must be signed by the applicant or 

patent owner, or the applicant’s or 

patent owner’s attorney, agent 

(representative), or other authorized 

official. 

(d) When and where to submit patent 

information—(1) Original NDA. An 

applicant must submit with its original 

NDA submitted under this part, 

including a 505(b)(2) application, the 

information described in paragraph (c) 

of this section on each drug substance 

(ingredient), drug product (formulation 

and composition), and method-of-use 

patent issued before the NDA is filed 

with FDA and for which patent 

information is required to be submitted 

under this section. If a patent is issued 

after the NDA is filed with FDA but 

before the NDA is approved, the 

applicant shall, within 30 days of the 

date of issuance of the patent, submit 

the required patent information in an 

amendment to the NDA under § 314.60. 

(2) Supplements. (i) An applicant 

must submit patent information 

required under paragraph (c) of this 

section for a patent that claims the drug 

substance, drug product, or method of 

use for which approval is sought in any 

of the following supplements: 

(A) To change the dosage form or 

route of administration; 

(B) To change the strength; or 

(C) To change the drug product from 

prescription use to over-the-counter use. 


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(ii) If the applicant submits a 

supplement for a change other than one 

of the changes listed under paragraph 

(d)(2)(i) of this section (for example, to 

change the formulation, to add a new 

indication or other condition of use, or 

to make any other patented change 

regarding the drug substance, drug 

product, or any method of use), the 

following patent information 

submission requirements apply: 

(A) If existing patents for which 

information has already been submitted 

to FDA for the product approved in the 

original NDA claim the changed 

product, the applicant is not required to 

resubmit this patent information unless 

the description of the patented method 

of use would change upon approval of 

the supplement, and FDA will continue 

to list this patent information for the 

product; 

(B) If one or more existing patents for 

which information has already been 

submitted to FDA no longer claim the 

changed product, the applicant must 

submit a request to remove that patent 

information from the list at the time of 

approval of the supplement; 

(C) If one or more existing drug 

substance (active ingredient), drug 

product (formulation and composition), 

or method-of-use patents claim the 

changed product for which approval is 

sought in the supplement and such 

patent information has not been 

submitted to FDA, the applicant must 

submit the patent information required 

under paragraph (c) of this section. 

(3) Newly issued patents. If a patent 

is issued for a drug substance, drug 

product, or method of use after an NDA 

is approved, the applicant must submit 

to FDA, as described in paragraph (d)(4) 

of this section, the required patent 

information within 30 days of the date 

of issuance of the patent. If the required 

patent information is not submitted 

within 30 days of the issuance of the 

patent, FDA will list the patent, but 

patent certifications will be governed by 

the provisions regarding untimely filed 

patents at §§ 314.50(i)(4) and (i)(6) and 

314.94(a)(12)(vi) and (a)(12)(viii). 

(4) Submission of Forms FDA 3542a 

and 3542. 

(i) Patent information submitted with 

the filing of an NDA, amendment, or 

supplement. The applicant must submit 

patent information required by 

paragraphs (c)(1) and (c)(2)(i) of this 

section and § 314.50(h) or § 314.70(f) on 

Form FDA 3542a to the Central 

Document Room, Center for Drug 

Evaluation and Research, Food and 

Drug Administration, 5901–B 

Ammendale Rd., Beltsville, MD 20705– 

1266. Form FDA 3542a should not be 

submitted to the Orange Book Staff in 

the Office of Generic Drugs. 

(ii) Patent information submitted 

upon and after approval of an NDA or 

supplement. The applicant must submit 

patent information required by 

paragraphs (c)(1) and (c)(2)(ii) of this 

section on Form FDA 3542 to the Office 

of Generic Drugs, OGD Document Room, 

Attention: Orange Book Staff, 7620 

Standish Pl., Rockville, MD 20855. 

(5) Submission date. Patent 

information will be considered to be 

submitted to FDA for purposes of 

paragraph (d)(3) of this section as of the 

earlier of the date the information 

submitted on Form FDA 3542 is datestamped by the Office of Generic Drugs, 

Document Room, or officially received 

electronically by FDA through the 

Electronic Submissions Gateway. 

(6) Identification. Each submission of 

patent information, except information 

submitted with an original NDA, must 

bear prominent identification as to its 

contents, i.e., ‘‘Patent Information,’’ or, 

if submitted after approval of an NDA, 

‘‘Time-Sensitive Patent Information.’’ 

(e) Public disclosure of patent 

information. FDA will publish in the list 

the patent number and expiration date 

of each patent that is required to be, and 

is, submitted to FDA by an applicant, 

and for each use patent, the approved 

indications or other conditions of use 

covered by a patent. FDA will publish 

such patent information upon approval 

of the NDA, or, if the patent information 

is submitted by the applicant after 

approval of an NDA as provided under 

paragraph (d)(2) of this section, as soon 

as possible after the submission to the 

Agency of the patent information. A 

request for copies of the submitted 

patent information must be sent in 

writing to the Division of Freedom of 

Information (ELEM–1029), Food and 

Drug Administration, 12420 Parklawn 

Dr., Element Bldg., Rockville, MD 

20857. This information, and requests 

for delisting patents, will be subject to 

public disclosure. 

(f) Correction or change of patent 

information—(1) Requests by persons 

other than the NDA holder. If any 

person disputes the accuracy or 

relevance of patent information 

submitted to the Agency under this 

section and published by FDA in the 

list, or believes that an NDA holder has 

failed to submit required patent 

information, that person must first 

notify the Agency in a written or 

electronic communication titled 

‘‘314.53(f) Patent Listing Dispute’’ that 

states the grounds for disagreement. 

Such notification should be directed to 

the Office of Generic Drugs, OGD 

Document Room, Attention: Orange 

Book Staff, 7620 Standish Pl., Rockville, 

MD 20855. The Agency will then 

request of the applicable NDA holder 

that the correctness of the patent 

information or omission of patent 

information be confirmed within 30 

days. For listed patents that claim an 

approved method of using the drug 

product, FDA will request that the NDA 

holder confirm the correctness of its 

description of the approved indication 

or method of use that has been included 

as the ‘‘Use Code’’ in the Orange Book, 

and provide information on the specific 

approved use claimed by the patent that 

enables the Agency to make a 

determination in accordance with 

section 505(b)(2)(B) or 505(j)(2)(C)(viii) 

of the Federal Food, Drug, and Cosmetic 

Act. Unless the NDA holder withdraws 

or amends its patent information in 

response to FDA’s request, the Agency 

will not change the patent information 

in the list. If the NDA holder does not 

change the patent information 

submitted to FDA, a 505(b)(2) 

application or an ANDA under section 

505(j) of the Federal Food, Drug, and 

Cosmetic Act submitted for a drug that 

is claimed by a patent for which 

information has been submitted must, 

despite any disagreement as to the 

correctness of the patent information, 

contain an appropriate certification for 

each listed patent. However, if there is 

insufficient information to make a 

determination in accordance with 

section 505(b)(2)(B) or 505(j)(2)(C)(viii) 

of the Federal Food, Drug, and Cosmetic 

Act, and the NDA holder has confirmed 

the correctness of its description of the 

specific approved use claimed by the 

patent, the Agency will review the 

proposed labeling for the 505(b)(2) 

application or ANDA with deference to 

the 505(b)(2) or ANDA applicant’s 

interpretation of the scope of the patent. 

(2) Requests by the NDA holder.—(i) 

Patents or patent claims that no longer 

meet the statutory requirements for 

listing. If the NDA holder determines 

that a patent or patent claim no longer 

meets the requirements for listing in 

section 505(b)(1) or 505(c)(2) of the 

Federal Food, Drug, and Cosmetic Act 

(including if there has been a judicial 

finding of invalidity for a listed patent, 

from which no appeal has been or can 

be taken), the NDA holder is required to 

promptly notify FDA to withdraw the 

patent or patent information and request 

that the patent or patent information be 

removed from the list. If the NDA holder 

is required by court order to amend 

patent information or withdraw a patent 

from the list, it must submit a copy of 

the order, within 14 days of the date the 

order was entered, to the Office of 


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Generic Drugs, OGD Document Room, 

Attention: Orange Book Staff, 7620 

Standish Pl., Rockville, MD 20855. FDA 

will remove a patent from the list if 

there is no first applicant eligible for 

180-day exclusivity or upon the 

expiration of the 180-day exclusivity 

period of a first applicant. 

(ii) Patent term restoration. If the term 

of a listed patent is extended under 35 

U.S.C. 156(e), the NDA holder must 

submit on Form FDA 3542 a correction 

to the expiration date of the patent. This 

correction must be submitted within 30 

days of receipt of a certificate of 

extension as described in 35 U.S.C. 

156(e)(1) or documentation of an 

extension of the term of the patent as 

described in 35 U.S.C. 156(e)(2). 

(iii) Submission of corrections or 

changes to patent information. 

Corrections or changes to previously 

submitted patent information, other 

than withdrawal of a patent and 

requests to remove a patent from the 

list, must be submitted on Form FDA 

3542 or 3542a, as appropriate. We will 

not accept the corrections or changes 

unless they are submitted on the 

appropriate forms. 

(iv) Submission of patent withdrawals 

and requests to remove a patent from 

the list. Withdrawal of a patent and 

requests to remove a patent from the list 

must be submitted to the same 

addresses described in paragraph (d)(4) 

of this section, except that the 

withdrawal or request to remove a 

patent from the list is not required to be 

submitted on Form FDA 3542 and may 

be submitted by letter. Withdrawal of a 

patent and a request to delist a patent 

must contain the following information: 

(A) The NDA number to which the 

request applies; 

(B) Each product(s) approved in the 

NDA to which the request applies; and 

(C) The patent number. 

6. Section 314.54 is amended by 

removing the word ‘‘shall’’ and adding 

in its place the word ‘‘must’’ in 

paragraph (a)(1) introductory text and 

paragraph (a)(1)(i) and by revising the 

section heading, paragraph (a) 

introductory text, and paragraphs 

(a)(1)(iii), (a)(1)(vi), (a)(4), and (b) to 

read as follows: 

§ 314.54 Procedure for submission of a 

505(b)(2) application requiring 

investigations for approval of a new 

indication for, or other change from, a listed 

drug. 

(a) The Federal Food, Drug, and 

Cosmetic Act does not permit approval 

of an ANDA for a new indication, nor 

does it permit approval of other changes 

in a listed drug if investigations, other 

than bioavailability or bioequivalence 

studies, are essential to the approval of 

the change. Any person seeking 

approval of a drug product that 

represents a modification of a listed 

drug (e.g., a new indication or new 

dosage form) and for which 

investigations, other than bioavailability 

or bioequivalence studies, are essential 

to the approval of the changes may, 

except as provided in paragraph (b) of 

this section, submit a 505(b)(2) 

application. This 505(b)(2) application 

need contain only that information 

needed to support the modification(s) of 

the listed drug. 

(1) * * * 

(iii) Identification of each listed drug 

for which FDA has made a finding of 

safety and effectiveness and on which 

finding the applicant relies in seeking 

approval of its proposed drug product 

by established name, if any, proprietary 

name, dosage form, strength, route of 

administration, name of listed drug’s 

application holder, and listed drug’s 

approved NDA number. The listed drug 

or drugs identified as relied upon must 

include any approved drug product that: 

(A) Is pharmaceutically equivalent to 

the drug product for which the 505(b)(2) 

application is submitted; and 

(B) Was approved before the 505(b)(2) 

application was submitted. 

* * * * * 

(vi) Any patent certification or 

statement required under section 

505(b)(2) of the Federal Food, Drug, and 

Cosmetic Act with respect to any 

relevant patents that claim the listed 

drug or drugs on which investigations 

relied on by the applicant for approval 

of the application were conducted, or 

that claim a use for the listed drug or 

drug(s). 

* * * * * 

(4) The applicant must submit a field 

copy of the 505(b)(2) application that 

contains the technical section described 

in § 314.50(d)(1), a copy of the 

information required under § 314.50(a) 

and (c), and certification that the field 

copy is a true copy of the technical 

section described in § 314.50(d)(1) 

contained in the archival and review 

copies of the 505(b)(2) application. 

(b) A 505(b)(2) application may not be 

submitted under this section for a drug 

product whose only difference from a 

listed drug is that: 

(1) The extent to which its active 

ingredient(s) is absorbed or otherwise 

made available to the site of action is 

less than that of the listed drug; or 

(2) The rate at which its active 

ingredient(s) is absorbed or otherwise 

made available to the site of action is 

unintentionally less than that of the 

listed drug. 

■ 7. Section 314.60 is amended by: 

■ a. Removing the word ‘‘application’’ 

each time it appears and adding in its 

place ‘‘NDA’’; 

■ b. Removing ‘‘(505)(c)(3)(D)(ii)’’ in 

paragraphs (c)(1)(i) and (c)(2) and 

adding in its place ‘‘(505)(c)(3)(E)(ii)’’; 

■ c. Adding paragraph headings in 

paragraphs (a), (b), and (c); 

■ d. Revising the section heading and 

paragraph (d); and 

■ e. Adding new paragraphs (e) and (f). 

The revisions read as follows: 

§ 314.60 Amendments to an unapproved 

NDA, supplement, or resubmission. 

(a) Submission of NDA. * * * 

(b) Submission of major amendment. 

* * * 

(c) Limitation on certain amendments. 

* * * 

(d) Field copy. The applicant must 

submit a field copy of each amendment 

to a section of the NDA described in 

§ 314.50(d)(1). The applicant must 

include in its submission of each such 

amendment to FDA a statement 

certifying that a field copy of the 

amendment has been sent to the 

applicant’s home FDA district office. 

(e) Different drug. An applicant may 

not amend a 505(b)(2) application to 

seek approval of a drug that is a 

different drug from the drug in the 

original submission of the 505(b)(2) 

application. For purposes of this 

section, a drug is a different drug if it 

has been modified to have a different 

active ingredient, different route of 

administration, different dosage form, or 

difference in excipients that requires 

either a separate clinical study to 

establish safety or effectiveness or, for 

topical products, that requires a separate 

in vivo demonstration of 

bioequivalence. However, 

notwithstanding the limitation 

described in this paragraph, an 

applicant may amend the 505(b)(2) 

application to seek approval of a 

different strength. 

(f) Patent certification requirements. 

An amendment to a 505(b)(2) 

application is required to contain patent 

certifications described in § 314.50(i) if 

approval is sought for any of the 

following types of amendments: 

(1) To add a new indication or other 

condition of use; 

(2) To add a new strength; 

(3) To make other than minor changes 

in product formulation; or 

(4) To change the physical form or 

crystalline structure of the active 

ingredient. 

■ 8. Section 314.70 is amended by: 

■ a. Removing the word ‘‘application’’ 

each time it appears and adding in its 

place ‘‘NDA’’; 


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■ b. Removing the words ‘‘cover letter’’ 

in paragraph (a)(6), and adding in their 

place the word ‘‘submission’’; 

■ c. Removing the words ‘‘and its 

mailing cover’’ in paragraph (b)(4); 

■ d. Revising the section heading and 

paragraph (f); and 

■ e. Adding paragraphs (h) and (i). 

The revisions read as follows: 

§ 314.70 Supplements and other changes 

to an approved NDA. 

* * * * * 

(f) Patent information. The applicant 

must comply with the patent 

information requirements under section 

505(c)(2) of the Federal Food, Drug, and 

Cosmetic Act and § 314.53. 

* * * * * 

(h) Different drug. An applicant may 

not supplement a 505(b)(2) application 

to seek approval of a drug that is a 

different drug from the drug in the 

approved 505(b)(2) application. For 

purposes of this section, a drug is a 

different drug if it has been modified to 

have a different active ingredient, 

different route of administration, 

different dosage form, or difference in 

excipients that requires either a separate 

clinical study to establish safety or 

effectiveness or, for topical products, 

that requires a separate in vivo 

demonstration of bioequivalence. 

However, notwithstanding the 

limitation described in this paragraph, 

an applicant may supplement the 

505(b)(2) application to seek approval of 

a different strength. 

(i) Patent certification requirements. 

(1) Except as provided in paragraph 

(i)(2) of this section, a supplement to a 

505(b)(2) application is required to 

contain patent certifications described 

in § 314.50(i) if approval is sought for 

either of the following types of 

supplements: 

(i) To add a new indication or other 

condition of use; or 

(ii) To add a new strength. 

(2) A supplement to a 505(b)(2) 

application that only seeks approval to 

add a new indication or other condition 

of use is required to contain patent 

certifications described in § 314.50(i) 

only for patents that are identified as 

claiming an approved use. If a methodof-use patent is identified as also 

claiming the drug substance or drug 

product, the patent certification also 

must address the drug substance and/or 

drug product claims. 

■ 9. Section 314.90 is amended by 

removing the word ‘‘application’’ each 

time it appears and adding in its place 

‘‘NDA’’ and by adding paragraph (c) to 

read as follows: 

§ 314.90 Waivers. 

* * * * * 

(c) If FDA grants the applicant’s 

waiver request with respect to a 

requirement under §§ 314.50 through 

314.81, the waived requirement will not 

constitute a basis for refusal to approve 

an NDA under § 314.125. 

■ 10. Section 314.93 is amended by: 

■ a. Removing the words ‘‘abbreviated 

new drug applications’’ in paragraph (a) 

and adding in their place ‘‘ANDAs’’; 

■ b. Removing the words ‘‘abbreviated 

new drug application’’ in paragraphs 

(b), (c), and (e)(3) and adding in their 

place ‘‘ANDA’’; 

■ c. Removing the word ‘‘or’’ from the 

end of paragraph (e)(1)(iv) ; 

■ d. Removing ‘‘reasons.’’ in paragraph 

(e)(1)(v) and adding in its place 

‘‘reasons; or’’; 

■ e. Adding paragraph (e)(1)(vi); 

■ f. Redesignating paragraph (f) as 

paragraph (f)(1); and 

■ g. Adding paragraph (f)(2). 

The revisions read as follows: 

§ 314.93 Petition to request a change from 

a listed drug. 

* * * * * 

(e) * * * 

(1) * * * 

(vi) A drug product is approved in an 

NDA for the change described in the 

petition. 

* * * * * 

(f) * * * 

(2) If, after approval of a petition and 

before approval of an ANDA submitted 

pursuant to the approved petition, a 

drug product is approved in an NDA for 

the change described in the petition, the 

petition and the listed drug identified in 

the petition can no longer be the basis 

for ANDA submission, irrespective of 

whether FDA has withdrawn approval 

of the petition. A person seeking 

approval for such drug product must 

submit a new ANDA that identifies the 

pharmaceutically equivalent reference 

listed drug as the basis for ANDA 

submission and comply with applicable 

regulatory requirements. 

■ 11. Section 314.94 is amended by: 

■ a. Removing the words ‘‘abbreviated 

application’’ in paragraphs (a)(5)(ii)(A), 

(a)(6)(ii), (d)(1)(i), and (d)(4) each time 

they appear and adding in their place 

‘‘ANDA’’; 

■ b. Removing the word ‘‘shall’’ in 

paragraphs (a)(9)(i) through (a)(9)(iv), 

(a)(12)(i)(A)(1) through (a)(12)(i)(A)(3), 

and (a)(12)(vii) each time it appears and 

adding in its place the word ‘‘must’’; 

■ c. Removing and reserving paragraph 

(a)(12)(iv); and 

■ d. Revising the section heading and 

the introductory text, paragraph (a) 

heading and introductory text, 

paragraphs (a)(1) and (a)(2), paragraph 

(a)(3) heading and introductory text, 

paragraphs (a)(3)(i), (a)(3)(iii), the first 

sentence of paragraph (a)(7)(ii), 

paragraphs (a)(7)(iii), (a)(8)(i),(a)(9)(v), 

paragraph (a)(12)(i)(A) introductory text, 

paragraphs (a)(12)(i)(A)(4), (a)(12)(i)(B), 

(a)(12)(iii)(A), (a)(12)(iii)(B), (a)(12)(v), 

(a)(12)(vi), (a)(12)(viii), (a)(13), (b), 

paragraph (d) heading, paragraph (d)(1) 

introductory text, and paragraphs (d)(2) 

and (d)(5). 

The revisions read as follows: 

§ 314.94 Content and format of an ANDA. 

ANDAs are required to be submitted 

in the form and contain the information 

required under this section. Three 

copies of the application are required, 

an archival copy, a review copy, and a 

field copy. FDA will maintain guidance 

documents on the format and content of 

applications to assist applicants in their 

preparation. 

(a) ANDAs. Except as provided in 

paragraph (b) of this section, the 

applicant must submit a complete 

archival copy of the ANDA that 

includes the following: 

(1) Application form. The applicant 

must submit a completed and signed 

application form that contains the 

information described under 

§ 314.50(a)(1), (a)(3), (a)(4), and (a)(5). 

The applicant must state whether the 

submission is an ANDA under this 

section or a supplement to an ANDA 

under § 314.97. 

(2) Table of contents. The archival 

copy of the ANDA is required to contain 

a table of contents that shows the 

volume number and page number of the 

contents of the submission. 

(3) Basis for ANDA submission. An 

ANDA must refer to a listed drug. 

Ordinarily, that listed drug will be the 

drug product selected by the Agency as 

the reference standard for conducting 

bioequivalence testing. The application 

must contain: 

(i) The name of the reference listed 

drug, including its dosage form and 

strength. For an ANDA based on an 

approved petition under § 10.30 of this 

chapter or § 314.93, the reference listed 

drug must be the same as the listed drug 

approved in the petition. 

* * * * * 

(iii) For an ANDA based on an 

approved petition under § 10.30 of this 

chapter or § 314.93, a reference to the 

FDA-assigned docket number for the 

petition and a copy of FDA’s 

correspondence approving the petition. 

* * * * * 

(7) * * * 

(ii) If the ANDA is submitted pursuant 

to a petition approved under § 314.93, 


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the results of any bioavailability or 

bioequivalence testing required by the 

Agency, or any other information 

required by the Agency to show that the 

active ingredients of the proposed drug 

product are of the same pharmacological 

or therapeutic class as those in the 

reference listed drug and that the 

proposed drug product can be expected 

to have the same therapeutic effect as 

the reference listed drug. * * * 

* * * * * 

(iii) For each in vivo or in vitro 

bioequivalence study contained in the 

ANDA: 

(A) A description of the analytical and 

statistical methods used in each study; 

and 

(B) With respect to each study 

involving human subjects, a statement 

that it either was conducted in 

compliance with the institutional 

review board regulations in part 56 of 

this chapter, or was not subject to the 

regulations under § 56.104 or § 56.105 of 

this chapter, and that it was conducted 

in compliance with the informed 

consent regulations in part 50 of this 

chapter. 

(8) Labeling—(i) Listed drug labeling. 

A copy of the currently approved 

labeling (including, if applicable, any 

Medication Guide required under part 

208 of this chapter) for the listed drug 

referred to in the ANDA, if the ANDA 

relies on a reference listed drug. 

* * * * * 

(9) * * * 

(v) Inactive ingredient changes 

permitted in drug products intended for 

topical use. Generally, a drug product 

intended for topical use, solutions for 

aerosolization or nebulization, and nasal 

solutions must contain the same 

inactive ingredients as the reference 

listed drug identified by the applicant 

under paragraph (a)(3) of this section. 

However, an ANDA may include 

different inactive ingredients provided 

that the applicant identifies and 

characterizes the differences and 

provides information demonstrating that 

the differences do not affect the safety 

or efficacy of the proposed drug 

product. 

* * * * * 

(12) Patent certification—(i) Patents 

claiming drug, drug product, or method 

of use. (A) A certification with respect 

to each patent issued by the U.S. Patent 

and Trademark Office that, in the 

opinion of the applicant and to the best 

of its knowledge, claims the reference 

listed drug or that claims a use of such 

listed drug for which the applicant is 

seeking approval under section 505(j) of 

the Federal Food, Drug, and Cosmetic 

Act and for which information is 

required to be filed under section 505(b) 

and (c) of the Federal Food, Drug, and 

Cosmetic Act and § 314.53. For each 

such patent, the applicant must provide 

the patent number and certify, in its 

opinion and to the best of its 

knowledge, one of the following 

circumstances: 

* * * * * 

(4) That the patent is invalid, 

unenforceable, or will not be infringed 

by the manufacture, use, or sale of the 

drug product for which the ANDA is 

submitted. The applicant shall entitle 

such a certification ‘‘Paragraph IV 

Certification’’. This certification must be 

submitted in the following form: 

I, (name of applicant), certify that Patent 

No. ____________(is invalid, unenforceable, 

or will not be infringed by the manufacture, 

use, or sale of) (name of proposed drug 

product) for which this application is 

submitted. 

The certification must be accompanied 

by a statement that the applicant will 

comply with the requirements under 

§ 314.95(a) with respect to providing a 

notice to each owner of the patent or 

their representatives and to the holder 

of the approved application for the 

listed drug, with the requirements under 

§ 314.95(b) with respect to sending the 

notice, and with the requirements under 

§ 314.95(c) with respect to the content of 

the notice. 

(B) If the ANDA refers to a listed drug 

that is itself a licensed generic product 

of a patented drug first approved under 

section 505(b) of the Federal Food, 

Drug, and Cosmetic Act, the appropriate 

patent certification under paragraph 

(a)(12)(i) of this section with respect to 

each patent that claims the firstapproved patented drug or that claims a 

use for such drug. 

* * * * * 

(iii) Method-of-use patent. (A) If 

patent information is submitted under 

section 505(b) or (c) of the Federal Food, 

Drug, and Cosmetic Act and § 314.53 for 

a patent claiming a method of using the 

listed drug, and the labeling for the drug 

product for which the applicant is 

seeking approval does not include any 

indications or other conditions of use 

that are covered by the use patent, a 

statement explaining that the methodof-use patent does not claim any of the 

proposed indications or other 

conditions of use. 

(B) If the labeling of the drug product 

for which the applicant is seeking 

approval includes an indication or other 

condition of use that, according to the 

patent information submitted under 

section 505(b) or (c) of the Federal Food, 

Drug, and Cosmetic Act and § 314.53 or 

in the opinion of the applicant, is 

claimed by a use patent, an applicable 

certification under paragraph (a)(12)(i) 

of this section. 

(iv) [Reserved] 

(v) Licensing agreements. If the ANDA 

is for a drug or method of using a drug 

claimed by a patent and the applicant 

has a licensing agreement with the 

patent owner, a paragraph IV 

certification as to that patent and a 

statement that it has been granted a 

patent license. 

(vi) Untimely filing of patent 

information. If a patent on the listed 

drug is issued and the holder of the 

approved NDA for the listed drug does 

not file with FDA the required 

information on the patent within 30 

days of issuance of the patent, an 

applicant who submitted an ANDA for 

that drug that contained an appropriate 

patent certification before the 

submission of the patent information is 

not required to submit an amended 

certification to address the patent that is 

late-listed with respect to the pending 

ANDA. Except as provided in 

§ 314.53(f)(1), an NDA holder’s 

amendment to the description of the 

approved method(s) of use claimed by 

the patent will be considered untimely 

filing of patent information if: 

(A) The amendment is submitted 

more than 30 days after patent issuance 

and it is not related to a corresponding 

change in approved product labeling; or 

(B) The amendment is submitted more 

than 30 days after a corresponding 

change in approved product labeling. 

An applicant whose ANDA is submitted 

after the NDA holder’s untimely filing of 

patent information, or whose pending 

ANDA was previously submitted but 

did not contain an appropriate patent 

certification at the time of the patent 

submission, must submit a certification 

under paragraph (a)(12)(i) of this section 

or a statement under paragraph 

(a)(12)(iii) of this section as to that 

patent. 

* * * * * 

(viii) Amended certifications. A 

certification submitted under 

paragraphs (a)(12)(i) through (a)(12)(iii) 

of this section may be amended at any 

time before the date of approval of the 

ANDA. If an applicant with a pending 

ANDA voluntarily makes a patent 

certification for an untimely filed 

patent, the applicant may withdraw the 

patent certification for the untimely 

filed patent. An applicant must submit 

an amended certification as an 

amendment to a pending ANDA. Once 

an amendment is submitted to change a 

certification, the ANDA will no longer 

be considered to contain the prior 

certification. 


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(A) After finding of infringement. An 

applicant who has submitted a 

paragraph IV certification and is sued 

for patent infringement must submit an 

amendment to change its certification if 

a court enters a final decision from 

which no appeal has been or can be 

taken, or signs a settlement order or 

consent decree in the action that 

includes a finding that the patent is 

infringed, unless the final decision, 

settlement order, or consent decree also 

finds the patent to be invalid. In its 

amendment, the applicant must certify 

under paragraph (a)(12)(i)(A)(3) of this 

section that the patent will expire on a 

specific date. Once an amendment for 

the change has been submitted, the 

ANDA will no longer be considered to 

be one containing a paragraph IV 

certification to the patent. If a final 

judgment finds the patent to be invalid 

and infringed, an amended certification 

is not required. 

(B) After request to remove a patent 

or patent information from the list. If the 

list reflects that an NDA holder has 

requested that a patent be removed from 

the list and no ANDA applicant is 

eligible for 180-day exclusivity based on 

a paragraph IV certification to that 

patent, the patent will be removed and 

any applicant with a pending ANDA 

(including a tentatively approved 

application) who has made a 

certification with respect to such patent 

must submit an amendment to 

withdraw its certification. In the 

amendment, the applicant must state 

the reason for withdrawing the 

certification (that the patent is or has 

been removed from the list). If the list 

reflects that an NDA holder has 

requested that a patent be removed from 

the list and one or more first applicants 

are eligible for 180-day exclusivity 

based on a paragraph IV certification to 

that patent, the patent shall remain 

listed until any 180-day exclusivity is 

extinguished. If one or more first 

applicants are eligible for 180-day 

exclusivity based on a paragraph IV 

certification to a patent that has been 

reissued, then the first applicant must 

submit a paragraph IV certification to 

the reissued patent within 30 days of 

listing to have lawfully maintained its 

paragraph IV certification for purposes 

of eligibility for 180-day exclusivity. 

After any applicable 180-day exclusivity 

has been extinguished, the patent will 

be removed and any applicant with a 

pending ANDA (including a tentatively 

approved application) who has made a 

certification with respect to such patent 

must submit an amendment to 

withdraw its certification. Once an 

amendment to withdraw the 

certification has been submitted, the 

ANDA will no longer be considered to 

be one containing a paragraph IV 

certification to the patent. If removal of 

a patent from the list results in there 

being no patents listed for the listed 

drug identified in the ANDA, the 

applicant must submit an amended 

certification reflecting that there are no 

listed patents. 

(C) Other amendments. (1) Except as 

provided in paragraphs (a)(12)(vi) and 

(a)(12)(viii)(C)(2) of this section: 

(i) An applicant must amend a 

submitted certification if, at any time 

before the date of approval of the 

ANDA, the applicant learns that the 

submitted certification is no longer 

accurate; and 

(ii) An applicant must submit a 

certification or statement under 

paragraph (a)(12)(i) of this section if, 

after submission of the ANDA, a new 

patent is issued by the U.S. Patent and 

Trademark Office that, in the opinion of 

the applicant and to the best of its 

knowledge, claims the reference listed 

drug or that claims an approved use for 

such reference listed drug and for which 

information is required to be filed under 

section 505(b) and (c) of the Federal 

Food, Drug, and Cosmetic Act and 

§ 314.53. For a paragraph IV 

certification, the certification must not 

be submitted earlier than the first 

working day after the day the patent is 

published in the list. 

(2) An applicant is not required to 

submit a supplement to change a 

submitted certification when 

information on a patent on the listed 

drug is submitted after the approval of 

the ANDA, except as provided in 

§ 314.97(c). 

(13) Financial certification or 

disclosure statement. An ANDA must 

contain a financial certification or 

disclosure statement as required by part 

54 of this chapter. 

(b) Drug products subject to the Drug 

Efficacy Study Implementation (DESI) 

review. If the ANDA is for a duplicate 

of a drug product that is subject to 

FDA’s DESI review (a review of drug 

products approved as safe between 1938 

and 1962) or other DESI-like review and 

the drug product evaluated in the 

review is a listed drug, the applicant 

must comply with the provisions of 

paragraph (a) of this section. 

(c) [Reserved] 

(d) Format of an ANDA. (1) The 

applicant must submit a complete 

archival copy of the ANDA as required 

under paragraphs (a) and (c) of this 

section. FDA will maintain the archival 

copy during the review of the ANDA to 

permit individual reviewers to refer to 

information that is not contained in 

their particular technical sections of the 

ANDA, to give other Agency personnel 

access to the ANDA for official business, 

and to maintain in one place a complete 

copy of the ANDA. 

* * * * * 

(2) For ANDAs, the applicant must 

submit a review copy of the ANDA that 

contains two separate sections. One 

section must contain the information 

described under paragraphs (a)(2) 

through (a)(6), (a)(8), and (a)(9) of this 

section, and section 505(j)(2)(A)(vii) of 

the Federal Food, Drug, and Cosmetic 

Act and a copy of the analytical 

procedures and descriptive information 

needed by FDA’s laboratories to perform 

tests on samples of the proposed drug 

product and to validate the applicant’s 

analytical procedures. The other section 

must contain the information described 

under paragraphs (a)(3), (a)(7), and (a)(8) 

of this section. Each of the sections in 

the review copy is required to contain 

a copy of the application form described 

under § 314.50(a). 

* * * * * 

(5) The applicant must submit a field 

copy of the ANDA that contains the 

technical section described in paragraph 

(a)(9) of this section, a copy of the 

application form required under 

paragraph (a)(1) of this section, and a 

certification that the field copy is a true 

copy of the technical section described 

in paragraph (a)(9) of this section 

contained in the archival and review 

copies of the ANDA. 

■ 12. Section 314.95 is revised to read 

as follows: 

§ 314.95 Notice of certification of invalidity 

or noninfringement of a patent. 

(a) Notice of certification. For each 

patent that claims the listed drug or that 

claims a use for such listed drug for 

which the applicant is seeking approval 

and for which the applicant submits a 

paragraph IV certification, the applicant 

must send notice of such certification by 

registered or certified mail, return 

receipt requested, or by a designated 

delivery service, as defined in paragraph 

(g) of this section to each of the 

following persons: 

(1) Each owner of the patent which is 

the subject of the certification or the 

representative designated by the owner 

to receive the notice. The name and 

address of the patent owner or its 

representative may be obtained from the 

U.S. Patent and Trademark Office; and 

(2) The holder of the approved NDA 

under section 505(b) of the Federal 

Food, Drug, and Cosmetic Act for the 

listed drug that is claimed by the patent 

and for which the applicant is seeking 

approval or, if the NDA holder does not 

reside or maintain a place of business 


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within the United States, the NDA 

holder’s attorney, agent, or other 

authorized official. The name and 

address of the NDA holder or its 

attorney, agent, or authorized official 

may be obtained from the Orange Book 

Staff, Office of Generic Drugs, 7620 

Standish Pl., Rockville, MD 20855. 

(3) This paragraph does not apply to 

a use patent that does not claim a use 

for which the applicant is seeking 

approval. 

(4) An applicant may send notice by 

an alternative method only if FDA has 

agreed in advance that the method will 

produce an acceptable form of 

documentation. 

(b) Sending the notice. (1) Except as 

provided under paragraph (d) of this 

section, the applicant must send the 

notice required by paragraph (a) of this 

section on or after the date it receives an 

acknowledgment letter or a paragraph 

IV acknowledgment letter from FDA, 

but not later than 20 days after the date 

of the postmark on the acknowledgment 

letter. The 20-day clock described in 

this paragraph begins on the day after 

the date of the postmark on the 

paragraph IV acknowledgment letter. 

When the 20th day falls on Saturday, 

Sunday, or a Federal holiday, the 20th 

day will be the next day that is not a 

Saturday, Sunday, or Federal holiday. 

(2) Any notice required by paragraph 

(a) of this section is invalid if it is sent 

before the applicant’s receipt of an 

acknowledgment letter or a paragraph 

IV acknowledgment letter, or before the 

first working day after the day the 

patent is published in the list. The 

applicant will not have complied with 

this paragraph until it sends valid 

notice. 

(3) At the same time it sends the 

notice required by paragraph (a) of this 

section, the applicant must submit to 

FDA an amendment to its ANDA that 

includes a statement certifying that the 

notice has been provided to each person 

identified under paragraph (a) of this 

section and that the notice met the 

content requirements under paragraph 

(c) of this section. A copy of the notice 

itself need not be submitted to the 

Agency. 

(c) Contents of a notice. In the notice, 

the applicant must cite section 

505(j)(2)(B)(iv) of the Federal Food, 

Drug, and Cosmetic Act and must 

include, but is not limited to, the 

following information: 

(1) A statement that FDA has received 

an ANDA submitted by the applicant 

containing any required bioavailability 

or bioequivalence data or information. 

(2) The ANDA number. 

(3) A statement that the applicant has 

received the acknowledgment letter or 

paragraph IV acknowledgment letter for 

the ANDA. 

(4) The established name, if any, as 

defined in section 502(e)(3) of the 

Federal Food, Drug, and Cosmetic Act, 

of the proposed drug product. 

(5) The active ingredient, strength, 

and dosage form of the proposed drug 

product. 

(6) The patent number and expiration 

date of each listed patent for the 

reference listed drug alleged to be 

invalid, unenforceable, or not infringed. 

(7) A detailed statement of the factual 

and legal basis of the applicant’s 

opinion that the patent is not valid, 

unenforceable, or will not be infringed. 

The applicant must include in the 

detailed statement: 

(i) For each claim of a patent alleged 

not to be infringed, a full and detailed 

explanation of why the claim is not 

infringed. 

(ii) For each claim of a patent alleged 

to be invalid or unenforceable, a full 

and detailed explanation of the grounds 

supporting the allegation. 

(8) If the applicant alleges that the 

patent will not be infringed and the 

applicant may later decide to file a civil 

action for declaratory judgment in 

accordance with section 505(j)(5)(C) of 

the Federal Food, Drug, and Cosmetic 

Act, then the notice must be 

accompanied by an offer of confidential 

access to the ANDA for the sole and 

limited purpose of evaluating possible 

infringement of the patent that is the 

subject of the paragraph IV certification. 

(9) If the applicant does not reside or 

have a place of business in the United 

States, the name and address of an agent 

in the United States authorized to 

accept service of process for the 

applicant. 

(d) Amendment or supplement to an 

ANDA. (1) If, after receipt of a paragraph 

IV acknowledgment letter, an applicant 

submits an amendment or supplement 

to its ANDA that includes a paragraph 

IV certification, the applicant must send 

the notice required by paragraph (a) of 

this section at the same time that the 

amendment or supplement to the ANDA 

is submitted to FDA, regardless of 

whether the applicant has already given 

notice with respect to another such 

certification contained in the 

application or in an amendment or 

supplement to the application. 

(2) If, before receipt of an 

acknowledgment letter or a paragraph 

IV acknowledgment letter, an applicant 

submits an amendment to its ANDA that 

includes a paragraph IV certification, 

the applicant must send the notice 

required by paragraph (a) of this section 

in accordance with the procedures in 

paragraph (b) of this section. If an 

ANDA applicant’s notice of its 

paragraph IV certification is timely 

provided in accordance with paragraph 

(b) of this section, FDA will base its 

determination of whether the applicant 

is a first applicant on the date of 

submission of the amendment 

containing the paragraph IV 

certification. 

(3) An applicant that submits an 

amendment or supplement to seek 

approval of a different strength must 

provide notice of any paragraph IV 

certification in accordance with 

paragraph (d)(1) or (d)(2) of this section, 

as applicable. 

(e) Documentation of timely sending 

and receipt of notice. The applicant 

must amend its ANDA to provide 

documentation of the date of receipt of 

the notice required under paragraph (a) 

of this section by each person provided 

the notice. The amendment must be 

submitted to FDA within 30 days after 

the last date on which notice was 

received by a person described in 

paragraph (a) of this section. The 

applicant’s amendment also must 

include documentation that its notice 

was sent on a date that complies with 

the timeframe required by paragraph (b) 

or paragraph (d) of this section, as 

applicable, and a dated printout of the 

entry for the reference listed drug in 

FDA’s ‘‘Approved Drug Products With 

Therapeutic Equivalence Evaluations’’ 

(the list) that includes the patent that is 

the subject of the paragraph IV 

certification. FDA will accept, as 

adequate documentation of the date the 

notice was sent, a copy of the registered 

mail receipt, certified mail receipt, or 

receipt from a designated delivery 

service, as defined in paragraph (g) of 

this section. FDA will accept as 

adequate documentation of the date of 

receipt a return receipt, signature proof 

of delivery by a designated delivery 

service, or a letter acknowledging 

receipt by the person who provided the 

notice. An applicant may rely on 

another form of documentation only if 

FDA has agreed to such documentation 

in advance. A copy of the notice itself 

need not be submitted to the Agency. 

(f) Approval. If the requirements of 

this section are met, FDA will presume 

the notice to be complete and sufficient, 

and it will count the day following the 

date of receipt of the notice by the 

patent owner or its representative and 

by the approved application holder as 

the first day of the 45-day period 

provided for in section 505(j)(5)(B)(iii) 

of the Federal Food, Drug, and Cosmetic 

Act. FDA may, if the applicant provides 

a written statement to FDA that a later 

date should be used, count from such 

later date. 


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(g) Designated delivery services. (1) 

For purposes of this section, the term 

‘‘designated delivery service’’ means 

any delivery service provided by a trade 

or business that the Agency determines: 

(i) Is available to the general public 

throughout the United States; 

(ii) Records electronically to its 

database, kept in the regular course of 

its business, or marks on the cover in 

which any item referred to in this 

section is to be delivered, the date on 

which such item was given to such 

trade or business for delivery; and 

(iii) Provides overnight or 2-day 

delivery service throughout the United 

States. 

(2) FDA will periodically issue 

guidance regarding designated delivery 

services that meet these criteria. 

■ 13. Section 314.96 is amended by: 

■ a. Revising the section heading; 

■ b. Removing from the heading of 

paragraph (a) and from paragraph (a)(1) 

the words ‘‘abbreviated new drug 

application’’ and adding in their place 

‘‘ANDA’’; 

■ c. Removing from paragraph (a)(1) 

‘‘320.1(g)’’ and adding in its place 

‘‘314.3’’; 

■ d. Removing from paragraph (b) the 

word ‘‘shall’’ each time it appears and 

adding in its place the word ‘‘must’’; 

■ e. Adding a heading to paragraph (b); 

and 

■ f. Adding paragraphs (c) and (d). 

The revisions read as follows: 

§ 314.96 Amendments to an unapproved 

ANDA. 

* * * * * 

(b) Field copy. * * * 

(c) Different listed drug. An applicant 

may not amend an ANDA to seek 

approval of a drug referring to a listed 

drug that is different from the reference 

listed drug identified in the ANDA. This 

paragraph applies if, at any time before 

the approval of the ANDA, a different 

listed drug is approved that is the 

pharmaceutical equivalent to the 

product in the ANDA and is designated 

as a reference listed drug. This 

paragraph also applies if changes are 

proposed in an amendment to the 

ANDA such that the proposed product 

is a pharmaceutical equivalent to a 

different listed drug than the reference 

listed drug identified in the ANDA. A 

change of the reference listed drug must 

be submitted in a new ANDA. However, 

notwithstanding the limitation 

described in this paragraph, an 

applicant may amend the ANDA to seek 

approval of a different strength. 

(d) Patent certification requirements. 

An amendment to an ANDA is required 

to contain patent certifications 

described in § 314.94(a)(12) if approval 

is sought for any of the following types 

of amendments: 

(1) To add a new indication or other 

condition of use; 

(2) To add a new strength; 

(3) To make other than minor changes 

in product formulation; or 

(4) To change the physical form or 

crystalline structure of the active 

ingredient. 

■ 14. Section 314.97 is revised to read 

as follows: 

§ 314.97 Supplements and other changes 

to an approved ANDA. 

(a) General requirements. The 

applicant must comply with the 

requirements of §§ 314.70 and 314.71 

regarding the submission of 

supplemental applications and other 

changes to an approved ANDA. 

(b) Different listed drug. An applicant 

may not supplement an ANDA to seek 

approval of a drug referring to a listed 

drug that is different from the current 

reference listed drug identified in the 

ANDA. This paragraph applies if 

changes are proposed in a supplement 

to the ANDA such that the proposed 

product is a pharmaceutical equivalent 

to a different listed drug than the 

reference listed drug identified in the 

ANDA. A change of reference listed 

drug must be submitted in a new 

ANDA. However, notwithstanding the 

limitation described in this paragraph, 

an applicant may supplement the 

ANDA to seek approval of a different 

strength. 

(c) Patent certification requirements. 

A supplement to an ANDA is required 

to contain patent certifications 

described in § 314.94(a)(12) if approval 

is sought for either of the following 

types of supplements: 

(1) To add a new indication or other 

condition of use; or 

(2) To add a new strength. 

■ 15. Section 314.99 is revised to read 

as follows: 

§ 314.99 Other responsibilities of an 

applicant of an ANDA. 

(a) An applicant must comply with 

the requirements of § 314.65 regarding 

withdrawal by the applicant of an 

unapproved ANDA and § 314.72 

regarding a change in ownership of an 

ANDA. 

(b) An applicant may ask FDA to 

waive under this section any 

requirement that applies to the 

applicant under §§ 314.92 through 

314.99. The applicant must comply with 

the requirements for a waiver under 

§ 314.90. If FDA grants the applicant’s 

waiver request with respect to a 

requirement under §§ 314.92 through 

314.99, the waived requirement will not 

constitute a basis for refusal to approve 

an ANDA under § 314.127. 

■ 16. Section 314.101 is revised to read 

as follows: 

§ 314.101 Filing an NDA and receiving an 

ANDA. 

(a) Filing an NDA. (1) Within 60 days 

after FDA receives an NDA, the Agency 

will determine whether the NDA may be 

filed. The filing of an NDA means that 

FDA has made a threshold 

determination that the NDA is 

sufficiently complete to permit a 

substantive review. 

(2) If FDA finds that none of the 

reasons in paragraphs (d) and (e) of this 

section for refusing to file the NDA 

applies, the Agency will file the NDA 

and notify the applicant in writing. In 

the case of a 505(b)(2) application that 

contains a paragraph IV certification, 

the applicant will be notified via a 

paragraph IV acknowledgment letter. 

The date of filing will be the date 60 

days after the date FDA received the 

NDA. The date of filing begins the 180- 

day period described in section 505(c) 

of the Federal Food, Drug, and Cosmetic 

Act. This 180-day period is called the 

‘‘filing clock.’’ 

(3) If FDA refuses to file the NDA, the 

Agency will notify the applicant in 

writing and state the reason under 

paragraph (d) or (e) of this section for 

the refusal. If FDA refuses to file the 

NDA under paragraph (d) of this 

section, the applicant may request in 

writing within 30 days of the date of the 

Agency’s notification an informal 

conference with the Agency about 

whether the Agency should file the 

NDA. If, following the informal 

conference, the applicant requests that 

FDA file the NDA (with or without 

amendments to correct the deficiencies), 

the Agency will file the NDA over 

protest under paragraph (a)(2) of this 

section, notify the applicant in writing, 

and review it as filed. If the NDA is filed 

over protest, the date of filing will be 

the date 60 days after the date the 

applicant requested the informal 

conference. The applicant need not 

resubmit a copy of an NDA that is filed 

over protest. If FDA refuses to file the 

NDA under paragraph (e) of this section, 

the applicant may amend the NDA and 

resubmit it, and the Agency will make 

a determination under this section 

whether it may be filed. 

(b) Receiving an ANDA. (1) An ANDA 

will be reviewed after it is submitted to 

determine whether the ANDA may be 

received. Receipt of an ANDA means 

that FDA has made a threshold 

determination that the ANDA is 

substantially complete. 


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(2) If FDA finds that none of the 

reasons in paragraphs (d) and (e) of this 

section for considering the ANDA not to 

have been received applies, the ANDA 

is substantially complete and the 

Agency will receive the ANDA and 

notify the applicant in writing. If an 

ANDA is determined to be substantially 

complete, the date of submission is 

considered to be the date of receipt. In 

the case of an ANDA that contains a 

paragraph IV certification, the applicant 

will be notified via a paragraph IV 

acknowledgment letter. 

(3) If FDA considers the ANDA not to 

have been received under paragraph (d) 

or (e) of this section, FDA will notify the 

applicant. The applicant may then: 

(i) Withdraw the ANDA under 

§ 314.99; or 

(ii) Amend the ANDA to correct the 

deficiencies; or 

(iii) Take no action, in which case 

FDA will refuse to receive the ANDA. 

(4) If, after an ANDA has been 

received under paragraph (b)(2) of this 

section, FDA determines that the 

applicant did not send notice of a 

paragraph IV certification as required 

under § 314.95 within the timeframe 

specified in paragraph (b) or (d) of that 

section, the date that the ANDA was 

submitted will be deemed to be delayed 

by the number of days by which the 

timeframe required by § 314.95(b) or (d) 

was exceeded. When the date as delayed 

falls on Saturday, Sunday, or a Federal 

holiday, the filing date will be the next 

day that is not a Saturday, Sunday, or 

a Federal holiday. 

(c) [Reserved] 

(d) Application deficiencies. FDA may 

refuse to file an NDA or may not 

consider an ANDA to be received if any 

of the following applies: 

(1) The NDA or ANDA does not 

contain a completed application form. 

(2) The NDA or ANDA is not 

submitted in the form required under 

§ 314.50 or § 314.94. 

(3) The NDA or ANDA is incomplete 

because it does not on its face contain 

information required under section 

505(b) or section 505(j) of the Federal 

Food, Drug, and Cosmetic Act and 

§ 314.50 or § 314.94. 

(4) The applicant fails to submit a 

complete environmental assessment that 

addresses each of the items specified in 

the applicable format under § 25.40 of 

this chapter or fails to provide sufficient 

information to establish that the 

requested action is subject to categorical 

exclusion under § 25.30 or § 25.31 of 

this chapter. 

(5) The NDA or ANDA does not 

contain an accurate and complete 

English translation of each part of the 

application that is not in English. 

(6) The NDA or ANDA does not 

contain a statement for each nonclinical 

laboratory study that it was conducted 

in compliance with the requirements set 

forth in part 58 of this chapter or, for 

each study not conducted in compliance 

with part 58 of this chapter, a brief 

statement of the reason for the 

noncompliance. 

(7) The NDA or ANDA does not 

contain a statement for each clinical 

study that it was conducted in 

compliance with the institutional 

review board regulations in part 56 of 

this chapter or was not subject to those 

regulations, and that it was conducted 

in compliance with the informed 

consent regulations in part 50 of this 

chapter or, if the study was subject to 

but was not conducted in compliance 

with those regulations, the NDA or 

ANDA does not contain a brief 

statement of the reason for the 

noncompliance. 

(8) The drug product that is the 

subject of the submission is already 

covered by an approved NDA or ANDA 

and the applicant of the submission: 

(i) Has an approved NDA or ANDA for 

the same drug product; or 

(ii) Is merely a distributor and/or 

repackager of the already approved drug 

product. 

(9) The NDA is submitted as a 

505(b)(2) application for a drug that is 

a duplicate of a listed drug and is 

eligible for approval under section 

505(j) of the Federal Food, Drug, and 

Cosmetic Act. 

(e) Regulatory deficiencies. The 

Agency will refuse to file an NDA or 

will consider an ANDA not to have been 

received if any of the following applies: 

(1) The drug product is subject to 

licensing by FDA under the Public 

Health Service Act (42 U.S.C. 201 et 

seq.) and subchapter F of this chapter. 

(2) Submission of a 505(b)(2) 

application or an ANDA for the active 

moiety is not permitted under 

§ 314.108(b)(2). 

(f) Outcome of FDA review. (1) Within 

180 days after the date of filing, plus the 

period of time the review period was 

extended (if any), FDA will either: 

(i) Approve the NDA; or 

(ii) Issue a notice of opportunity for a 

hearing if the applicant asked FDA to 

provide it an opportunity for a hearing 

on an NDA in response to a complete 

response letter. 

(2) Within 180 days after the date of 

receipt, plus the period of time the 

review clock was extended (if any), FDA 

will either approve or disapprove the 

ANDA. If FDA disapproves the ANDA, 

FDA will issue a notice of opportunity 

for hearing if the applicant asked FDA 

to provide it an opportunity for a 

hearing on an ANDA in response to a 

complete response letter. 

(3) This paragraph does not apply to 

NDAs or ANDAs that have been 

withdrawn from FDA review by the 

applicant. 

■ 17. Section 314.105 is revised to read 

as follows: 

§ 314.105 Approval of an NDA and an 

ANDA. 

(a) FDA will approve an NDA and 

send the applicant an approval letter if 

none of the reasons in § 314.125 for 

refusing to approve the NDA applies. 

An NDA is approved on the date of the 

issuance of the approval letter. FDA will 

issue a tentative approval letter if an 

NDA otherwise meets the requirements 

for approval under the Federal Food, 

Drug, and Cosmetic Act, but cannot be 

approved because there is a 7-year 

period of orphan exclusivity for the 

listed drug under section 527 of the 

Federal Food, Drug, and Cosmetic Act 

and § 316.31, or if a 505(b)(2) 

application otherwise meets the 

requirements for approval under the 

Federal Food, Drug, and Cosmetic Act, 

but cannot be approved until the 

conditions in § 314.107(b)(3) or (c) are 

met; because there is a period of 

exclusivity for the listed drug under 

§ 314.108; or because there is a period 

of pediatric exclusivity for the listed 

drug under section 505A of the Federal 

Food, Drug, and Cosmetic Act. A drug 

product that is granted tentative 

approval is not an approved drug and 

will not be approved until FDA issues 

an approval after any necessary 

additional review of the NDA. FDA’s 

tentative approval of a drug product is 

based on information available to FDA 

at the time of the tentative approval 

letter (i.e., information in the 505(b)(2) 

application and the status of current 

good manufacturing practices of the 

facilities used in the manufacturing and 

testing of the drug product) and is 

therefore subject to change on the basis 

of new information that may come to 

FDA’s attention. A new drug product 

may not be marketed until the date of 

the approval letter. 

(b) FDA will approve an NDA and 

issue the applicant an approval letter on 

the basis of draft labeling if the only 

deficiencies in the NDA concern 

editorial or similar minor deficiencies in 

the draft labeling. Such approval will be 

conditioned upon the applicant 

incorporating the specified labeling 

changes exactly as directed, and upon 

the applicant submitting to FDA a copy 

of the final printed labeling prior to 

marketing. 

(c) FDA will approve an NDA after it 

determines that the drug meets the 


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statutory standards for safety and 

effectiveness, manufacturing and 

controls, and labeling, and an ANDA 

after it determines that the drug meets 

the statutory standards for 

manufacturing and controls, labeling, 

and, where applicable, bioequivalence. 

While the statutory standards apply to 

all drugs, the many kinds of drugs that 

are subject to the statutory standards 

and the wide range of uses for those 

drugs demand flexibility in applying the 

standards. Thus FDA is required to 

exercise its scientific judgment to 

determine the kind and quantity of data 

and information an applicant is required 

to provide for a particular drug to meet 

the statutory standards. FDA makes its 

views on drug products and classes of 

drugs available through guidance 

documents, recommendations, and 

other statements of policy. 

(d) FDA will approve an ANDA and 

send the applicant an approval letter if 

none of the reasons in § 314.127 for 

refusing to approve the ANDA applies. 

The date of approval is the date of the 

issuance of the Agency’s approval letter. 

FDA will issue a tentative approval 

letter if an ANDA otherwise meets the 

requirements for approval under the 

Federal Food, Drug, and Cosmetic Act, 

but cannot be approved because there is 

a 7-year period of orphan exclusivity for 

the listed drug under section 527 of the 

Federal Food, Drug, and Cosmetic Act 

and § 316.31, or cannot be approved 

until the conditions in § 314.107(b)(3) or 

(c) are met; because there is a period of 

exclusivity for the listed drug under 

§ 314.108; or because there is a period 

of pediatric exclusivity for the listed 

drug under section 505A of the Federal 

Food, Drug, and Cosmetic Act. A drug 

product that is granted tentative 

approval is not an approved drug and 

will not be approved until FDA issues 

an approval after any necessary 

additional review of the ANDA. FDA’s 

tentative approval of a drug product is 

based on information available to FDA 

at the time of the tentative approval 

letter (i.e., information in the ANDA and 

the status of current good manufacturing 

practices of the facilities used in the 

manufacturing and testing of the drug 

product) and is therefore subject to 

change on the basis of new information 

that may come to FDA’s attention. A 

new drug product may not be marketed 

until the date of the approval letter. 

■ 18. Section 314.107 is revised to read 

as follows: 

§ 314.107 Date of approval of a 505(b)(2) 

application or ANDA. 

(a) General. A drug product may be 

introduced or delivered for introduction 

into interstate commerce when the 

505(b)(2) application or ANDA for the 

drug product is approved. A 505(b)(2) 

application or ANDA for a drug product 

is approved on the date FDA issues an 

approval letter under § 314.105 for the 

505(b)(2) application or ANDA. 

(b) Effect of patent(s) on the listed 

drug. As described in paragraphs (b)(1) 

and (b)(2) of this section, the status of 

patents listed for the listed drug(s) 

relied upon or reference listed drug, as 

applicable, must be considered in 

determining the first possible date of 

approval of a 505(b)(2) application or 

ANDA. The criteria in paragraphs (b)(1) 

and (b)(2) of this section will be used to 

determine, for each relevant patent, the 

date that patent will no longer prevent 

approval. The first possible date of 

approval will be calculated for each 

patent, and the 505(b)(2) application or 

ANDA may be approved on the last 

applicable date. 

(1) Timing of approval based on 

patent certification or statement. If none 

of the reasons in § 314.125 or § 314.127 

for refusing to approve the application 

applies, and none of the reasons in 

paragraph (d) of this section for delaying 

approval applies, the 505(b)(2) 

application or ANDA may be approved 

as follows: 

(i) Immediately, if the applicant 

certifies under § 314.50(i) or 

§ 314.94(a)(12) that: 

(A) The applicant is aware of a 

relevant patent but the patent 

information required under section 

505(b) or (c) of the Federal Food, Drug, 

and Cosmetic Act has not been 

submitted to FDA; or 

(B) The relevant patent has expired; or 

(C) The relevant patent is invalid, 

unenforceable, or will not be infringed, 

except as provided in paragraphs (b)(3) 

and (c) of this section, and the 45-day 

period provided for in section 

505(c)(3)(C) and (j)(5)(B)(iii) of the 

Federal Food, Drug, and Cosmetic Act 

has expired; or 

(D) There are no relevant patents. 

(ii) Immediately, if the applicant 

submits an appropriate statement under 

§ 314.50(i) or § 314.94(a)(12) explaining 

that a method-of-use patent does not 

claim an indication or other condition 

of use for which the applicant is seeking 

approval. 

(iii) On the date specified, if the 

applicant certifies under § 314.50(i) or 

§ 314.94(a)(12) that the relevant patent 

will expire on a specified date. 

(2) Patent information filed after 

submission of 505(b)(2) application or 

ANDA. If the holder of the approved 

NDA for the listed drug submits patent 

information required under § 314.53 

after the date on which the 505(b)(2) 

application or ANDA was submitted to 

FDA, the 505(b)(2) applicant or ANDA 

applicant must comply with the 

requirements of § 314.50(i)(4) and (i)(6) 

and § 314.94(a)(12)(vi) and (a)(12)(viii) 

regarding amendment of its patent 

certification or statement. If the 

applicant submits an amendment 

certifying under § 314.50(i)(1)(i)(A)(4) or 

§ 314.94(a)(12)(i)(A)(4) that the relevant 

patent is invalid, unenforceable, or will 

not be infringed, and complies with the 

requirements of § 314.52 or § 314.95, the 

505(b)(2) application or ANDA may be 

approved immediately upon submission 

of documentation of receipt of notice of 

paragraph IV certification under 

§ 314.52(e) or § 314.95(e). The 45-day 

period provided for in section 

505(c)(3)(C) and (j)(5)(B)(iii) of the 

Federal Food, Drug, and Cosmetic Act 

does not apply in these circumstances. 

(3) Disposition of patent litigation—(i) 

Approval upon expiration of 30-month 

period or 71⁄2 years from date of 

reference product approval. (A) Except 

as provided in paragraphs (b)(3)(ii) 

through (b)(3)(viii) of this section, if, 

with respect to patents for which 

required information was submitted 

under § 314.53 before the date on which 

the 505(b)(2) application or ANDA was 

submitted to FDA (excluding an 

amendment or supplement to the 

505(b)(2) application or ANDA), the 

applicant certifies under § 314.50(i) or 

§ 314.94(a)(12) that the relevant patent 

is invalid, unenforceable, or will not be 

infringed, and the patent owner or its 

representative or the exclusive patent 

licensee brings suit for patent 

infringement within 45 days of receipt 

of the notice of certification from the 

applicant under § 314.52 or § 314.95, the 

505(b)(2) application or ANDA may be 

approved 30 months after the later of 

the date of the receipt of the notice of 

certification by any owner of the listed 

patent or by the NDA holder who is an 

exclusive patent licensee (or their 

representatives) unless the court has 

extended or reduced the period because 

of a failure of either the plaintiff or 

defendant to cooperate reasonably in 

expediting the action; or 

(B) If the patented drug product 

qualifies for 5 years of exclusive 

marketing under § 314.108(b)(2) and the 

patent owner or its representative or the 

exclusive patent licensee brings suit for 

patent infringement during the 1-year 

period beginning 4 years after the date 

the patented drug was approved and 

within 45 days of receipt of the notice 

of certification from the applicant under 

§ 314.52 or § 314.95, the 505(b)(2) 

application or ANDA may be approved 

at the expiration of 71⁄2 years from the 

date of approval of the NDA for the 

patented drug product. 


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(ii) Federal district court decision of 

invalidity, unenforceability, or noninfringement. If before the expiration of 

the 30-month period, or 71⁄2 years where 

applicable, the district court decides 

that the patent is invalid, unenforceable, 

or not infringed (including any 

substantive determination that there is 

no cause of action for patent 

infringement or invalidity), the 505(b)(2) 

application or ANDA may be approved 

on: 

(A) The date on which the court 

enters judgment reflecting the decision; 

or 

(B) The date of a settlement order or 

consent decree signed and entered by 

the court stating that the patent that is 

the subject of the certification is invalid 

or not infringed. 

(iii) Appeal of Federal district court 

judgment of infringement. If before the 

expiration of the 30-month period, or 

71⁄2 years where applicable, the district 

court decides that the patent has been 

infringed, and if the judgment of the 

district court is appealed, the 505(b)(2) 

application or ANDA may be approved 

on: 

(A) The date on which the mandate is 

issued by the court of appeals entering 

judgment that the patent is invalid or 

not infringed (including any substantive 

determination that there is no cause of 

action for patent infringement or 

invalidity); or 

(B) The date of a settlement order or 

consent decree signed and entered by 

the court of appeals stating that the 

patent that is the subject of the 

certification is invalid or not infringed. 

(iv) Affirmation or non-appeal of 

Federal district court judgment of 

infringement. If before the expiration of 

the 30-month period, or 71⁄2 years where 

applicable, the district court decides 

that the patent has been infringed, and 

if the judgment of the district court is 

not appealed or is affirmed, the 

505(b)(2) application or ANDA may be 

approved no earlier than the date 

specified by the district court in an 

order under 35 U.S.C. 271(e)(4)(A). 

(v) Grant of preliminary injunction by 

Federal district court. If before the 

expiration of the 30-month period, or 

71⁄2 years where applicable, the district 

court grants a preliminary injunction 

prohibiting the applicant from engaging 

in the commercial manufacture or sale 

of the drug product until the court 

decides the issues of patent validity and 

infringement, and if the court later 

decides that the patent is invalid, 

unenforceable, or not infringed, the 

505(b)(2) application or ANDA may be 

approved as provided in paragraph 

(b)(3)(ii) of this section. If the court 

decides that the patent has been 

infringed, the 505(b)(2) application or 

ANDA may be approved as provided in 

paragraph (b)(3)(iii) or (b)(3)(iv) of this 

section, whichever is applicable. 

(vi) Written consent to approval by 

patent owner or exclusive patent 

licensee. If before the expiration of the 

30-month period, or 71⁄2 years where 

applicable, the patent owner or the 

exclusive patent licensee (or their 

representatives) agrees in writing that 

the 505(b)(2) application or ANDA may 

be approved any time on or after the 

date of the consent, approval may be 

granted on or after that date. 

(vii) Court order terminating 30- 

month or 71⁄2 year period. If before the 

expiration of the 30-month period, or 

71⁄2 years where applicable, the court 

enters an order requiring the 30-month 

or 71⁄2-year period to be terminated, the 

505(b)(2) application or ANDA may be 

approved in accordance with the court’s 

order. 

(viii) Court order of dismissal without 

a finding of infringement. If before the 

expiration of the 30-month period, or 

71⁄2 years where applicable, the court 

enters an order of dismissal, with or 

without prejudice, without a finding of 

infringement, the 505(b)(2) application 

or ANDA may be approved on or after 

the date of the order. 

(4) Tentative approval. FDA will issue 

a tentative approval letter when 

tentative approval is appropriate in 

accordance with paragraphs (b)(3) or 

(e)(1)(vi) of this section. In order for a 

505(b)(2) application or ANDA to be 

approved under paragraph (b)(3) of this 

section, the applicant must receive an 

approval letter from the Agency. 

Tentative approval of an application 

does not constitute ‘‘approval’’ of an 

application and cannot, absent an 

approval letter from the Agency, result 

in an approval under paragraph (b)(3) of 

this section. 

(c) Subsequent ANDA submission. (1) 

If an ANDA contains a paragraph IV 

certification for a relevant patent and 

the ANDA is not that of a first applicant, 

the ANDA is regarded as the ANDA of 

a subsequent applicant. The ANDA of a 

subsequent applicant will not be 

approved during the period when any 

first applicant is eligible for 180-day 

exclusivity or during the 180-day 

exclusivity period of a first applicant. 

Any applicable 180-day exclusivity 

period cannot extend beyond the 

expiration of the patent upon which the 

180-day exclusivity period was based. 

(2) For purposes of paragraph (c)(1) of 

this section, a first applicant must 

submit correspondence to its ANDA 

notifying FDA within 30 days of the 

date of first commercial marketing of its 

drug product. If an applicant does not 

notify FDA, as required in this 

paragraph, of this date, the date of first 

commercial marketing will be deemed 

to be the date of the drug product’s 

approval. 

(d) Delay due to exclusivity. The 

Agency will also delay the approval of 

a 505(b)(2) application or an ANDA if 

delay is required by the exclusivity 

provisions in § 314.108, § 316.31, or 

section 505A of the Federal Food, Drug, 

and Cosmetic Act. When the approval of 

a 505(b)(2) application or ANDA is 

delayed under this section and 

§ 314.108, § 316.31, or section 505A of 

the Federal Food, Drug, and Cosmetic 

Act, the 505(b)(2) application or ANDA 

will be approved on the latest of the 

days specified under this section and 

§ 314.108, § 316.31, or section 505A of 

the Federal Food, Drug, and Cosmetic 

Act, as applicable. 

(e) Notification of court actions or 

documented agreement. (1) The 

applicant must submit the following 

information to FDA, as applicable: 

(i) A copy of any judgment by the 

court (district court or mandate of the 

court of appeals) or settlement order or 

consent decree signed and entered by 

the court (district court or court of 

appeals) finding a patent described in 

paragraph (b)(3) of this section invalid, 

unenforceable, or not infringed, or 

finding the patent valid and infringed; 

(ii) Written notification of whether or 

not any action by the court described in 

paragraph (e)(1)(i) of this section has 

been appealed within the time 

permitted for an appeal; 

(iii) A copy of any order entered by 

the court terminating the 30-month or 

71⁄2-year period described in paragraphs 

(b)(3)(i) and (b)(3)(ii) of this section; 

(iv) A copy of any documented 

agreement described in paragraph 

(b)(3)(vi) of this section; 

(v) A copy of any preliminary 

injunction described in paragraph 

(b)(3)(v) of this section, and a copy of 

any subsequent court order lifting the 

injunction; and 

(vi) A copy of any court order 

pursuant to 35 U.S.C. 271(e)(4)(A) 

ordering that a 505(b)(2) application or 

ANDA may be approved no earlier than 

the date specified (irrespective of 

whether the injunction relates to a 

patent described in paragraph (b)(3) of 

this section). 

(2) All information required by 

paragraph (e)(1) of this section must be 

sent to the Office of Generic Drugs 

(HFD–600) or to the appropriate 

division in the Office of New Drugs 

within 14 days of the date of entry by 

the court, the date of appeal or 

expiration of the time for appeal, or the 


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date of documented agreement, as 

applicable. 

(f) Forty-five day period after receipt 

of notice of paragraph IV certification— 

(1) Computation of 45-day time clock. 

The 45-day clock described in 

paragraph (b)(3) of this section as to 

each recipient required to receive notice 

of paragraph IV certification under 

§ 314.52 or § 314.95 begins on the day 

after the date of receipt of the 

applicant’s notice of paragraph IV 

certification by the recipient. When the 

45th day falls on Saturday, Sunday, or 

a Federal holiday, the 45th day will be 

the next day that is not a Saturday, 

Sunday, or a Federal holiday. 

(2) Notification of filing of legal 

action. (i) The 505(b)(2) or ANDA 

applicant must notify FDA in writing 

within 14 days of the filing of any legal 

action filed within 45 days of receipt of 

the notice of paragraph IV certification 

by any recipient. A 505(b)(2) applicant 

must send the notification to the 

appropriate division in the Office of 

New Drugs reviewing the 505(b)(2) 

application. An ANDA applicant must 

send the notification to FDA’s Office of 

Generic Drugs (HFD–600). The 

notification to FDA of the legal action 

must include: 

(A) The 505(b)(2) application or 

ANDA number. 

(B) The name of the 505(b)(2) or 

ANDA applicant. 

(C) The established name of the drug 

product or, if no established name 

exists, the name(s) of the active 

ingredient(s), the drug product’s 

strength, and dosage form. 

(D) A statement that an action for 

patent infringement, identified by the 

court, case number, and the patent 

number(s) of the patent(s) at issue in the 

action, has been filed in an appropriate 

court on a specified date. 

(ii) A patent owner or NDA holder (or 

their representatives) may also notify 

FDA of the filing of any legal action for 

patent infringement. The notice should 

contain the information and be sent to 

the offices or divisions described in 

paragraph (f)(2)(i) of this section. 

(iii) If the 505(b)(2) or ANDA 

applicant, the patent owner(s), the NDA 

holder, or their representatives do not 

notify FDA in writing before the 

expiration of the 45-day time period or 

the completion of the Agency’s review 

of the 505(b)(2) application or ANDA, 

whichever occurs later, that a legal 

action for patent infringement was filed 

within 45 days of receipt of the notice 

of paragraph IV certification, the 

505(b)(2) application or ANDA may be 

approved upon expiration of the 45-day 

period (if the 505(b)(2) or ANDA 

applicant confirms that a legal action for 

patent infringement has not been filed) 

or upon completion of the Agency’s 

review of the 505(b)(2) application or 

ANDA, whichever is later. 

(3) Waiver. If the patent owner or 

NDA holder who is an exclusive patent 

licensee (or their representatives) 

waives its opportunity to file a legal 

action for patent infringement within 45 

days of a receipt of the notice of 

certification and the patent owner or 

NDA holder who is an exclusive patent 

licensee (or their representatives) 

submits to FDA a valid waiver before 

the 45 days elapse, the 505(b)(2) 

application or ANDA may be approved 

upon completion of the Agency’s review 

of the application. FDA will only accept 

a waiver in the following form: 

(Name of patent owner or NDA holder who 

is an exclusive patent licensee or their 

representatives) has received notice from 

(name of applicant) under (section 505(b)(3) 

or 505(j)(2)(B) of the Federal Food, Drug, and 

Cosmetic Act) and does not intend to file an 

action for patent infringement against (name 

of applicant) concerning the drug (name of 

drug) before (date on which 45 days elapses). 

(Name of patent owner or NDA holder who 

is an exclusive patent licensee) waives the 

opportunity provided by (section 505(c)(3)(C) 

or 505(j)(5)(B)(iii) of the Federal Food, Drug, 

and Cosmetic Act) and does not object to 

FDA’s approval of (name of applicant)’s 

(505(b)(2) application or ANDA) for (name of 

drug) with an approval date on or after the 

date of this submission. 

(g) Conversion of approval to tentative 

approval. If FDA issues an approval 

letter in error or a court enters an order 

requiring, in the case of an already 

approved 505(b)(2) application or 

ANDA, that the date of approval be 

delayed, FDA will convert the approval 

to a tentative approval if appropriate. 

■ 19. Section 314.108 is amended by: 

■ a. Revising paragraph (a) introductory 

text and the definitions of ‘‘Approved 

under section 505(b)’’, ‘‘Essential to 

approval’’, and ‘‘New chemical entity’’; 

■ b. Removing from paragraph (a) the 

definitions of ‘‘Active moiety’’, ‘‘Date of 

approval’’, and ‘‘FDA’’; 

■ c. Adding alphabetically to paragraph 

(a) the definition of ‘‘Bioavailability 

study’’; and 

■ d. Revising paragraph (b). 

The revisions read as follows: 

§ 314.108 New drug product exclusivity. 

(a) Definitions. The definitions at 

§ 314.3 and the following definitions of 

terms apply to this section: 

Approved under section 505(b) means 

an NDA submitted under section 505(b) 

and approved on or after October 10, 

1962, or an application that was 

‘‘deemed approved’’ under section 

107(c)(2) of Public Law 87–781. 

Bioavailability study means a study to 

determine the bioavailability or the 

pharmacokinetics of a drug. 

* * * * * 

Essential to approval means, with 

regard to an investigation, that there are 

no other data available that could 

support approval of the NDA. 

New chemical entity means a drug 

that contains no active moiety that has 

been approved by FDA in any other 

NDA submitted under section 505(b) of 

the Federal Food, Drug, and Cosmetic 

Act. 

* * * * * 

(b) Submission of and date of 

approval of a 505(b)(2) application or 

ANDA. 

(1) [Reserved] 

(2) If a drug product that contains a 

new chemical entity was approved after 

September 24, 1984, in an NDA 

submitted under section 505(b) of the 

Federal Food, Drug, and Cosmetic Act, 

no person may submit a 505(b)(2) 

application or ANDA under section 

505(j) of the Federal Food, Drug, and 

Cosmetic Act for a drug product that 

contains the same active moiety as in 

the new chemical entity for a period of 

5 years from the date of approval of the 

first approved NDA, except that the 

505(b)(2) application or ANDA may be 

submitted after 4 years if it contains a 

certification of patent invalidity or 

noninfringement described in 

§ 314.50(i)(1)(i)(A)(4) or 

§ 314.94(a)(12)(i)(A)(4). 

(3) The approval of a 505(b)(2) 

application or ANDA described in 

paragraph (b)(2) of this section will 

occur as provided in § 314.107(b)(1) or 

(b)(2), unless the owner of a patent that 

claims the drug, the patent owner’s 

representative, or exclusive licensee 

brings suit for patent infringement 

against the applicant during the 1-year 

period beginning 48 months after the 

date of approval of the NDA for the new 

chemical entity and within 45 days after 

receipt of the notice described at 

§ 314.52 or § 314.95, in which case, 

approval of the 505(b)(2) application or 

ANDA will occur as provided in 

§ 314.107(b)(3). 

(4) If an NDA: 

(i) Was submitted under section 

505(b) of the Federal Food, Drug, and 

Cosmetic Act; 

(ii) Was approved after September 24, 

1984; 

(iii) Was for a drug product that 

contains an active moiety that has been 

previously approved in another NDA 

under section 505(b) of the Federal 

Food, Drug, and Cosmetic Act; and 

(iv) Contained reports of new clinical 

investigations (other than bioavailability 


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studies) conducted or sponsored by the 

applicant that were essential to approval 

of the application, for a period of 3 years 

after the date of approval of the 

application, the Agency will not 

approve a 505(b)(2) application or an 

ANDA for the conditions of approval of 

the original NDA, or an ANDA 

submitted pursuant to an approved 

petition under section 505(j)(2)(C) of the 

Federal Food, Drug, and Cosmetic Act 

that relies on the information 

supporting the conditions of approval of 

an original NDA. 

(5) If a supplemental NDA: 

(i) Was approved after September 24, 

1984; and 

(ii) Contained reports of new clinical 

investigations (other than bioavailability 

studies) that were conducted or 

sponsored by the applicant that were 

essential to approval of the 

supplemental NDA, for a period of 3 

years after the date of approval of the 

supplemental application, the Agency 

will not approve a 505(b)(2) application 

or an ANDA for a change, or an ANDA 

submitted pursuant to an approved 

petition under section 505(j)(2)(C) of the 

Federal Food, Drug, and Cosmetic Act 

that relies on the information 

supporting a change approved in the 

supplemental NDA. 

■ 20. Section 314.125 is amended by: 

■ a. Removing the word ‘‘application’’ 

wherever it appears in the section 

heading, paragraph (a) introductory text, 

and paragraphs (a)(2), (b)(7), (b)(9), 

(b)(10), (b)(12), and (b)(14) through 

(b)(18) and adding in its place ‘‘NDA’’; 

■ b. Revising paragraph (b) introductory 

text; and 

■ c. Adding paragraph (b)(19). 

The revisions read as follows: 

§ 314.125 Refusal to approve an NDA. 

* * * * * 

(b) FDA may refuse to approve an 

NDA for any of the following reasons, 

unless the requirement has been waived 

under § 314.90: 

* * * * * 

(19) The 505(b)(2) application failed 

to contain a patent certification or 

statement with respect to each listed 

patent for an approved drug product 

that: 

(i) Is pharmaceutically equivalent to 

the drug product for which the 505(b)(2) 

application is submitted; and 

(ii) Was approved before the 505(b)(2) 

application was submitted. 

* * * * * 

■ 21. Section 314.127 is amended by: 

■ a. Removing the words ‘‘abbreviated 

application’’ and ‘‘abbreviated new drug 

application’’ wherever they appear in 

paragraphs (a) and (b) and adding in 

their place ‘‘ANDA’’; 

■ b. Revising the section heading and 

paragraph (a) introductory text; and 

■ c. Adding paragraph (a)(14). 

The revisions read as follows: 

§ 314.127 Refusal to approve an ANDA. 

(a) FDA will refuse to approve an 

ANDA for a new drug under section 

505(j) of the Federal Food, Drug, and 

Cosmetic Act for any of the following 

reasons, unless the requirement has 

been waived under § 314.99: 

* * * * * 

(14) For an ANDA submitted pursuant 

to an approved suitability petition, an 

NDA subsequently has been approved 

for the change described in the 

suitability petition. 

* * * * * 

PART 320—BIOAVAILABILITY AND 

BIOEQUIVALENCE REQUIREMENTS 

■ 22. The authority citation for part 320 

continues to read as follows: 

Authority: 21 U.S.C. 321, 351, 352, 355, 

371. 

■ 23. Section 320.1 is revised to read as 

follows: 

§ 320.1 Definitions. 

The definitions contained in § 314.3 

of this chapter apply to those terms 

when used in this part. 

■ 24. Section 320.23 is amended by: 

■ a. Revising the last sentence in 

paragraph (a)(1); 

■ b. Removing the word ‘‘shall’’ in 

paragraph (a)(2) and adding in its place 

the word ‘‘must’’; 

■ c. Redesignating paragraph (b) as 

paragraph (b)(1); and 

■ d. Adding new paragraph (b)(2). 

The revisions read as follows: 

§ 320.23 Basis for measuring in vivo 

bioavailability or demonstrating 

bioequivalence. 

(a)(1) * * * For drug products that 

are not intended to be absorbed into the 

bloodstream, bioavailability may be 

assessed by scientifically valid 

measurements intended to reflect the 

rate and extent to which the active 

ingredient or active moiety becomes 

available at the site of action. 

* * * * * 

(b) * * * 

(2) For drug products that are not 

intended to be absorbed into the 

bloodstream, bioequivalence may be 

demonstrated by scientifically valid 

methods that are expected to detect a 

significant difference between the drug 

and the listed drug in safety and 

therapeutic effect. 

Dated: January 23, 2015. 

Leslie Kux, 

Associate Commissioner for Policy. 

[FR Doc. 2015–01666 Filed 2–5–15; 8:45 am] 

BILLING CODE 4164–01–P 


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