Abbreviated New Drug Application Regulations; Patent and Exclusivity Provisions; Final Rule DEPARTMENT OF HEALTH AND HUMAN SERVICES

SUMMARY: The Food and Drug Administration (FDA) is issuing regulations

on certain requirements governing the submission, review, and approval

of abbreviated new drug applications (ANDA's). Specifically, these new

regulations pertain to patent issues, certification and notice of

certification of invalidity or noninfringement of a patent by ANDA

applicants, effective date of approval of an application under the

Federal Food, Drug, and Cosmetic Act (the act), and new drug product

exclusivity. These regulations are intended to complete FDA's

implementation of Title I of the Drug Price Competition and Patent Term

Restoration Act of 1984.

EFFECTIVE DATE: November 2, 1994.

FOR FURTHER INFORMATION CONTACT: Sharon M. Sheehan, Center for Drug

Evaluation and Research (HFD-600), Food and Drug Administration, 7500

Standish Pl., Rockville, MD 20855, 301-594-0340.

SUPPLEMENTARY INFORMATION:

I. Background

On September 24, 1984, the Drug Price Competition and Patent Term

Restoration Act of 1984 (Pub. L. 98-417) (the 1984 amendments) was

enacted. The law consisted of two different titles. Title I authorized

the approval of duplicate versions of approved drug products (other

than those reviewed and approved under section 507 of the act (21

U.S.C. 357)) under an ANDA procedure. Title II authorized the extension

of patent terms for approved new drug products (including antibiotics

and biological drug products), some medical devices, food additives,

and color additives. Congress intended these provisions to provide a

careful balance between promoting competition among brand-name and

duplicate or ``generic'' drugs and encouraging research and innovation.

Title I also amended section 505 of the act (21 U.S.C. 355) by

requiring all New Drug Application (NDA) applicants and holders to

provide certain patent information, requiring ANDA applicants to

certify as to the status of patents claiming the drug product they

intend to copy, providing for the submission and approval of

applications for which the investigations relied on by the applicant to

satisfy the ``full reports'' of safety and effectiveness requirements

were not conducted by the applicant or for which the applicant had not

obtained a right of reference or use from the person who conducted the

investigations, establishing rules for disclosure of safety and

effectiveness data submitted as part of an NDA, and providing specific

time periods during which an NDA or an ANDA cannot be submitted or

approved. The 1984 amendments also required FDA to promulgate new

regulations implementing the statute. In the Federal Register of July

10, 1989 (54 FR 28872), FDA published a proposed rule on Title I. In

the Federal Register of April 28, 1992 (57 FR 17950), FDA published a

final rule on some aspects of Title I, such as ANDA content and format,

approval and nonapproval of an application, and suitability petitions.

In that final rule, FDA stated that it was still examining issues

concerning patents and market exclusivity, and would issue a final rule

once it had completed its deliberations. This document now finalizes

those provisions.

In the Federal Register of March 7, 1988 (53 FR 7298), FDA

published a final rule implementing Title II. That rule is codified at

21 CFR part 60.

II. Highlights of the Final Rule

A. Patent Information, Certification, and Notice of Certification to

Patent Owner and Certain Application Holders

The statute prohibits the agency from making effective the approval

of an ANDA or an application described by section 505(b)(2) of the act

(referred to as a 505(b)(2) application) before all relevant product

and use patents for the listed drug (a drug product listed in an

approved drug product list published by the agency) have expired,

except where the generic applicant asserts either that its product will

not infringe the patent or that the patent is invalid. In the latter

case, approval of the ANDA or the 505(b)(2) application may not be made

effective until the patent owner and the NDA holder have been notified

and have had an opportunity to litigate the issue of patent

infringement or validity. To facilitate the patent protection

provisions, the statute requires that applications submitted under

section 505(b) of the act include the patent number and expiration date

of all relevant patents that claim the drug (including product and

formulation patents) in the application or use patents that claim a

method of using the drug. The agency publishes this patent information

in its approved drug product list (``Approved Drug Products With

Therapeutic Equivalence Evaluations,'' also known as the ``Orange

Book'') for each listed drug for which patent information has been

submitted.

A generic drug applicant submitting an ANDA that refers to a listed

drug must include a certification as to the status of all patents

applicable to the listed drug. Similarly, an applicant submitting a

505(b)(2) application must make certifications with respect to patents

claiming any listed drug or claiming a use for such listed drug. If a

generic applicant certifies that a relevant patent expires on a

specified date, the effective date of approval of the ANDA or 505(b)(2)

application will be delayed until the expiration of the patent. Thus,

for example, if the patent expired on January 1, 1995, the effective

date of approval of the ANDA or 505(b)(2) application would be January

1, 1995. The agency regards drug products with delayed effective dates

as having tentative approvals; it does not consider the approval to be

final until the effective date and the issuance of a final approval

letter (see 57 FR 17950 at 17956). When a generic applicant certifies

that any product or use patent is invalid or will not be infringed, the

applicant must give notice of such certification to the patent owner

and appropriate approved application holder for the listed drug. The

generic applicant must include in the notice the factual and legal

basis for the applicant's opinion that the patent is invalid or will

not be infringed. Finally, a patent owner has 45 days from receipt of

the notice of certification to file suit against the generic applicant

to defend the patent. If the patent owner files suit within 45 days,

the effective date of approval of the ANDA or 505(b)(2) application may

be delayed up to 30 months pending resolution of the lawsuit.

The final rule describes: (1) The requirements for the submission

of patent information by an NDA holder or applicant, (2) the patent

certification requirements applicable to generic applicants, and (3)

the content of a patent certification notice. The final rule also

specifies: (1) When and to whom the notice is to be sent, and (2) the

effect of each type of patent certification on the effective date of

approval of an application for a generic drug product.

B. Exclusivity

Section 505(c)(3)(D) and (j)(4)(D) of the act protects certain

listed drugs, or certain changes in listed drugs, from generic copying

for specified periods by placing a moratorium on the submission, or by

delaying the effective date of approval, of ANDA's and 505(b)(2)

applications for those listed drugs. These so-called ``exclusivity

provisions'' provide the following periods of protection from generic

competition: (1) A 10-year period of exclusivity for new chemical

entities approved during the period January 1, 1982, to September 24,

1984, the date of enactment of the 1984 amendments; (2) a 5-year period

of exclusivity for new chemical entities approved after September 24,

1984; (3) a 3-year period of exclusivity for drugs that are not new

chemical entities approved after September 24, 1984, if the applicant

submitted an application containing reports of ``new clinical

investigations (other than bioavailability studies) essential to

approval and conducted or sponsored by the applicant''; (4) a 3-year

period of exclusivity for certain changes made after September 24,

1984, if the applicant submitted a supplement containing reports of

``new clinical investigations (other than bioavailability studies)

essential to approval and conducted or sponsored by the person

submitting the application''; and (5) a 2-year period of exclusivity

for drugs that are not new chemical entities, or for certain changes

made to already approved drug products, approved during the period

January 1, 1982, to September 24, 1984.

The agency is codifying the provisions regarding 5- and 3-year

exclusivity; FDA is not codifying the other exclusivity provision

because they have expired. The final rule also defines certain terms

used in the regulations, and clarifies the agency's interpretation of

each of the provisions.

III. Comments on the Proposed Rule

A. Section 314.50--Content and Format of an Application (21 CFR 314.50)

The proposed rule contained several additions to the existing

requirements in Sec. 314.50. The proposed additions focused on patent

information and certifications and claimed exclusivity. Under proposed

Sec. 314.50(i), for example, a 505(b)(2) applicant would be required to

include in its application one of four possible certifications: (1)

That patent information on the reference listed drug had not been

submitted to FDA; (2) that the patent had expired; (3) the date on

which the patent will expire; or (4) that the patent was invalid or

would not be infringed by the manufacture, use, or sale of the proposed

drug product.

1. Two comments objected to the provision regarding use patents

(patents that claim a use for the patented invention) under proposed

Sec. 314.50(i). The comments explained that the provision would permit

applicants to decide whether a use would infringe a patent and whether

the patent owner should be notified. Both comments asked FDA to require

applicants to send a certification of invalidity or noninfringement to

all patent owners whose patents claim the active ingredient involved in

the proposed drug product. One comment would also revise the provision

to withhold approval of an application if the patent owner disagreed

with the patent certification in order to give the patent owner an

opportunity to initiate a lawsuit.

The regulation corresponds to the statutory language at section

505(b)(2)(B) of the act. The statute does not require a patent

certification with respect to a use patent if the applicant is seeking

approval for a drug product that does not claim a use protected by the

patent. FDA also declines to revise the provision to have FDA withhold

approval of an application under these circumstances. The statute

provides express and specific grounds for delaying an effective date of

approval (see section 505(c)(3) of the act). These do not include any

express authority to delay an effective date of approval based on an

inadequate notice, and the agency is not prepared to infer such

authority. NDA holders are advised, however, to notify FDA of the

patented uses that appear in the approved labeling for their products;

this will enable the agency to provide some guidance to applicants

required to submit either a patent certification under section

505(b)(2)(A) or (j)(2)(A) of the act, or a statement under section

505(b)(2)(B) or (j)(2)(A)(viii) of the act. These uses will be listed

in the Orange Book.

2. One comment noted that ``United States Office of Patent and

Trademark'' in proposed Sec. 314.50(i)(1)(i) should be ``United States

Patent and Trademark Office.''

FDA agrees and has revised the provision accordingly.

3. One comment asked FDA to give examples of patent certifications

under proposed Sec. 314.50(i)(1)(i)(A)(1) to (i)(1)(i)(A)(3). As

proposed, these provisions would require an applicant to certify that:

(1) No patent information had been submitted to FDA, (2) the patent has

expired, or (3) the patent would expire on a specific date.

Generally, most applicants making paragraph I, II, or III patent

certifications simply paraphrase the language used in

Sec. 314.50(i)(1)(i)(A)(1) to (i)(1)(i)(A)(3) for each patent.

4. The agency, on its own initiative, has amended

Sec. 314.50(i)(1)(i)(A) to replace the reference to a patent that

claims ``the drug or drugs'' with a patent that claims ``a drug (the

drug product or drug substance that is a component of the drug

product).'' The agency has made this amendment to clarify the types of

patents for which a certification should be made.

5. The agency, on its own initiative, has also amended

Sec. 314.50(i)(1)(i)(A)(4) and Sec. 314.94(a)(12)(i)(A)(4) (21 CFR

314.94(a)(12)(i)(A)(4)) to include a reference to unenforceable

patents. As proposed, these provisions would have required applicants

to certify that a patent is invalid or will not be infringed by the

manufacture, use, or sale of the drug product that is the subject of

the application. The agency has revised these certification statements

to clarify how an applicant challenging a patent as unenforceable

should word its paragraph IV certification. Although the agency

realizes that courts have, in patent cases, distinguished invalid

patents from unenforceable patents, the only court addressing the issue

of unenforceable patents in the context of the provisions of section

505 of the act interpreted the phrase ``invalid or not infringed'' to

include an unenforceable patent. (See Merck v. Danbury Pharmacal, Inc.,

694 F.Supp. 1 (D. Del. 1988), aff'd, 873 F.2d 1418 (Fed. Cir. 1989)

(applying section 505(j)(4)(B)(iii) of the act).) The agency agrees

with the court's construction of the act. The alternative

interpretation, precluding applicants challenging patents as

unenforceable from filing certifications under paragraph IV, would be

contrary to Congress' obvious intent in allowing patent challenges

under section 505 of the act and would lead to absurd results.

Subsequent to the Merck decision, the agency has accepted paragraph IV

certifications from applicants challenging patents as unenforceable.

The agency has also made corresponding changes to other provisions,

such as the notice requirements in Secs. 314.52 and 314.95, to include

certifications for ``unenforceable'' patents.

6. Two comments disagreed with proposed Sec. 314.50(i)(1)(ii),

which would require an applicant to state that, in its opinion and to

the best of its knowledge, there are no patents that claim the drug or

drugs on which investigations that the applicant relied upon in its

application were conducted or that claim a use for the drug or drugs.

One comment said applicants should only be required to certify that

there are no listed patents. The other comment suggested deleting the

provision and combining this patent certification with a paragraph I

(no patent information submitted) certification.

FDA believes the comments have misconstrued proposed

Sec. 314.50(i)(1)(ii). The provision would require a ``no relevant

patents'' certification if, ``in the opinion of the applicant and to

the best of its knowledge,'' there are no patents described in the

patent certification section (Sec. 314.50(i)(1)(i)). In other words, if

an applicant made one of the four patent certifications under

Sec. 314.50(i)(1)(i), the applicant would not make another

certification under Sec. 314.50(i)(1)(ii).

7. One comment strongly objected to proposed Sec. 314.50(i)(4). The

provision would require section 505(b)(2) applicants whose applications

were submitted after the late patent information is filed, or did not

contain an appropriate patent certification at the time of the late

submission, to submit a patent certification on such patents. The

comment explained that section 505(d)(6) and 505(e)(4) of the act

authorizes the agency, after providing an opportunity for a hearing, to

refuse to approve an application or to withdraw approval of an NDA for

failure to provide patent information. Thus, the comment argued that

proposed Sec. 314.50(i)(4) conferred a benefit on NDA applicants by

permitting late patent information submissions without applying the

statutory requirements for timely submission.

The agency has considered this and other comments which suggest

regulatory approaches for handling patents that are filed outside the

statutory time limits. Congress clearly intended to enforce timely

submission of patent information. The statute requires that patent

information be submitted with the application, by amendment prior to

approval of the application, or within 30 days after the patent issues.

(See 21 U.S.C. 355(b)(1) and (c)(2)). For the most extreme example of

untimely patent filing--when a pioneer fails to file required patent

information within 30 days of notice from the agency--Congress has

provided the extreme remedy of withdrawal of approval of the new drug

application. (See 21 U.S.C. 355(e)(4)). Congress did not directly

address the question of patent filings that occur more than 30 days

after issuance of the patent and for which the agency does not provide

notice of the deficiency. The agency could treat these filings in a

number of ways. The agency could refuse to publish in the list the

untimely patent information. This approach has been rejected because it

would provide no notice to subsequent 505(b)(2) or ANDA applicants that

a patent exists that the NDA holder believes is applicable to the

pioneer drug product. Absence of publication could lead an applicant to

submit a 505(b)(2) application or an ANDA that it would not have

submitted had the patent been listed. As a result, the applicant and

the agency may expend resources unnecessarily. In addition, 505(b)(2)

or ANDA applicants could thereby subject themselves and the NDA holder

to unnecessary patent litigation.

Prior to publication of the proposed rule, the agency was asked to

consider regulatory language designed to allow a pioneer holder to

update, at any time, its patent information. This approach has been

rejected because it would allow for manipulation of the patent filing

system by the holder of the NDA and could result in delays in approval

of otherwise approvable ANDA's. For example, if patents could be filed

at any time after issuance, the holder of the NDA could delay the

filing of a patent, and subsequent publication, until within 30 months

prior to the expiration of the latest-expiring patent. Even if the ANDA

applicant does not believe the patent is applicable to the pioneer

drug, it will then be required either to file a paragraph III

certification and wait until the patent expires, or to file a paragraph

IV certification and therefore initiate the procedure set out at

section 505(c)(3)(C) and (j)(4)(B). This procedure requires that the

agency wait at least 30 months, unless a shorter or longer period is

judicially ordered, before it makes effective approval of the

application. Even if the NDA holder is unsuccessful in defending the

late-filed patent, it will have extended its period of market monopoly

in a manner inconsistent with the intent of Congress when it struck the

balance between protecting the patent rights of innovators and

encouraging prompt and efficient entry of generics onto the market. By

requiring timely filing of patent information, the agency hopes to

permit judicial resolution of patent disputes without unduly extending

the innovator's period of patent protection.

The 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 who have previously submitted a certification, i.e. those

applicants who would be prejudiced by the late submission, to recertify

to the new patent. Only applicants who 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. (See Secs. 314.50(i)(4) and 314.94(a)(12)(vi).) While

this could result in two categories of ANDA's for a pioneer drug, those

without certifications for the late-filed patent and those with

certifications for that patent, this approach is the best means for

discouraging manipulation of the patent filing scheme and providing

optimum notice of applicable patents. Disputes over patent issues

arising from this approach will be resolved by Federal courts.

It is the agency's opinion that this remedy may also prove suitable

in certain instances when an NDA holder fails to respond to an agency

request for patent information within the statutory 30-day period. It

is a less severe sanction than withdrawing the approval of the NDA, but

nonetheless effectuates congressional intent to encourage timely filing

and protect patent rights.

8. One comment asked FDA to clarify supplemental patent

certifications under proposed Sec. 314.50(i)(6)(i). The comment noted

that the provision would have applicants submit new patent

certifications if a patent were found valid and infringed, but does not

instruct applicants what to do if a patent is found to be infringed,

but also invalid.

FDA has revised Secs. 314.50(i)(6)(i) and 314.94(a)(12)(vii)(A) to

state that an applicant does not have to provide an amended patent

certification if a court finds a patent to be invalid and infringed.

FDA recognizes that courts have the discretion to focus on patent

infringement issues and not decide patent validity. However, court

decisions have also recognized the desirability of a court ruling on

patent infringement even if the patent is held invalid. (See, e.g.,

Medtronic, Inc. v. Cardiac Pacemakers, Inc., 721 F.2d 1563 at 1583

(Fed. Cir. 1983).) (``Though an invalid claim cannot give rise to

liability for infringement, whether it is infringed is an entirely

separate question capable of determination without regard to its

validity. Because both validity and infringement involve construction

of a claim, and because the construction must be the same in

determining both, it is desirable to decide both questions at the same

time.'') Moreover, in such instances, the Supreme Court has indicated

that ``of the two questions, validity has the greater public

importance.'' (See Sinclair & Carroll Co. v. Interchemical Corp., 325

U.S. 327, 330 (1945).) Consequently, if a court finds a patent to be

invalid and infringed, FDA will attach more importance to the finding

of invalidity, and will not require an amended patent certification

even if the patent is also found to be infringed.

9. The agency, on its own initiative, has also revised

Sec. 314.50(i)(6)(ii) regarding patent certifications when a patent is

removed from the list of patents for any reason other than a

declaration of invalidity. Section 314.50(i)(6)(ii), as proposed, would

have required an applicant to certify that there are no patents that

claim the drug or, if other relevant patents claim the drug, to submit

a request to withdraw the paragraph IV (patent is invalid,

unenforceable, or will not be infringed) certification. FDA has revised

this section so that an applicant must certify that there are no

patents that claim the drug or, if other relevant patents claim the

drug, to provide an appropriate patent certification.

10. On its own initiative, the agency has also revised

Sec. 314.50(i)(6)(iii)(b) (now renumbered as

Sec. 314.50(i)(6)(iii)(B)). As proposed, this provision would not

require an applicant to amend a patent certification ``when information

on an otherwise applicable patent is submitted after the 505(b)(2)

application is approved, whether or not the approval of the abbreviated

application is effective.'' Because an approval with a delayed

effective date is tentative and is not final (see 57 FR 17950 at

17956), the agency has revised Sec. 314.50(i)(6)(iii)(B) to require

section 505(b)(2) applicants to amend their patent certifications until

the effective date of approval.

11. FDA received five comments on proposed Sec. 314.50(j) and the

applicant's obligations when claiming marketing exclusivity for a

product. One comment would change proposed Sec. 314.50(j) to have an

applicant submit exclusivity information ``with'' its application

rather than ``to'' its application.

FDA agrees, in part, with the comment. In general, applicants

should submit exclusivity information with their NDA's. If the NDA has

been submitted, but has not been approved, the applicant should submit

exclusivity information as an amendment.

12. One comment would revise proposed Sec. 314.50(j)(3) to have an

applicant state that, ``to the best of its knowledge or belief, a drug

has not been approved.'' The comment said proposed Sec. 314.50(j)(3)

would require applicants to ``prove a negative'' because they would

have to show that ``no drug has previously been approved under section

505(b) of the act containing any active moiety in the drug for which

the applicant is seeking approval.''

FDA agrees and has amended the rule accordingly.

13. Proposed Sec. 314.50(j)(4)(i) contained a typographical error.

As originally drafted, the provision interpreted ``new clinical

investigations'' as a certification that, to the best of the

applicant's knowledge, the clinical investigations included in the

application ``meet the definitions of `new' and `clinical

investigations' set forth in Sec. 314.108(a).'' Proposed section

314.108(a), however, only defined ``new clinical investigation.'' The

agency has corrected Sec. 314.50(j)(4)(i) to refer to ``new clinical

investigation.'' The agency has also replaced the reference to ``the

clinical investigations'' with ``each of the clinical investigations.''

This change is intended to clarify that each clinical investigation, as

opposed to some clinical investigations, must meet the definition of a

``new clinical investigation'' in Sec. 314.108. The agency has also

made a minor grammatical change to Sec. 314.50(j)(4) to simplify its

sentence structure.

14. Proposed Sec. 314.50(j)(4)(ii) interpreted the phrase

``essential to approval'' as:

A list of all published studies or publicly available reports of

clinical investigations known to the applicant through a literature

search that are relevant to the conditions for which the applicant

is seeking approval, a certification that the applicant has

thoroughly searched the scientific literature and, to the best of

the applicant's knowledge, the list is complete and accurate and, in

the applicant's opinion, such published studies or publicly

available reports do not provide a sufficient basis for the approval

of the conditions for which the applicant is seeking approval

without reference to the new clinical investigation(s) in the

application, and an explanation as to why the studies or reports are

insufficient.

Three comments would revise proposed Sec. 314.50(j)(4)(ii) to have FDA

declare whether a study is ``essential to approval'' before the

applicant begins the study or at the applicant's request. Another

comment would consider the agency's rejection of a suitability petition

or ANDA as conclusive evidence that studies are ``essential to

approval.''

As stated elsewhere in this final rule, determining whether a study

is essential for approval before a firm submits an application or even

begins the study is not always feasible. Research goals and objectives

often change during clinical investigations. Moreover, as stated in the

preamble to the proposed rule, one cannot determine what studies will

be essential to approval of an application by a review of protocols

without knowing what drugs have been approved and what is in the

published literature at the time the application is approved. If

published reports of investigations, other than those conducted or

sponsored by the applicant, are sufficient to approve a drug product,

no additional studies would be essential to approval of that drug

product as of the date of approval, and no exclusivity would be granted

(see 54 FR 28872 at 28900 and 28901). Thus, it is far more practical

for FDA to decide whether a study is essential for approval at the time

the application is approved. FDA also believes that, if a pivotal study

that could form the basis for approval were published by someone other

than the applicant after submission but before approval of the

application, there would be no exclusivity.

The agency also declines to treat its rejection of a suitability

petition or ANDA as conclusive evidence that studies are ``essential to

approval.'' FDA may refuse to approve a suitability petition or ANDA

for a variety of reasons. For example, under 21 CFR 314.93(e)(1)(ii),

the agency may not approve a suitability petition that seeks to change

an active ingredient if the drug product that is the subject of the

petition is not a combination drug. Under 21 CFR 314.127(a), the agency

may refuse to approve an ANDA if the methods used in, or the facilities

and controls used for, the manufacture, processing, and packing of the

drug product are inadequate to ensure and preserve its identity,

strength, quality, and purity. Thus, the agency's refusal to approve a

suitability petition or ANDA does not necessarily mean that studies

conducted or sponsored by the applicant are ``essential to approval.''

15. One comment also interpreted the terms ``scientific

literature'' in proposed Sec. 314.50(j)(4)(ii) as literature existing

at the time the application was submitted.

FDA agrees that Sec. 314.50(j)(4)(ii) only requires applicants to

provide a list of all published studies or publicly available reports

of clinical investigations known to the applicant at the time the

applicant submits the application.

B. Section 314.52--Notice of Certification of Invalidity or

Noninfringement of a Patent

Proposed Sec. 314.52 described the process whereby an applicant

would provide notice of certification of invalidity or noninfringement

of a patent. Proposed Sec. 314.52(a) would have required applicants to

provide notice to each patent owner that is the subject of the

certification and the holder of the approved application. Proposed

Sec. 314.52(b) instructed applicants to provide notice after receipt of

a letter from FDA stating that the application has been filed. Proposed

Sec. 314.52(c)(6) specified the content of a notice, including a

``detailed statement of the factual and legal basis of the applicant's

opinion that the patent is not valid or will not be infringed.''

Proposed Sec. 314.52(d) would have required an applicant who amended

its application to contain a patent certification to provide notice of

certification of invalidity or noninfringement of a patent. Proposed

Sec. 314.52(e) would have required applicants to document receipt of

notice.

16. FDA received two comments on proposed Sec. 314.52(a). One

comment agreed with the provision, but stated that notice to the holder

of the approved application should be considered only as informational

``with no legal ramifications since the NDA holder has no patent rights

by reason of its NDA.'' (Emphasis added in original.)

The legal ramifications under patent law, if any, of this notice of

certification of invalidity or noninfringement of a patent are beyond

the scope of this rulemaking.

17. One comment objected to proposed Sec. 314.52(a)(3). The comment

explained that the provision would permit an applicant whose

application did not cover any use claimed in a patent to refrain from

making any patent certifications or providing any notice. The comment

would require all applicants to provide notice of certification of

invalidity or noninfringement of a patent to all patent owners whose

patents claim the active ingredient that is the subject of the

application.

Under section 505(b)(2)(A) of the Act, an application must contain

a certification with respect to each patent which claims the listed

drug or which claims a use for such listed drug for which the 505(b)(2)

applicant is seeking approval. One of these patent certifications is

that the patent is invalid or will not be infringed by the manufacture,

use, or sale of the new drug for which the application is submitted.

(See section 505(b)(2)(A)(iv) of the Act). If an applicant makes a

``paragraph IV'' certification, it must give notice to the patent owner

and the NDA holder. (See section 505(b)(3)(A) of the Act.) If, however,

the applicant is not seeking approval for a use that is covered by a

use patent, the statute does not require a ``paragraph IV''

certification or notice to that patent owner and NDA holder. (See

section 505(b)(2)(B) and (b)(2)(A) of the Act.)

Thus, Sec. 314.52(a) is consistent with the statute, and FDA

declines to revise it as suggested by the comment.

18. FDA received three comments on proposed Sec. 314.52(c)

regarding the content of a notice of certification of invalidity or

noninfringement of a patent. Two comments favored extremely detailed

statements of the factual and legal basis of the applicant's opinion

that the patent is not valid or will not be infringed. These comments

would require the applicant to list all components used in the proposed

drug product, the proportions of each component, and list all grounds

supporting its opinion that the patent is invalid or will not be

infringed. One comment opposed disclosure of the proposed drug

product's formulation and also objected to the use of a ``designated

intermediary'' in proposed Sec. 314.52(c)(6)(iii).

In general, the statute requires a notice of certification of

invalidity or noninfringement of a patent to state that an application

has been submitted and to include ``a detailed statement of the factual

and legal basis of the applicant's opinion that the patent is not valid

or will not be infringed.'' (See section 505(b)(3)(B) and

355(j)(2)(B)(ii).) The proposed rule listed the type of information FDA

considered necessary to enable patent owners to decide whether to sue

for patent infringement. The list at proposed Secs. 314.52(c) and

314.95(c) generated substantial debate, as reflected in the comments,

as to the details to be included in a notice. The agency is neither

prepared nor required to become involved in issues concerning

sufficiency of notice for purposes of enforcing patent law. Therefore,

FDA has revised both Secs. 314.52(c) and 314.95(c) so that the detailed

statement of the factual and legal basis behind the applicant's opinion

that the patent is invalid, unenforceable, or will not be infringed

must include: (1) For each claim of the patent alleged not to be

infringed, a full and detailed explanation why the claim is not

infringed; and (2) for each claim of a patent alleged to be invalid or

unenforceable, a full and detailed explanation of the grounds

supporting the allegation. These provisions, as revised, paraphrase the

statutory language. The sufficiency of the notice, for purposes of

patent enforcement, is an issue to be resolved by the applicant and the

patent owner or the holder of the approved application.

The agency has also revised Secs. 314.52(c)(6) and 314.95(c)(6) by

removing paragraphs (c)(6)(iii) entirely. FDA is making this change due

to the numbers of comments that objected to the use of a ``designated

intermediary'' and the ``referee'' concept in proposed Secs. 314.52 and

314.95.

19. One comment would amend proposed Sec. 314.52(e) pertaining to

documentation of receipt of notice of certification of invalidity or

noninfringement of a patent. The comment would include a signed receipt

or delivery manifest as documentation of notice.

Section 314.52(e) clearly states that documentation of notice may

be a copy of the return receipt or ``other similar evidence of the date

the notification was received.'' The provision also states that 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.'' Thus, Sec. 314.52(e) does not limit an applicant to a

particular form of documentation of notice. Applicants are required,

however, to obtain agreement from FDA in advance if they intend to use

a form of documentation other than return receipt.

20. The agency has also revised Sec. 314.52(f) to state that the

45-day period provided for in section 505(c)(3)(C) of the Act will

begin on the day following the date of receipt of the notice by the

patent owner or its representative and by the approved application

holder. The reasons for this change are described in comment 62 below.

The agency, on its own initiative, has also revised Sec. 314.52(f)

to state that the agency may begin the 45-day period on a later date if

the applicant has amended its application to state that a later date

should be used. This could occur, for example, where the applicant has

amended its notice to the patent owner to provide more information

regarding the applicant's notice of invalidity or noninfringement. This

revision is also consistent with the corresponding provision for

ANDA's.

C. Section 314.53--Submission of Patent Information

Proposed Sec. 314.53 contained general requirements for the

submission of patent information by NDA applicants and NDA holders. For

example, proposed Sec. 314.53(b) would have required an NDA applicant

to submit information on each patent that claims the drug or drug

product for which the applicant is seeking approval or a method of

using the drug that is the subject of the NDA or amendment or

supplement 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. Proposed Sec. 314.53(c) described general reporting

requirements, such as information on the type of patent and the name of

the patent owner, and also required applicants to submit

``certifications'' with respect to formulation or composition patents

(proposed Sec. 314.53(c)(2)) and method of use patents (proposed

Sec. 314.53(c)(3)).

21. One comment addressed patent information and amendments of

patent information under proposed Secs. 314.50(h) and 314.53. These

provisions would require each application under section 505(b) of the

act to contain specific information about each patent that claimed the

drug product or a method of using the drug product. The provisions also

would require applicants to amend patent information or patent

certifications and would permit the agency to disclose patent

information. The comment said FDA should only publish patent

information filed by NDA applicants at the time FDA approves the NDA.

A drug product does not necessarily have a patent by the time FDA

approves the NDA. The statute expressly recognizes that a patent might

issue after NDA approval, and, under such circumstances, instructs the

NDA holder to file patent information within 30 days of the patent's

issue date. Once FDA receives this information, the agency is obliged

to publish it (see section 505(c)(2) of the act). Patent information

might also change after NDA approval. For example, the patent term

restoration provisions at 35 U.S.C. 156 give patent holders the

opportunity to extend patent terms. The extended patent term may be as

long as 5 years. However, patent owners cannot apply for patent term

extension until FDA approves the product for marketing (see 35 U.S.C.

156(d)(1)). Thus, patent term restoration (also known as ``patent term

extension'') always occurs after NDA approval, and patent owners who

obtain such extensions usually notify FDA of the new patent expiration

date. The new expiration date will be important to ANDA applicants

because section 505(j)(2)(A)(vii) of the act requires ANDA applicants

to submit patent certifications. Consequently, FDA does not accept the

comment's suggestion.

22. One comment would amend proposed Sec. 314.53 to establish a

mechanism ``for review of submitted patent information to determine, at

least on a very general basis, applicability to the particular NDA in

question.''

FDA declines to adopt the comment. As stated elsewhere in this

final rule, FDA does not have the expertise to review patent

information. The agency believes that its scarce resources would be

better utilized in reviewing applications rather than reviewing patent

claims.

23. FDA, on its own initiative, has amended Sec. 314.53(b) by

replacing the phrase, ``such patents consist of drug (ingredient)

patents'' with ``such patents consist of drug substance (ingredient)

patents.'' The final rule also replaces the phrase ``For patents that

claim a drug or drug product'' with ``For patents that claim a drug

substance or drug product.'' These changes are intended to clarify the

type of patents involved.

24. One comment would amend proposed Sec. 314.53(b) by requiring an

applicant to declare that it holds each patent or is the exclusive

licensee of the patent owner or is authorized to submit patent

information on behalf of the patent owner. The comment would also

prohibit an applicant from submitting patent information and would

prohibit the agency from listing any patent information if the

applicant did not make any of these declarations.

The agency declines to amend the provision. Under Sec. 314.53(c),

the applicant must provide the name of the patent owner or, if the

patent owner or applicant does not reside or have a place of business

within the United States, the name of an agent or representative who

resides or maintains a place of business within the United States and

is authorized to receive notice of patent certification. Requiring an

applicant to declare that it is the patent owner or exclusive licensee

or is authorized to submit patent information would go beyond the

statutory language at section 505(b)(1) of the act and would not serve

any statutory purpose.

FDA also declines to amend the rule to prohibit the applicant from

submitting patent information or to prohibit the agency from listing

patent information without a declaration of ownership or license. Such

an amendment would be contrary to section 505(b)(1) of the act and may

result in less published patent information, thereby causing applicants

to question the accuracy and validity of any patent information listed

by FDA.

25. FDA received two comments that objected to proposed

Sec. 314.53(b) and (c) regarding the submission of patent information

by NDA applicants. Both comments claimed that the 1984 amendments only

require NDA applicants to provide patent numbers and patent expiration

dates.

FDA disagrees with the comments. Section 505(b)(1) of the act

requires an applicant to file ``the patent number and the expiration

date of any patent which claims the drug for which the applicant

submitted the application * * * 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.'' The requirement in Sec. 314.53(b) and (c) that applicants

provide information on the type of patent and the name of the patent

owner or authorized representative is consistent with the purpose of

section 505(b)(1) of the act.

26. One comment objected to proposed Sec. 314.53(c)(2) and (c)(3).

Proposed Sec. 314.53(c)(2) would have required an applicant to provide

a patent certification for each formulation or composition patent in

addition to certain, general patent information. Proposed

Sec. 314.53(c)(3) would have required applicants to provide similar

certifications for method of use patents. The comment said that a

patent may contain formulation, composition, and method of use claims.

The comment suggested deleting the proposed rule's classification of

patents and replacing it with a general certification that the patents

listed by the applicant contain claims with respect to which the

applicant could reasonably assert a claim of infringement against a

person engaged in the unlicensed manufacture, use, or sale of the drug

for which the application was submitted.

FDA acknowledges that a patent may contain a variety of claims, and

has revised proposed Sec. 314.53(c)(2) by creating a single

certification statement. The new certification statement would have an

applicant state that, ``The undersigned declares that Patent No.

________ covers the formulation, composition, and/or method of use of

(name of drug product). This product is (currently approved under

section 505 of the Federal Food, Drug, and Cosmetic Act) [or] (the

subject of this application for which approval is being sought):

________________.'' However, because section 505(b)(1) of the act

specifically requires applicants 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 because FDA lacks patent law

expertise, the agency strongly encourages applicants to identify, to

the best of their ability, the type of patent covering the drug or drug

product. This information will help FDA determine which claims cover

the drug or drug product and which claims cover a method of use.

27. One comment said FDA should not list formulation patents.

Proposed Sec. 314.53(c)(2) would require applicants under section

505(b) of the act to provide information on formulation or composition

patents, and FDA would publish this information under Sec. 314.53(e).

The comment said this would increase the number of generic drug

applications by avoiding difficult questions of exclusivity for

``patentably distinct formulations'' and noted that patent owners can

always resort to patent law to halt possible patent infringement.

FDA disagrees with the comment. The statute expressly requires

applicants to file ``the patent number and the expiration date of any

patent which claims the drug for which the applicant submitted the

application * * *'' (section 505(b)(1) of the act). Thus, if the

formulation patent claimed the drug product in the application, the

applicant must file information on that patent.

28. One comment would revise proposed Sec. 314.53(c)(2)(i),

(c)(3)(i), and (c)(4) to refer to a ``declaration'' rather than

``certification.'' The comment explained that the 1984 amendments used

the word ``certification'' with respect to patent information to be

submitted by applicants under section 505(b)(2)(A) and (j)(2)(A)(vii)

of the act, so use of the word ``certification'' in proposed

Sec. 314.53(c) would be confusing.

The agency agrees and has revised these and other sections of the

rule accordingly.

29. One comment would delete proposed Sec. 314.53(c)(2)(ii) and

(c)(3)(ii). The comment said that the provision for the correction of

patent information at proposed Sec. 314.53(f) would ensure that patent

information is correct.

The provisions cited by the comment serve different purposes. As

revised, Sec. 314.53(c)(2)(ii) requires an applicant to provide patent

information about a product within 30 days after the date of approval;

these provisions contemplate the possibility that the patents

pertaining to a product's formulation, composition, and uses may change

between the time the application is initially submitted and the time

the application is approved (see 54 FR 28872 at 28909). Although

Sec. 314.53(f) enables any person to dispute the accuracy or relevance

of the patent information submitted to FDA, it is the responsibility of

the applicant, not the general public or the applicant's competitors,

to ensure that the information provided by the applicant is accurate.

These provisions for amending patent information are necessary for

maintaining an accurate list of patent information and useful for

applicants who must comply with the patent certification requirements.

Therefore, FDA declines to adopt the comment.

30. FDA received two comments on proposed Sec. 314.53(c)(4) (now

renumbered as Sec. 314.53(c)(3)), which would enable an applicant to

claim that there are no relevant patents that claim the drug product or

a method of using the drug product. One comment supported the

provision; the other recommended deleting it entirely, stating that the

only party that would be injured by the failure to list a patent is the

NDA applicant.

FDA declines to delete the provision as suggested. The agency

disagrees with the assertion that the NDA applicant would be the only

party injured by the failure to list a patent. The patent holder may be

a person other than the NDA applicant and may be injured if the

patented invention is made, sold, or used without the patent owner's

knowledge or consent. Failure to list a patent may also result in

injury to other applicants who devote resources towards submitting

applications for duplicate products without realizing that those

products may be covered by the patent.

31. FDA, on its own initiative, has reorganized Sec. 314.53(d) to

clarify further when and where patent information should be submitted.

As revised, Sec. 314.53(d)(1) pertains to patent information

requirements for original applications. New Sec. 314.53(d)(2), formerly

Sec. 314.53(d)(2)(ii), applies to patent information requirements for

supplements, and a new Sec. 314.53(d)(3), formerly

Sec. 314.53(d)(2)(i), applies to patent information submitted after an

application has been approved. The agency has renumbered the remaining

paragraphs accordingly.

32. Proposed Sec. 314.53(d) instructed applicants when and where to

submit patent information in an original application and in a

supplement and would require an applicant to provide patent information

within 30 days if a patent issues for a drug, drug product, or method

of use after the application had been approved. Three comments asked

FDA to extend the 30-day period in proposed Sec. 314.53(d) to 60 days.

FDA declines to accept the comment. The 30-day period is consistent

with section 505(c)(2) of the act and permits the agency to include the

latest patent information in supplements to the Orange Book. If FDA

provided for a longer time period, the Orange Book and its supplements

might be less likely to contain current patent information for each

product, and potential applicants might be misled by outdated patent

information. FDA has, on its own initiative, clarified

Sec. 314.53(d)(1) and (d)(3) to mention the 30-day deadline.

33. Proposed Sec. 314.53(d)(2)(ii) (now renumbered as

Sec. 314.53(d)(2)) would require an applicant to submit patent

information for a patent that claims the drug, drug product, or a

method of using the product if the applicant sought approval of

certain, listed changes through a supplemental application. One comment

would revise proposed Sec. 314.53(d)(2)(ii) to require an applicant to

provide a patent declaration for each supplement. The comment explained

that this would ``eliminate the risk that the four types of supplements

described in the proposal do not comprise the entire universe of

supplements that may affect the patent information filed with the

FDA.'' The comment would also require an NDA applicant to submit

information on patents that claim the formulation or composition each

time the NDA applicant submits a supplement to revise the formulation

or composition.

FDA disagrees with the comment. Section 505(b)(1) of the act

requires an applicant to submit information on each patent that claims

the drug or a method of using a drug product for 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. The supplements listed in new Sec. 314.53(d)(2)(i)--supplements

to change a formulation, to add a new indication or other condition of

use, to change the strength, or to make any other patented change

regarding the drug, drug product, or any method of use--are those that

concern the drug product or a method of using the drug product.

Additionally, new Sec. 314.53(d)(2)(i)(D) provides for the submission

of patent information for any other type of patented change. Requiring

an applicant to provide patent information for all supplements, even if

the supplement did not involve a change to the drug product or a method

of using the product (i.e., a change in the site of manufacturing),

would increase the workload on applicants and the agency without a

significant benefit.

The suggestion that FDA require an applicant to submit information

on patents that claim the formulation or composition each time the NDA

applicant submits a supplement to revise the formulation or composition

is apparently based on a misreading of proposed

Sec. 314.53(d)(2)(ii)(A) (now renumbered as Sec. 314.53(d)(2)(i)(A)).

This section already requires an applicant to provide such information.

Thus, the comment's suggestion is unnecessary.

34. One comment would revise proposed Sec. 314.53(d)(2)(ii)(D) (now

renumbered as Sec. 314.53(d)(2)(i)(D)) to require the submission of

patent information if the applicant submits a supplement to make any

other patented change ``except patented manufacturing processes.''

The suggested revision is unnecessary because Sec. 314.53(b)

clearly states that, ``Process patents are not covered by [Sec. 314.53]

and information on process patents may not be submitted to FDA.''

35. One comment would delete proposed Sec. 314.53(d)(2)(v) (now

renumbered as Sec. 314.53(d)(2)(iv)), which would require an applicant

to comply with the requirements for amending formulation, composition,

or method of use patent information. The comment said applicants are

already required to comply with such requirements.

FDA disagrees with the comment. Section 314.53(d)(2)(iv) requires

applicants to amend the patent information to account for changes

proposed in supplemental applications whereas Sec. 314.53(c)(2)(ii) and

(d)(2)(ii) require an applicant to amend patent information when there

have been changes in status, or there is other new information

regarding the relevant patents.

36. Proposed Sec. 314.53(d)(3) (now renumbered as

Sec. 314.53(d)(4)) would require an applicant to submit two copies of

each submission of patent information. One copy would go to the

archival copy of the application and the other copy would go to the

chemistry, manufacturing, and controls section of the review copy. One

comment would delete the phrase ``of the review copy'' from proposed

Sec. 314.53(d)(3) on the grounds that the phrase appeared to be a

typographical error.

FDA believes that the comment misreads proposed Sec. 314.53(d)(3).

An applicant is required to submit an archival copy and a review copy

of an application consisting of several separately bound technical

sections. New Sec. 314.53(d)(4) requires an applicant to provide two

copies of each submission of patent information. One copy will go to

the archival copy of the NDA; the other will go to the chemistry,

manufacturing, and controls technical section of the review copy of the

NDA.

37. FDA, on its own initiative, has amended Sec. 314.53(e)

regarding public disclosure of patent information. As originally

proposed, Sec. 314.53(e) stated that, for each use patent, FDA would

publish the ``approved indications or other conditions of use covered

by a patent and any unapproved indications or condition of use to which

the applicant certified.'' The agency is deleting the reference to

``any unapproved indications or condition of use'' to be consistent

with the patent information requirements in Sec. 314.53(c).

38. FDA received two comments on proposed Sec. 314.53(f) regarding

corrections of patent information errors. The proposed provision would

require a person disputing the accuracy or relevance of patent

information submitted to and published by FDA to first notify the

agency in writing stating the grounds for the disagreement. The agency

would then ask the NDA holder to confirm whether the patent information

was correct, but would not change the patent information listed in the

Orange Book unless the NDA holder withdrew or amended that information.

If the NDA holder did not change the patent information, a 505(b)(2)

applicant or ANDA applicant would be required to make a certification

for the listed patent despite any disagreement as to its correctness.

Both comments said that FDA should ensure that patent information

submitted to the agency is complete and applies to a particular NDA.

One comment would also amend the rule to have FDA confirm, upon request

from any person, the accuracy or relevance of the patent information

submitted to the agency. One comment said the agency should not provide

applicants the grounds for a disagreement on the accuracy or relevance

of patent information.

As stated elsewhere in this rule, FDA does not have the resources

or the expertise to review patent information for its accuracy and

relevance to an NDA. Therefore, the agency declines the comment's

requests to ensure that patent information is complete and relevant to

an NDA and to confirm, upon request, the validity of patent information

submitted to the agency. The agency believes that the declaration

requirements under Sec. 314.53(c), as well as an applicant's potential

liability if it submits an untrue statement of material fact, will help

ensure that accurate patent information is submitted.

FDA also declines to amend the rule to prevent the agency from

providing applicants the grounds for a disagreement on the accuracy or

relevance of patent information. Absent such information, a patent

owner will be unable to evaluate the disagreement or to explain whether

the patent information is correct.

39. One comment noted that proposed Sec. 314.53(f) does not require

applicants to correct patent listings. The comment would revise the

provision to permit applicants to ``make otherwise pertinent

certifications while a listing dispute is pending.'' The comment would

also require FDA to notify the NDA holder of the disagreement within 15

days of notification and require patent owners or NDA holders to

respond to a disagreement on patent information or to withdraw or amend

the patent information within 30 days. The comment would then require

FDA to immediately send the NDA holder's response to the party that

began the disagreement and inform the party whether the patent would

remain listed.

As originally proposed, Sec. 314.53(f) expressly required an

applicant to make ``an appropriate certification for each listed

patent'' notwithstanding any disagreement as to the correctness of the

listed patent information. If, as FDA assumes, the proposed reference

to ``otherwise pertinent certifications'' means ``appropriate

certifications,'' the proposal is unnecessary. If the proposed

reference is to negate any responsibility to file an appropriate

certification for a patent that is subject to a dispute over listing,

FDA rejects the proposal. Until the dispute is resolved, the patent is

listed within the meaning of the act. FDA also declines to amend the

rule to impose deadlines for resolving patent disagreements. The agency

believes that such deadlines would be impractical, considering the

agency's lack of expertise in patent matters and the volume of

applications FDA receives, and agency resources would be better spent

on reviewing applications rather than exchanging disputed patent

information among parties as proposed by the comment. The agency also

notes that it has not had any significant problems with the informal

procedures described in proposed Sec. 314.53(f) as most NDA holders

have amended or corrected their patent information after FDA has

informed them of a dispute.

The agency has, however, revised Sec. 314.53(f) to provide a new

address for the submission of written statements disputing the

relevance or accuracy of patent information. Such statements should now

be directed to the Drug Information Services Branch in the Division of

Drug Information Resources. This change reflects current FDA

operations.

D. Section 314.54--Procedure for Submission of an Application Requiring

Investigations for Approval of a New Indication for, or Other Change

From, a Listed Drug

Proposed Sec. 314.54(a)(1)(vii) would require an applicant seeking

approval of a drug product that represents a modification of a listed

drug, to provide certain information regarding marketing exclusivity if

the applicant believed the modification would be entitled to such

exclusivity.

The agency received no comments on this provision and has finalized

it without change.

E. Section 314.70--Supplements and Other Changes to an Approved

Application

Proposed Sec. 314.70(e) (now renumbered as Sec. 314.70(f)) would

require applicants submitting a supplement to an approved application

to provide certain marketing exclusivity information if the applicant

intended to seek market exclusivity.

The agency received no comments on this provision and has finalized

it without change.

F. Section 314.94--Content and Format of an Abbreviated Application (21

CFR 314.94)

Proposed Sec. 314.94(a)(12) contained the patent certification

requirements for ANDA's. For example, under proposed

Sec. 314.94(a)(12)(i), an ANDA applicant would provide a patent

certification with respect to each patent that claims the reference

listed drug or that claims a use of the reference listed drug for which

the ANDA applicant is seeking approval. Proposed Sec. 314.94(a)(12)(ii)

would permit an ANDA applicant to certify that there are no relevant

patents that claim the listed drug or a method of use of the listed

drug. Proposed Sec. 314.94(a)(12)(iii) would permit an ANDA applicant

to state that the use for which the applicant is seeking approval is

not covered by a patent claiming a use for the listed drug.

40. One comment claimed that proposed Sec. 314.94(a)(12)(i)(A) was

inconsistent with the statute because the statute only requires ANDA

applicants to make certifications for listed patents rather than

patents issued by the United States Patent and Trademark Office. Two

comments added that the suggestion regarding patent searches that FDA

made in the preamble to the proposed rule was irrational and legally

insupportable. One company, however, agreed that ANDA applicants should

submit patent certifications with respect to all patents, including

those that had not been submitted to FDA for listing.

The rule simply paraphrases the statutory language in section

505(j)(2)(A)(vii) of the act. The rule does not require ANDA applicants

to conduct patent searches. If the applicant believes that no patent

exists, the applicant is to submit a patent certification under

Sec. 314.94(a)(12)(ii) that no relevant patents exist. If the applicant

believes that a patent exists but that the patent owner has not filed

patent information at FDA, the ANDA applicant would certify that, ``in

its opinion and to the best of its knowledge,'' no patent information

has been submitted (i.e., make a paragraph I certification). FDA,

however, believes it would be prudent for applicants to conduct patent

searches if possible. A patent search could reveal the existence of an

unlisted, but valid, patent and thus prevent an unnecessary expenditure

of resources by applicants and FDA on a product that might not be

marketable. A patent search might also enable ANDA applicants to avoid

unnecessary patent infringement litigation.

41. One comment suggested that FDA publish all patent information,

including descriptions of the patents and patent numbers, in the Orange

Book.

The Orange Book already contains an addendum listing both patent

and exclusivity information. This section provides patent numbers and

patent expiration dates as well as exclusivity codes and expiration

dates. In addition, for a use patent, FDA includes in the Orange Book a

code identifying the indication covered by the patent. As for patent

descriptions, FDA lacks the expertise to review and summarize patents

and individual patent claims and does not believe that expanding the

Orange Book to include patent descriptions would be an efficient use of

FDA resources. However, persons who wish to obtain a synopsis of a

particular patent can consult the Official Gazette for Patents, which

is published by the United States Patent and Trademark Office. The

Official Gazette for Patents contains short descriptions of patents and

is publicly available.

42. One comment asserted that FDA should list patents that claim

drug products for which the patent owner is not seeking or has not

obtained approval. The comment explained that the statute requires NDA

holders and applicants to submit information on ``any patent which

claims the drug for which the applicant submitted the application''

(section 505(b)(1) of the act). The comment, citing Sec. 314.50(d)(1),

claimed that ``drug'' means the active ingredient while ``drug

product'' denotes a marketed product composed of active and inactive

ingredients. Thus, because section 505(b)(1) of the act uses the term

``drug,'' the comment continued, any patent that claims the active

ingredient is a patent that claims the drug for which the applicant

submitted the application and should be listed.

FDA disagrees with the comment's interpretation of section

505(b)(1) of the act. The statutory provision states that patent

information is to be filed on patents that claim the drug ``for which

the applicant submitted the application.'' Similarly, the House Report

accompanying the Drug Price Competition and Patent Term Restoration Act

indicates that the patent information to be filed ``includes the patent

number and the expiration date of any patent which claims the drug in

the NDA or which claims a method of using such drug with respect to

which a claim of patent infringement could reasonably be asserted * *

*.'' H. Rept. 857, 98th Cong., 2d sess. 31-32 (1984) (emphasis added).

Thus, both the statute and its legislative history reveal that Congress

intended the term ``drug'' to mean ``drug product'' rather than

``active ingredient'' because NDA's are granted only for drug products

and not for active ingredients. FDA's interpretation of this provision

has been upheld by a United States magistrate in Pfizer v. FDA, No. HM-

88-1019, slip op. at 10-13 (D. Md. October 2, 1989) and adopted by a

Federal district court (see Pfizer, Inc. v. Food and Drug

Administration, 753 F.Supp. 171 (D. Md. 1990)).

43. Several comments sought clarification regarding the interaction

between proposed Sec. 314.94(a)(12)(i)(A)(4) and Sec. 314.94(a)(12)(v),

180-day exclusivity periods under section 505(j)(4)(B)(iv) of the act,

and licensees.

Because patent licensees are subject to 180-day exclusivity that

has been granted to another applicant, the only instance in which

proposed Sec. 314.94(a)(12)(v) would apply would be where a patent

licensee would seek to have an effective approval of its ANDA or

505(b)(2) application within 45 days of its receipt or filing (because

the patent holder has 45 days to file a lawsuit against an ANDA

applicant making a paragraph IV certification). Because the agency does

not anticipate approving an ANDA or 505(b)(2) application in 45 days,

FDA, on its own initiative, removed the provisions in

Sec. 314.94(a)(12)(v) and Sec. 314.107(b)(1)(iv) related to consent by

a patent owner to an immediate effective date of approval for a

licensee.

44. Two comments disagreed with proposed Sec. 314.94(a)(12)(ii),

which would require ANDA applicants to certify that there are no

relevant patents that claim the listed drug referred to in the ANDA.

One comment said that ANDA applicants should only be required to

certify that no listed patents claim the listed drug referred to in the

ANDA. The second comment suggested deleting the provision and revising

proposed Sec. 314.94(a)(12)(i)(A)(1) so ANDA applicants would certify

that no patent information had been filed.

FDA declines to accept the comments. As stated in the preamble to

the proposed rule, an applicant makes a patent certification under

Sec. 314.94(a)(12)(ii) if ``in the applicant's opinion and to the best

of its knowledge, no relevant patents claim the listed drug or a method

of using the listed drug'' (54 FR 28872 at 28885). The applicant makes

the patent certifications under Sec. 314.94(a)(12)(i) when it is aware

of or believes that a patent covers the listed drug. (Id.) FDA believes

that Sec. 314.94(a)(12)(ii) will enable FDA to ensure that each

applicant has complied with the patent certification requirements.

45. One comment asked FDA to define ``relevant'' for proposed

Sec. 314.94(a)(12)(ii). The word ``relevant'' refers to those patents

defined by section 505(j)(2)(A)(vii) of the act for which a patent

certification would be required, i.e., patents that claim the listed

drug, or drug substance component thereof, referred to in the ANDA or

that claim a use of the listed drug or drug substance for which the

ANDA applicant seeks approval and for which patent information is

required to be filed under section 505 (b) and (c) of the act and

Sec. 314.53.

Although patents that are held to be invalid or unenforceable in a

judicial decision may be removed from the list by FDA, a patent that

has been declared invalid or unenforceable in a lawsuit resulting in

180-day exclusivity will be deemed relevant under

Sec. 314.94(a)(12)(ii) and will not be removed from the list until the

end of the 180-day exclusivity period. This will ensure that 180-day

exclusivity cannot be avoided by changing a patent certification.

46. Several comments objected to proposed Sec. 314.94(a)(12)(iii),

which would require ANDA applicants to provide a patent statement if

the listed patent is for a method of use and that applicant does not

intend to claim any of the patented uses. The comments recommended that

such ANDA applicants certify, under Sec. 314.94(a)(12)(i)(A)(4), that

the listed use patent would not be infringed, thereby giving the patent

owner notice of possible patent infringement. One comment asked how

proposed Sec. 314.94(a)(12)(iii) would affect eligibility for the 180-

day exclusivity period. The comment explained that the statute requires

ANDA applicants to make patent certifications under section

505(j)(2)(A)(vii) of the act and statements for method of use patents

under section 505(j)(2)(A)(viii) of the act. However, the comment

stated, for method of use patents, the proposed rule could be

interpreted as giving ANDA applicants the option of making a patent

certification of noninfringement under proposed

Sec. 314.94(a)(12)(i)(A)(4) or a statement that the applicants' drug

products do not involve a patented claim under proposed

Sec. 314.94(a)(12)(iii).

FDA does not intend Sec. 314.94(a)(12)(i)(A)(4) to authorize

certifications with respect to patents that claim a use for the listed

drug for which the applicant is not seeking approval. The statute

requires patent certifications only if the patent ``claims a use for

[the] listed drug for which the applicant is seeking approval * * *''

(section 505(j)(2)(A)(vii) of the act). The statute requires an

applicant to make a patent statement when a method of use patent ``does

not claim a use for which the applicant is seeking approval * * *''

(section 505(j)(2)(A)(viii) of the act).) The proposed rule recognized

this distinction. FDA stated that if a patent claims a method of using

the listed drug, and labeling for the ANDA applicant's proposed drug

product does not contain any indications covered by the method of use

patent, the ANDA applicant ``should not submit a certification under

Sec. 314.94(a)(12)(i)(A) for such a patent'' (54 FR 28872 at 28886).

The preamble also indicated that if the labeling for the ANDA

applicant's product did contain an indication that was claimed by a

patent, the applicant should make a certification under

Sec. 314.94(a)(12)(i)(A). (Id.) Thus, the two provisions cited by the

comment are not overlapping, and an applicant does not have the option

of making a certification under Sec. 314.94(a)(12)(i)(A)(4) in lieu of,

or in addition to, a statement under Sec. 314.94(a)(12)(iii).

If, however, there are listed patents that present both a product

and method of use claim, the applicant may file a paragraph IV

certification with respect to the product patent or patent claim and a

statement that the product that is the subject of the application does

not involve a patented method of use with respect to the method of use

patent or patent claim.

47. One comment recommended revising proposed Sec. 314.94(a)(12)(v)

to provide NDA holders the opportunity to consent to licensing

agreements between ANDA applicants and patent owners. As written,

proposed Sec. 314.94(a)(12)(v) did not address this issue.

Neither the statute nor the legislative history suggests that NDA

holders should be given such a right, and the agency is not prepared to

infer such a right to interfere in the patent holder's enjoyment of its

right to license. However, as stated earlier, FDA has elected to remove

the language in Sec. 314.94(a)(12)(v) regarding consent by the patent

owner.

48. One comment objected, in part, to proposed

Sec. 314.94(a)(12)(vi), which would require an ANDA applicant to

provide a patent certification in response to an untimely submission of

patent information if the ANDA was submitted after the untimely

submission of patent information or did not contain an appropriate

patent certification at the time the patent information was submitted.

The comment correctly noted that FDA may refuse to approve or may even

withdraw approval of an application for failure to submit patent

information (see section 505 (d)(6) and (e)(4) of the act). The comment

said these sanctions emphasize the importance of filing patent

information, and FDA ``should not provide any benefit to the NDA

applicant who ignores the statutory requirement for timely submission

of such information.''

Section 314.94(a)(12)(vi) is intended to effectuate Congress'

intent to enforce timely submission of patent information. As discussed

more fully in the response to comment 7 above, FDA believes a less

severe sanction than the withdrawal of NDA approval for late submission

of patent information would ordinarily effectuate congressional intent.

For the reasons discussed in response to comment 7 FDA has concluded

that if an NDA applicant submits required patent information on an

approved drug product more than 30 days after issuance of the patent,

the agency will publish the untimely information but will not require

ANDA applicants with pending applications who have previously submitted

a certification that was correct at the time it was submitted, i.e.,

those applicants who would be prejudiced by the late submission, to

recertify as to the new patent. Applicants who initially submit ANDA's

after the submission of the patent information or whose pending

applications do not contain a valid certification at the time of the

submission would be required to submit a certification as to that

patent. The agency, therefore, declines to revise this provision.

FDA also notes that, if an ANDA applicant with a pending

application voluntarily makes a patent certification for an untimely

filed patent, the ANDA applicant may withdraw the patent certification

for the untimely filed patent. The agency, on its own initiative, has

amended Sec. 314.94(a)(12)(viii) to make this clear. Additionally, if

the patent certification for the untimely filed patent was a paragraph

IV certification (claiming that the patent is invalid or would not be

infringed), the agency would not consider the withdrawn paragraph IV

certification to preclude FDA from granting 180-day exclusivity to

another ANDA applicant.

49. Proposed Sec. 314.94(a)(12)(vii) would permit an ANDA applicant

to seek confirmation of the correctness of patent information, but

would also require an ANDA applicant to submit the appropriate patent

certification if the disputed patent information was not amended or

withdrawn. One comment suggested amending proposed

Sec. 314.94(a)(12)(vii) to declare the end of the error correction

process for patent information to be final agency action. The comment

explained that this section permits challenges to listed patents but,

in conjunction with proposed Sec. 314.53(f), neglects to contain a

process to require patent owners to withdraw or modify patent listings.

The comment said that declaring the end of the error correction process

to be final agency action would enable ANDA applicants to seek judicial

review rather than wait for the patent owner to voluntarily correct the

patent information.

FDA disagrees with the comment. Disputes between ANDA applicants

and patent holders regarding the validity or correctness of the listed

patent information must be resolved among the ANDA applicants and the

patent holders rather than by agency action. FDA stated this position

in the preamble to the proposed rule (see 54 FR 28872 at 28910).

50. One comment addressed proposed Sec. 314.94(a)(12)(viii) and

asked FDA to permit applicants to amend their patent certifications if

a patent is declared invalid. The comment proposed that any amendment,

with the exception of a paragraph IV certification being changed to a

paragraph III certification, be considered nunc pro tunc (now for

then). If a patent were declared invalid, the comment suggested that an

amendment from paragraph IV to paragraph III be considered ``as if a

III were originally filed, subject to a prior IV certificant's

exclusivity rights during the remaining lifetime of the patent.''

Finally, the comment said that applicants should be permitted to make a

paragraph I certification if the patent were removed from the list.

FDA agrees in part with the comment. An applicant may change its

certification at any time. Although there is no need for the agency to

pronounce such changes in certification nunc pro tunc, the agency

agrees that the protection offered by 180-day exclusivity should not be

undermined by changes from paragraph IV certification or by the filing

of original certifications other than paragraph IV certifications. If a

patent were removed from the list immediately upon a court decision

that the patent is invalid or unenforceable, an applicant with a

subsequently filed application might seek to certify that there is no

relevant patent and seek an immediately effective approval. To ensure

that this does not occur, the agency has required that a patent remain

on the list after being declared invalid or unenforceable until the end

of any applicable 180-day exclusivity period. This means that a patent

is deemed to be relevant under Sec. 314.94(a)(12)(ii) until the end of

the term of the patent or applicable 180-day exclusivity period,

whichever occurs first. Thus, where there is a patent that has been

challenged by a paragraph IV applicant, a subsequent applicant will not

be able to file a certification that there is no relevant patent or

seek an immediately effective approval until either the patent or the

180-day exclusivity period expires. The agency has amended

Sec. 314.94(a)(12)(viii)(B) and made a similar change to

Sec. 314.50(i)(6)(ii) to reflect this position.

The agency also notes that an applicant may withdraw its patent

certification at any time. However, as stated earlier, if an ANDA

applicant made a paragraph IV certification and later withdraws that

certification, the agency will not regard the withdrawn paragraph IV

certification as precluding the agency from granting 180-day

exclusivity to a subsequent ANDA applicant.

51. One comment suggested that ANDA applicants amend their patent

certifications to a paragraph I certification if FDA or the NDA holder

``delists'' a patent.

As stated in the preamble to the proposed rule, the agency believes

that a certification under Sec. 314.94(a)(12)(ii), stating that no

relevant patents claim the listed drug, would be more appropriate if a

patent is ``delisted'' (see 54 FR 28872 at 28886).

52. One comment asked FDA to clarify proposed

Sec. 314.94(a)(12)(viii)(A) so that an amended patent certification

would be required if a patent were held valid and infringed but not

required if a patent were held infringed, but not valid.

If a claim is found to be invalid or unenforceable, the patent will

ordinarily be removed from the list, and applicants with pending

applications containing certifications with respect to that patent must

amend their certifications accordingly to certify that no relevant

patents claim the drug or, if another relevant patent claims the drug,

to make an appropriate certification regarding that patent. In the

amendment, the applicant must state the reason for the change in

certification (that the patent has been removed from the list). A

patent that is the subject of a lawsuit under Sec. 314.107(c) will not

be removed from the list until FDA determines either that no delay in

effective dates of approval is required as a result of the lawsuit or

that any such period of delay in effective dates of approval is ended.

The agency has amended Sec. 314.94(a)(12)(viii)(B) to clarify its

position regarding certifications and patents removed from the list.

The agency also advises applicants to submit any patent

certification changes by letter if the applicant has not received a

``not approvable'' letter from the agency. If the applicant has

received a ``not approvable'' letter, it may include the amended

certification along with the complete response to the deficiencies in

the ``not approvable'' letter. This will enable FDA to process

amendments more efficiently.

53. Six comments addressed amended certifications under proposed

Sec. 314.94(a)(12)(viii)(C)(2) which would not require applicants to

amend their patent certifications when patent information is submitted

after the abbreviated application's approval ``whether or not the

approval of the abbreviated application is effective.'' One comment

would require amended patent certifications only if a new patent issued

after the ANDA had been submitted and make supplements optional after

ANDA approval. Five comments would require ANDA applicants to amend

patent certifications until the effective date of their ANDA approvals

because the existence of a patent would affect the ANDA's effective

date of approval.

In the Federal Register of April 28, 1992 (57 FR 17950 at 17953),

FDA stated that it had clarified its policies with respect to drug

products with delayed effective dates of approval. The agency stated

that an approval with a delayed effective date is tentative and does

not become final until the effective date. Therefore, FDA has amended

Sec. 314.94(a)(12)(viii)(C)(2) by deleting the phrase ``whether or not

the approval of the abbreviated application is effective,'' and,

consistent with this change, and in response to the comments, by

requiring an ANDA applicant to amend its patent certifications until

the effective date of ANDA approval.

G. Section 314.95--Notice of Certification of Invalidity or

Noninfringement of a Patent

Proposed Sec. 314.95 described an ANDA applicant's obligations with

respect to a notice of certification of invalidity or noninfringement

of a patent. Proposed Sec. 314.95(a), for example, would require an

ANDA applicant to provide notice to the patent owner and the NDA

holder. Proposed Sec. 314.95(b) would require an ANDA applicant to send

the notice when it receives an acknowledgment letter from FDA stating

that the ANDA is sufficiently complete for review to begin. Proposed

Sec. 314.95(c) prescribed the contents of a notice of certification of

invalidity or noninfringement of a patent, including ``a detailed

statement of the factual and legal basis of the applicant's opinion

that the patent is not valid or will not be infringed.''

54. One comment recommended that FDA revise the regulation by

adding a mechanism whereby FDA or the United States Patent and

Trademark Office would review notices of certification of invalidity or

noninfringement. The comment would have FDA suspend the 45-day period

provided by section 505(j)(4)(B)(iii) of the act until FDA or the

United States Patent and Trademark Office determined that the notice

was sufficient.

FDA declines to adopt the comment. As stated elsewhere in this

preamble, FDA lacks expertise in patent law. Moreover, neither FDA nor

the United States Patent and Trademark Office currently has access to

the additional resources that would be necessary to review these

notices, and a patent certification review system would subject the

agency's decisions to questioning that would require further resource

expenditures and create delays in the statutory patent certification

and challenge process.

The agency does note, however, that in cases where the notice was

deemed inadequate by the patent owner or exclusive patent licensee and

where the ANDA applicant subsequently amends the notice, the agency

may, if the applicant amends its ANDA with a written statement that the

date of receipt of the amended notification should be considered the

date of receipt of notice, use the date of the amended notification to

begin the 45-day statutory period for institution of an action for

patent infringement (see 54 FR 28872 at 28888; see also

Sec. 314.95(f)).

55. Two comments addressed return receipts under proposed

Sec. 314.95(a). One comment would amend the rule to provide for signed

receipts while the second would revise the rule to permit reliance on

``any appropriate federal rule for transmitting notice to another party

or for receipt of such notice.''

Under Sec. 314.95(e), applicants are required to document receipt

of a notice of invalidity or noninfringement by submitting ``a copy of

the return receipt or other similar evidence of the date the

notification was received.'' The rule states that FDA will accept

return receipts, letters acknowledging receipt by the person provided

the notice, or ``another form of documentation only if FDA has agreed

to such documentation in advance.'' Thus, the rule provides several

methods for documenting receipt of a notice, so the comment's

recommendations are unnecessary.

56. One comment asked FDA to clarify when multiple notices might be

required.

Section 314.95(a) requires applicants to send notices to each

patent owner and each holder (or its attorney, agent, or other

authorized official) of the approved application under section 505(b)

of the act for the listed drug that is claimed by the patent and for

which the applicant is seeking approval (Sec. 314.95 (a)(1) and

(a)(2)). Consequently, applicants could be obliged to send multiple

notices under several situations. For example, a patent owner is

usually an individual whereas the holder of an approved application is

often a corporation. The applicant, therefore, would send one notice to

the patent owner and another to the firm holding the approved

application. If several patents cover the listed drug, there may be

several different patent owners, so the applicant would be required to

provide separate notices to each patent owner.

57. Two comments suggested revising proposed Sec. 314.95(a)(1) to

include the patent owner's name and address in the Orange Book.

The patent owner's name and address are printed on each patent. As

a result, whenever a prospective applicant examines a patent to

determine whether its proposed product would infringe any of the patent

claims, the applicant would have access to the patent owner's name and

address. The comment's suggestion, therefore, is unnecessary.

58. Several comments asked when and how applicants should send

notices under proposed Sec. 314.95(b). Two comments would have an

applicant provide a statement to FDA declaring that the applicant

``will give,'' rather than ``has provided,'' notice of certification of

invalidity or noninfringement of a patent. These comments explained

that the statute does not specify a time for the notice, so the rule

should permit applicants to decide when to send such notices. One

comment would revise the rule to give FDA 30 days to determine whether

the ANDA was complete before the applicant would be required to send a

notice of certification of invalidity or noninfringement of a patent.

The legislative history discussing a notice of certification of

invalidity or noninfringement of a patent clearly states that ANDA

applicants should provide notice ``simultaneously with the submission

of an ANDA'' and that Congress did ``not intend that applicants be

permitted to circumvent this notice requirement by filing sham ANDA's

or ANDA's which are substantially incomplete'' (see H. Rept. 857, 98th

Cong., 2d sess. 24 (1984)). Thus, to permit applicants to state that

they ``will provide'' notice to the patent owner and holder of the

approved application would be contrary to congressional intent.

Moreover, such a statement would be redundant relative to that required

under Sec. 314.94(a)(12)(i) and would not inform FDA whether notice

has, in fact, been provided. With regard to the suggestion of a 30-day

deadline for FDA to respond before an applicant sends notice, FDA

believes such a requirement would be impractical. The time required to

review an application may vary depending upon the application's

complexity, the review division's workload, the timing and scope of an

applicant's response to FDA's questions or requests, etc. Although FDA

intends to review applications expeditiously, current resources and

priorities may not, in all instances, enable the agency to determine

whether an application is sufficiently complete for review to begin

within 30 days after receiving the application. Consequently, FDA

declines to adopt the comments.

59. One comment argued that proposed Sec. 314.95(b) creates a delay

that is detrimental to ANDA applicants and is contrary to the 1984

amendments and the legislative history. The comment said that proposed

Sec. 314.95(b) would deprive ANDA applicants of ``statutory rights''

associated with the 45-day period and the 30-month period for the

effective date of an ANDA approval and could present problems among

competing ANDA applicants. The comment said FDA should permit ANDA

applicants to provide notice upon submission of an application or have

ANDA applicants await an initial FDA determination (presumably as to

whether the application is received) before providing notice.

FDA disagrees with the comment. As stated above, the legislative

history expressly states that notice of certification of invalidity or

noninfringement of a patent must be given simultaneously with the

submission of an ANDA and that the ANDA cannot be a ``sham'' ANDA or

one that is substantially incomplete (see H. Rept. 857, 98th Cong., 2d

sess. 24 (1984)). As written, Sec. 314.95(b) is consistent with the

legislative history because it requires the ANDA applicant to provide

notice once FDA has determined that the ANDA is substantially complete

to permit a substantive review. To permit an ANDA applicant to provide

notice before FDA has determined whether the ANDA is sufficiently

complete would be contrary to the legislative history because it would

only encourage ANDA applicants to file incomplete or ``sham'' ANDA's

and to supplement them later to secure a place in the review queue in

an attempt to secure the first ANDA approval.

60. FDA received five comments regarding the exact contents of a

notice of certification of invalidity or noninfringement of a patent.

Two comments would revise the rule to require applicants to disclose

all components, including active and inactive ingredients, in the

applicant's prospective formulation, the proportions of those

components, and all grounds supporting the applicant's assertion that

the patent is invalid or will not be infringed. Three comments opposed

disclosure of the applicant's formulation or composition information or

a detailed statement of the applicant's legal reasoning. These comments

explained that such information and statements might compromise the

applicant's trade secrets and adversely affect the applicant's ability

to engage in litigation.

As noted above in comment 18, the agency did not anticipate that

the list in proposed Sec. 314.95(c) would generate the debate reflected

in the comments and, again, reiterates that the agency does not have

the expertise or the desire to become involved in issues concerning

patent law and sufficiency of notice. Therefore, FDA has revised

Sec. 314.95 to require that the detailed statement of the factual and

legal basis behind the applicant's opinion that the patent is invalid,

unenforceable, or will not be infringed include the following: (1) For

each claim of a patent alleged not to be infringed, a full and detailed

explanation why the claim is not infringed; and (2) for each claim of a

patent alleged to be invalid or unenforceable, a full and detailed

explanation of the grounds supporting the allegation (see

Secs. 314.52(c)(6)(i) and (c)(6)(ii) and 314.95(c)(6)(i) and

(c)(6)(ii)). Disputes involving the sufficiency of the notice must be

resolved by the applicant, patent owner, and holder of the approved

application rather than by action on the part of FDA.

61. FDA also received five comments opposing the use of a referee

or designated intermediary under proposed Sec. 314.95(c)(6)(iii). The

proposal would have required an ANDA applicant to describe a mechanism

for disclosing the formulation or composition of the proposed drug

product to the patent owner or to a ``designated intermediary who will

act as a referee'' on the subject of patent invalidity or

noninfringement. The comments said that the concept was legally

unauthorized and interfered with the traditional judicial process for

resolving patent disputes.

FDA agrees that traditional processes for resolving patent

disputes, which do not involve the agency's regulations, are

appropriate under these circumstances. Therefore, the agency has

deleted the provision in its entirety.

62. Proposed Sec. 314.95(f) would presume a notice of certification

of invalidity or noninfringement to be complete and sufficient if the

ANDA applicant complied with the regulatory requirements under

Sec. 314.95(a) through (e) and would start the 45-day clock for filing

a patent infringement suit on the date following receipt of the notice.

One comment challenged the presumption that a notice is complete and

sufficient to permit the statutory 45-day period to begin. The comment

would revise the rule to require applicants to file a complete copy of

the certification and notice of service with FDA and delay the start of

the 45-day period if any dispute over the certification's sufficiency

arose. A second comment argued that an approved application holder who

is also an exclusive patent licensee might have different interests

than the patent owner. The comment would revise the rule to require

notice to both the patent owner and to the licensee or approved

application holder.

With respect to FDA's presumption that a notice is complete and

sufficient to begin the 45-day period, Sec. 314.95(c), as amended,

paraphrases the statutory language concerning notices and does not

attempt to establish more detailed requirements for ``sufficiency'' of

a notice. FDA has revised Sec. 314.95(f) to state that it will begin

the 45-day period on the first day after the documented date of receipt

by the person(s) receiving the notice. FDA will be able to determine

this date because Sec. 314.95(e) requires applicants to submit

documentation of receipt of notice. FDA may, if the applicant amends

its ANDA with a written statement that a later date should be used,

count from the later date.

FDA also agrees that an exclusive patent licensee's interests may

differ from those of the patent owner. Therefore, FDA has revised

Secs. 314.52(f) and 314.95(f) to start the 45-day period on the day

following the date of receipt of the notice by the patent owner or its

representative and by the approved application holder.

H. Section 314.101--Filing an Application and an Abbreviated Antibiotic

Application and Receiving an Abbreviated New Drug Application (21 CFR

314.101)

63. The agency, on its own initiative, is revising Sec. 314.101(e)

to add a new paragraph stating that the agency will refuse to file a

505(b)(2) application or receive an ANDA if the drug product that is

the subject of the 505(b)(2) application or ANDA is protected by a 5-

year exclusivity period under section 505(c)(3)(D)(ii) and

(j)(4)(D)(ii) of the act. This amendment is consistent with the

statutory language and Sec. 314.108(b)(2).

I. Section 314.107--Effective Date of Approval of a 505(b)(2)

Application or Abbreviated New Drug Application Under Section 505(j) of

the Act)

Proposed Sec. 314.107 was intended to codify the requirements under

section 505(c)(3) and (j)(4) of the act regarding the effective dates

of approval for a 505(b)(2) application or an ANDA. For example, if the

505(b)(2) applicant or ANDA applicant certified that there are no

relevant patents, that patent information has not been submitted, that

the patent has expired, or that the patent is invalid, unenforceable,

or not infringed, and the patent owner has not brought suit for patent

infringement, proposed Sec. 314.107(b)(1) would treat the date FDA

issues an approval letter as the effective date of approval. If the

505(b)(2) applicant or ANDA applicant certified that the patent would

expire on a specific date, proposed Sec. 314.107(b)(2) would treat that

specific date as the effective date of approval. Proposed

Sec. 314.107(b)(3) described several situations in which the effective

date of approval could vary, depending upon the disposition of patent

litigation.

Proposed Sec. 314.107 also implemented the ``180-day exclusivity

period'' described in section 505(j)(4)(B)(iv) of the act. In brief,

section 505(j)(4)(B)(iv) of the act states that if an ANDA contains a

paragraph IV patent certification (declaring the patent to be invalid

or not infringed) and the ANDA is for a drug for which a previous ANDA

containing a paragraph IV patent certification has been submitted,

approval of the subsequently submitted ANDA will be made effective 180

days after the date FDA receives from the previous ANDA applicant

notice of the first commercial marketing of the drug or the date a

court holds the patent that is the subject of the patent certification

to be invalid or not infringed, whichever date is earlier (see section

505(j)(4)(B)(iv) of the act). Proposed Sec. 314.107(c) provided that an

applicant must be the first ANDA applicant to submit a substantially

complete application with a paragraph IV certification and must have

been sued for patent infringement in order to qualify for 180-day

exclusivity.

64. One comment asked FDA to permit any person to contact FDA

informally to determine whether the listed patent information was

correct and later petition the agency to correct any errors. As

proposed, Sec. 314.107 did not provide for inquiries concerning patent

information.

Sections 314.53(f) and 314.94(a)(12)(vii) describe the procedures

that an applicant can use to question the validity of patent

information. In brief, if an applicant disputes the accuracy or

relevance of patent information, it should first notify FDA in writing

and state the reasons for the disagreement. FDA will then request that

the relevant NDA holder confirm the validity of the patent information,

but will not change the patent information itself unless the NDA holder

withdraws or amends the patent information. The agency believes that

these procedures for determining the validity of patent information are

sufficient, and, therefore, declines to adopt the change suggested by

the comment.

65. FDA, on its own initiative, has amended Sec. 314.107(b)(1) to

state that an approval will become effective on the date FDA issues an

approval letter except as provided under paragraphs (b)(3), pertaining

to approvals resulting from the disposition of patent litigation;

(b)(4), pertaining to approvals where an applicant has submitted

multiple certifications; and (c), regarding subsequent ANDA

submissions. These changes are to clarify that there are other

situations that may make an approval effective.

66. Two comments would revise proposed Sec. 314.107(b)(1)(iv)

regarding a certification that a patent is ``invalid or will not be

infringed.'' The comments would have this certification state that the

patent is ``invalid and will not be infringed.''

FDA declines to adopt the suggested language. The provision simply

paraphrases the statutory language for a paragraph IV certification

(see section 505(j)(2)(A)(vii)(IV) of the act). The agency has,

however, amended the provision to account for a certification that a

patent is unenforceable and, as stated earlier, removed the language

regarding consent from the patent holder.

67. One comment asked FDA to amend proposed

Sec. 314.107(b)(1)(iv)(B)(2) to require NDA holders to have a role in

or consent to licensing agreements between patent owners and ANDA

applicants. The proposed rule would consider the effective date of

approval for a 505(b)(2) application or an ANDA to be the date FDA

issues an approval letter if, among other things, the drug product is

covered by a patent licensing agreement and the 505(b)(2) application

or ANDA contains a statement that the applicant has been granted a

patent license and a statement from the patent owner that it has a

licensing agreement with the applicant for the proposed drug product

and that the patent owner consents to an immediate effective date.

As stated elsewhere in this final rule, FDA believes that the

negotiations surrounding licensing agreements and the parties entering

into such agreements are outside the scope of this rule. Additionally,

as stated in the response to comment 43 above, the agency has deleted

the provisions in Sec. 314.107(b)(1)(iv) relating to consent by a

patent owner to an immediate effective date of approval for a licensee.

68. The agency, on its own initiative, has made minor grammatical

changes and other revisions to Sec. 314.107 (b)(2) and (b)(3). These

revisions replace ``Upon patent expiration'' with ``Patent Expiration''

and ``Upon disposition of patent litigation'' with ``Disposition of

patent litigation.'' Additionally, the changes specify that the patent

owner must receive the notice of certification and clarify, in

Sec. 314.107(b)(3)(i)(B), the effective date of approval.

69. Proposed Sec. 314.107(b)(3) described the effective date of

approval of a 505(b)(2) application or ANDA upon disposition of patent

litigation. Under proposed Sec. 314.107(b)(3)(i)(A), if an applicant

certified that the relevant patent was invalid or would not be

infringed, and the patent owner or its representative brought suit for

patent infringement, the effective date of approval for the 505(b)(2)

application or ANDA would be 30 months after the date of receipt of the

notice of certification of patent invalidity or noninfringement by the

patent owner or its representative unless a court extended or reduced

the 30-month period. Proposed Sec. 314.107(b)(3)(i)(B) described the

effective date of approval of a 505(b)(2) application or an ANDA upon

disposition of patent litigation when the patented drug product also

qualified for 5 years of market exclusivity. Proposed

Sec. 314.107(b)(3)(ii) through (b)(3)(iv) represented additional

modifications to the effective date of approval due to court decisions

or orders.

One comment concerned the proposed language in

Sec. 314.107(b)(3)(i) regarding the 30-month period. The comment would

amend this provision to shorten or lengthen the 30-month period

pursuant to a court order.

The suggested change is unnecessary because Sec. 314.107(b)(3)(i)

through (b)(3)(iv) explains how the 30-month period may be changed due

to court decisions or orders.

The agency also emphasizes that disposition of patent litigation

will not result in automatic approval of a pending application. FDA

notes that section 505(c)(3)(C) and (j)(4)(B)(iii) of the act describe

when approval of a 505(b)(2) application or an ANDA shall be made

effective if an applicant submitting a 505(b)(2) application or ANDA

has made a paragraph IV certification and has or has not been sued for

patent infringement. For example, if the applicant made a paragraph IV

certification, was sued for patent infringement, and the court hearing

the patent infringement suit decided that the patent was either invalid

or not infringed, section 505(c)(3)(C)(i) and (j)(4)(B)(iii)(I) of the

act state, respectively, that approval of the 505(b)(2) application or

ANDA may ``be made effective on the date of the court decision.''

However, the agency interprets these provisions of the act as

requiring, as a preliminary matter, final agency approval of the

application in order for any approval to be made effective. Thus, an

applicant with a tentative approval may not begin marketing its drug

product until it has received an approval letter from the agency

because a tentative approval letter does not constitute a final

``approval'' of the application. In such cases, the agency will examine

the application to determine whether there have been any changes in the

conditions under which the application was tentatively approved. The

tentative approval would become final and, therefore, effective only

when the agency sends an approval letter to the applicant.

Similarly, an applicant that has not yet received a tentative

approval letter may not begin marketing its drug product in the event

that a court reaches a decision in any related patent infringement

litigation because there is no final ``approval'' by FDA that could be

made ``effective'' within section 505(c)(3)(C)(i) or (j)(4)(B)(iii) of

the act.

Other provisions of the act support this interpretation of section

505(c)(3)(C)(i) and 505(j)(4)(B)(iii) of the act as they relate to the

expiration of the 30-month period or the date of the court decision.

For example, section 505(j)(3) of the act states that the agency shall

approve an ANDA unless certain circumstances are found to exist.

Section 505(j)(3)((A) of the act prevents the agency from approving an

ANDA if the agency finds that ``the methods used in, or the facilities

and controls used for, the manufacture, processing, and packing of the

drug are inadequate to assure and preserve its identity, strength,

quality, and purity.'' Consequently, until FDA assesses the available

information, often from an additional current good manufacturing

practices inspection, it cannot determine whether the applicant's

methods and controls used for the manufacture, processing, and packing

of the drug are adequate to assure and preserve the drug's identity,

strength, quality, and purity and therefore, under section 505(j)(3) of

the act, whether the ANDA should be approved. Thus, unless FDA has

formally approved an ANDA under section 505(j)(3) of the act, there is

no ``approval'' that could be made effective under section 505(j)(4)(B)

of the act upon resolution of the patent litigation. (Section 505(d) of

the act establishes an analogous approval requirement for 505(b)(2)

applications.)

The legislative history provides additional support for FDA's

interpretation. In describing the provisions regarding effective dates

of approval and court decisions, the House Report states:

The Committee wishes to emphasize that the court may not order

an ANDA approved under this provision. These are times when approval

of an ANDA may be made effective if the FDA has approved the ANDA.

See H. Rept. 857, 98th Cong., 2d sess., Part 1, 27-28 (1984)

(emphasis added). The same concept is applicable to 505(b)(2)

applications (see id. at 34).

This interpretation of section 505(j)(4)(B) of the act reflects

current FDA practice and revises the agency's previous policy that was

stated in the preamble to the proposed rule (see 54 FR 28872 at 28894).

It also clarifies the agency's position on delayed effective dates of

approvals as expressed in the preamble to the final rule on ANDA

content and format that was published in the Federal Register on April

28, 1992 (57 FR 17950 at 17956). Consequently, FDA, on its own

initiative, has amended Sec. 314.107(b)(3) to clarify when approval of

an application may become effective and by adding a new paragraph

(b)(3)(v) to state that, in order for an approval to become effective

under paragraph (b)(3), the applicant must first receive a final

approval letter from the agency.

70. One comment would restrict proposed Sec. 314.107(b)(3)(ii) to

district court orders. The comment would revise the rule to state: ``If

before the expiration of the 30-month period, or 7\1/2\ years where

applicable, the district court decides such patent is invalid or not

infringed, the approval will be made effective on the date of the

district court order or judgment.'' The comment would also replace the

words ``a final order'' in proposed Sec. 314.107(b)(3)(iii) and

(b)(3)(iv) with ``an order or judgment.''

FDA declines to limit the rule to district court orders. As stated

in the preamble to the proposed rule, FDA interprets the requirement of

a ``court decision'' to mean ``a final decision of a court from which

no appeal can or has been taken'' (see 54 FR 28872 at 28895). Beginning

the 180-day exclusivity period before the resolution of the appeals

process would render the exclusivity valueless to a prudent applicant

who delayed marketing until the issues were resolved on appeal.

FDA has, however, revised Sec. 314.107(b)(3)(iii) and (b)(3)(iv) to

refer to an ``order or judgment'' because both terms are sometimes used

to refer to actions that terminate an action or decide a matter in

litigation.

71. Proposed Sec. 314.107(b)(4) concerned applicants who made

multiple patent certifications. In essence, the proposed provision

would consider the approval of a 505(b)(2) application or an ANDA to be

effective on the last applicable date. One comment would amend proposed

Sec. 314.107(b)(4) by adding a new sentence stating:

If the applicant has submitted certifications under

Sec. 314.50(i) or Sec. 314.94(a)(12) and has submitted notice to the

owner of the patent pursuant to Sec. 314.95, and FDA subsequently

receives a stipulation or order by the district court notifying it

that the applicant has amended its answer to add new arguments, not

included in that notice, in any ensuing suit for patent

infringement, the date of approval will be calculated based on a 30-

month period starting at the date of receipt by FDA of each such

stipulation or order, and the approval will become effective on the

last applicable date.

Alternatively, the comment suggested that an ANDA applicant who amended

its answer to a patent infringement suit to include arguments that were

not in the notice to the patent owner under Sec. 314.95 would be

considered to have been uncooperative in expediting the lawsuit. The

comment explained that these revisions would prevent generic drug

companies from amending their answers during patent infringement

litigation to delay completion of a trial and also delay the start of

the 30-month period.

FDA declines to adopt the comment's suggestion. As stated above,

FDA has revised the notice requirements in Secs. 314.52(c) and

314.95(c) to parallel the statutory language rather than specify notice

requirements. The agency has neither the resources nor the expertise to

engage in patent disputes or questions regarding sufficiency of notice.

The statute leaves the issue of extending the 30-month period (based on

a lack of cooperation between the parties in patent litigation) to the

discretion of the trial court. The agency believes that the trial court

should make determinations of cooperation on a case-by-case basis.

Accordingly, the agency declines to amend the rule to consider an

applicant to be uncooperative and to extend the 30-month period if the

applicant amends an answer to a complaint in patent litigation to

include an argument not reflected in the notice to the patent holder.

72. FDA received several comments on proposed Sec. 314.107(c) and

the 180-day exclusivity period against subsequent ANDA's. As proposed,

Sec. 314.107(c) would provide 180-day exclusivity to the first ANDA

applicant that made a paragraph IV patent certification (that the

patent was invalid or not infringed) and was sued for patent

infringement. Seven comments said the language requiring an ANDA

applicant to have been sued in order for the 180-day exclusivity period

to become effective was contrary to the statute and to a judicial

ruling in the U.S. District Court for the District of Columbia.

Section 505(j)(4)(B)(iv) of the act can be applied

straightforwardly only when an applicant who seeks the 180-day period

of exclusive marketing has been involved in a patent infringement

lawsuit. To apply the section where there has been no lawsuit would

require that the agency ignore the textual relationship between section

505(j)(4)(B)(iii) and (j)(4)(B)(iv) of the act and assume that Congress

intended, contrary to the goals it stated in the legislative history,

to create an incentive for delay in generic competition, without any

countervailing benefit to society. Moreover, it would provide a

windfall to an applicant who has not devoted the considerable time and

money necessary for patent litigation. Thus, consistent with the

agency's longstanding interpretation of the act, Sec. 314.107(c)

applies only when the first applicant has been sued. Although, as the

comments state, one Federal district court reached a contrary

conclusion, the agency appealed that decision and, on appeal, the

decision was vacated as moot (Inwood Laboratories, Inc. v. Young, 723

F.Supp. 1523 (D.D.C. 1989), vacated as moot, no. 89-5209 (D.C. Cir.,

November 13, 1989). The agency has not altered its interpretation of

the act.

FDA has, however, revised Sec. 314.107(c) to clarify other issues,

such as the start and end of the 180-day exclusivity period, and to

make minor editorial changes.

73. One comment suggested revising proposed Sec. 314.107(c) to

state that the 180-day exclusivity period does not apply to delay the

effective date of approval of licensees to the NDA holder.

As stated above, FDA does not believe that an ANDA applicant who

has made a paragraph IV certification and obtained a patent license

should be able to circumvent a 180-day exclusivity period.

Consequently, the agency declines to amend the provision as requested

by the comment.

74. Two comments would revise proposed Sec. 314.107(c) to extend

the 45-day period in which patent owners have to file suit against an

ANDA applicant. The proposal referred to the statutory 45-day period in

which a patent owner would have to file suit against an ANDA applicant.

The comments would extend the 45-day period upon request or when the

ANDA applicant and the patent owner agree to an extension.

FDA declines to accept the comments' suggestion. The 45-day period

for filing a lawsuit against an ANDA applicant is fully consistent with

section 505(j)(4)(B)(iii) of the act, and the agency finds that there

are sound policy reasons that outweigh extensions of the 45-day period.

For example, if an ANDA applicant has provided notice to a patent owner

stating that the ANDA applicant believes that the patent is invalid or

would not be infringed (a paragraph IV certification), the patent owner

may elect to bring suit against the ANDA applicant for patent

infringement. If the suit is brought within 45 days from the date the

ANDA applicant provided the notice, section 505(j)(4)(B)(iii) of the

act precludes the agency from granting a final approval of the ANDA. If

suit is not brought within 45 days, FDA could grant a final approval of

the ANDA upon expiration of this time period, assuming that the ANDA

met all applicable requirements for approval. Thus, amending the rule

to provide the patent owner an extension to file suit beyond the 45-day

period would not prevent the agency from approving ANDA's during the

extension (because the statutory restriction against making an approval

effective would no longer apply), even if the patent owner later

decided to bring suit against the ANDA applicant and prevailed in that

lawsuit. Such a result would waste agency and industry resources.

FDA also notes that, in situations where an ANDA applicant has

amended its notification to the patent owner and approved NDA holder to

make it more complete, the agency may, under Sec. 314.95(f), consider

the 45-day period to begin on the day after the date of receipt of the

amended notification.

75. One comment would revise proposed Sec. 314.107(c) to begin the

180-day exclusivity period ``on the first day that a court would allow

non-infringing marketing (unless that decision were stayed)'' or ``30

months from receipt of notice.''

The agency declines to revise the rule as suggested. The rule,

which paraphrases the statutory language at section 505(j)(4)(B)(iv) of

the act, better reflects the plain meaning of the act. Revising the

rule as requested by the comment would begin the 180-day exclusivity

period at the end of the 30-month period without regard to whether the

applicant had commenced marketing on that date.

76. Proposed Sec. 314.107(c)(1)(i) would provide 180-day

exclusivity to the first ANDA applicant to submit a complete ANDA with

a paragraph IV patent certification and ``to be sued within 45 days of

the patent owner's receipt of notice.'' One comment said the rule, as

drafted, created an incentive for frivolous claims of patent invalidity

or noninfringement because it would give ANDA applicants exclusivity

even if the applicant was unsuccessful in defending against the patent

owner's lawsuit. The comment would replace the phrase ``to be sued

within 45 days'' with ``and to successfully defend a suit brought

within 45 days.''

FDA agrees and has amended Sec. 314.107(c) accordingly.

77. FDA received several comments regarding proposed

Sec. 314.107(c)(1)(i) and (c)(1)(ii). These provisions concerned the

start of the 180-day exclusivity period. Proposed Sec. 314.107(c)(1)(i)

would begin the 180-day exclusivity period on the date of the first

commercial marketing of the drug product by the first ANDA applicant

who submitted a substantially complete ANDA containing a certification

that the patent was invalid or not infringed and who was sued for

patent infringement within 45 days after providing notice to the patent

owner. Alternatively, proposed Sec. 314.107(c)(1)(ii) would begin the

180-day exclusivity period on the ``date a decision of the court

holding the relevant patent invalid or not infringed'' if that date was

earlier than the date of the first commercial marketing. One comment

would revise proposed Sec. 314.107(c)(1)(ii) to include a cross-

reference to the language in Sec. 314.107(b)(3) on patent litigation.

FDA declines to adopt the suggested revision. The agency believes

that the meaning of Sec. 314.107(c)(1)(ii) is sufficiently clear so

that the court referred to in Sec. 314.107(c)(1)(ii) is the court

deciding the patent infringement suit. However, for reasons stated

elsewhere in this document, the agency has amended this provision to

include a reference to unenforceable patents.

78. One comment would amend Sec. 314.107(c), (c)(1)(i), and

(c)(1)(ii) to permit an ANDA applicant to decide whether to start the

180-day exclusivity period on the date it notifies the agency that the

applicant has begun commercial marketing of the drug product or to wait

to see whether the court decision is appealed. If an appeal did result,

the comment would permit the ANDA applicant to have the 180-day period

begin when a court issues a decision on the appeal.

FDA declines to amend the provision as suggested by the comment.

The provision is consistent with section 505(j)(4)(B)(iv) of the act by

beginning the 180-day period on the date the first ANDA applicant has

notified the agency that it has begun commercial marketing of the drug

product or the date of a court decision holding the patent to be

invalid or not infringed, ``whichever is earlier'' (see section

505(j)(4)(B)(iv) of the act).) Allowing an applicant to begin marketing

before the commencement of the 180-day exclusivity period would, in

effect, extend the exclusivity period in a manner that is inconsistent

with the plain meaning of the act. FDA also notes that the court

decision must be a final decision from which no appeal can be or has

been taken (see 54 FR 28872 at 28895).

79. FDA received four comments regarding ``substantially complete''

applications under proposed Sec. 314.107(c)(2). Proposed

Sec. 314.107(c)(2) would consider an ANDA to have been ``previously

submitted'' with respect to another application for the same listed

drug ``if the date on which the first application was both

substantially complete and contained a certification that the patent

was invalid or not infringed is earlier than the date on which the

second application was both substantially complete and contained the

same certification.'' The proposal also stated that a ``substantially

complete'' application ``must contain the results of any required

bioequivalence studies, or, if applicable, a request for a waiver of

such studies.''

One comment asked FDA to provide information as to which ANDA was

the first ``substantially complete'' ANDA. The comment suggested that

disclosing such information did not present any confidentiality

problems because the ANDA applicant would have revealed the existence

of the ANDA when it provided notice of certification of invalidity or

noninfringement of the patent to the patent owner and NDA holder.

FDA agrees, in part, with the comment. Disclosing whether an ANDA

had been received for a specific listed drug would enable manufacturers

to decide whether to develop a generic version of that drug and perhaps

conserve the manufacturer's resources. Such knowledge could, in turn,

effectively reduce the number of applications for the same product and

thus also conserve agency resources. The agency, therefore, will

disclose whether an ANDA has been received for a particular drug, but,

in order to preserve the confidentiality of the applicant, will not

disclose when the application had been received or the applicant's

identity. Potential applicants who wish to inquire whether an ANDA for

a specific drug has been received can contact the Regulatory Support

Branch (HFD-615), Food and Drug Administration, 7500 Standish Pl.,

Rockville, MD 20855, 301-594-0315.

80. Two comments disagreed with the language regarding

``substantially complete'' applications. One comment said FDA should

only determine whether an ANDA contains a bioequivalence test or waiver

request and not focus on the results of any required bioequivalence

studies. The second comment suggested that a ``substantially complete''

ANDA be one that contained a paragraph IV patent certification and a

bioequivalence study that is ultimately approved. The comment said this

change would deter ANDA applicants from submitting ``superficial''

bioequivalence tests. The comment also suggested that the agency

establish criteria as to whether changes to an ANDA were so substantial

that the ANDA could no longer be considered as the first to be filed.

Since publication of the proposed rule, FDA has clarified its

policies regarding the submission of incomplete ANDA's. Under the

earlier policy, ANDA applicants could submit ANDA's with bioequivalence

study protocols and could provide bioequivalence study data at a later

date. This policy resulted in a significant and unwarranted expenditure

of resources in reviewing applications that had little potential for

approval. Thus, in the Federal Register of April 28, 1992, FDA

announced that it would no longer accept an ANDA that does not contain

complete bioequivalence study data if such data are required for

approval (see 57 FR 17950 at 17959). A ``substantially complete''

application, therefore, should have a complete bioequivalence study, or

other information to show bioequivalence that could support approval of

the application. FDA will examine the bioequivalence information upon

submission and, if the agency determines that the bioequivalence

information is facially insufficient to support a finding of

bioequivalence, the agency will not review the application under

Sec. 314.101(d). A decision by the agency after receipt of an

application that the bioequivalence information is inadequate for

approval does not necessarily mean that the application was not

substantially complete at the time of submission.

FDA also declines to establish criteria to establish whether

changes to an ANDA were so substantial that it could not be considered

to have been filed. While certain changes in an ANDA (e.g., a change in

the listed drug) would amount to a new filing for purposes of

Sec. 314.107(c)(2), other changes (e.g., minor labeling changes) would

not. The agency believes a case-by-case approach is preferable because

many products and manufacturers may be unique.

81. The agency, on its own initiative, has revised the provisions

in Sec. 314.107 (c)(2) and (c)(3) to clarify their intent. These

provisions address the issues of the ``applicant submitting the first

application'' for exclusivity purposes, what constitutes a

``substantially complete'' application, and the effective dates of

approval for subsequently submitted applications if the first applicant

is not ``actively pursuing'' approval. FDA has made similar editorial

changes at Sec. 314.107(c)(4).

82. Four comments addressed proposed Sec. 314.107(c)(3). The

proposed provision would make an ANDA that had been received after FDA

had already received an ANDA for the same drug immediately effective if

the agency concluded that the first ANDA applicant ``is not actively

pursuing approval of its abbreviated application.'' Three comments

asked FDA to define the phrase ``actively pursuing approval.''

For purposes of this rule, the phrase ``actively pursuing

approval'' is intended to encompass a drug sponsor's good faith effort

to pursue marketing approval in a timely manner. In determining whether

a sponsor is actively pursuing marketing approval, FDA will consider

all relevant factors, such as the sponsor's compliance with regulations

and the timeliness of its responses to FDA's questions or application

deficiencies during the review period.

83. One comment would revise proposed Sec. 314.107(c)(3) to make a

subsequently received ANDA immediately effective upon a finding that

the first applicant is not actively pursuing approval ``if [the

subsequent application is] otherwise eligible for an immediately

effective approval.''

The agency agrees and has amended the provision accordingly. This

change will remind applicants that FDA will make approval of a

subsequent abbreviated application immediately effective if it

satisfies all applicable requirements and FDA has concluded that the

first applicant is not actively pursuing approval of its abbreviated

application.

84. FDA received five comments regarding the interpretation of

``the court'' and court judgments in proposed Sec. 314.107(e)(1).

Proposed Sec. 314.107(e)(1) stated that ``the court'' in

Sec. 314.107(b) and (c) referred to ``the court that enters final

judgment from which no appeal can be or has been taken.'' Three

comments supported the proposal, but two comments argued that FDA had

misconstrued the 1984 amendments. One comment argued that the court

finding a patent to be invalid or not infringed should be ``the court

of first instance'' or district court because a decision that a patent

was invalid or not infringed or a decision to issue an injunction would

be done by a district court. Another comment argued that interpreting

``the court'' to mean the court that enters final judgment

``effectively gives a patent owner an additional extension of the

patent * * * for the duration of the appeal'' and delay generic

competition. The comment would revise the rule to permit an ANDA

applicant to market its drug product after it had prevailed at the

trial court level.

FDA declines to amend Sec. 314.107(e)(1) as suggested by the

comments. To construe ``the court'' as a district court, regardless of

any appeal of the district court decision, would deny the benefits of

exclusivity to a prudent applicant that delayed marketing its product

until resolution of an appeal by the patent holder (see 54 FR 28872 at

28894). Moreover, if the patent holder appealed the district court

decision and were able to obtain a stay or an injunction against the

marketing of the applicant's product, the applicant could lose the

entire 180-day exclusivity period before the stay or injunction were

lifted.

Given these considerations, FDA believes that any reference to

``the court'' must be the court that enters final judgment from which

no appeal can be or has been taken. (The reference to ``appeals'' does

not include the certiorari process. The likelihood of an appellate

court decision being heard and overruled by the Supreme Court is too

remote to warrant delaying marketing and exclusivity pending resolution

of a petition for writ of certiorari.) This interpretation avoids

potentially premature decisions on the effective date of ANDA approval

and the loss of 180-day exclusivity. FDA has, however, also revised

Sec. 314.107(e)(2) to clarify which court decisions will represent the

``final'' judgment.

85. One comment would revise proposed Sec. 314.107(e)(2) to refer

to a court order or judgment rather than simply a court judgment.

As amended, Sec. 314.107(e)(2) refers to a court ``decision,''

which could be in the form of either an order or a judgment. The agency

has also made minor changes to Sec. 314.107(e)(2) to clarify that the

court decisions involve patent issues and that a higher court can hold

or affirm a lower court decision that a patent is invalid,

unenforceable, or not infringed.

86. A second comment would revise proposed Sec. 314.107(e)(2) to

require applicants to submit copies of a court order or judgment to the

Division of Generic Drugs or ``New Drug Evaluation Division (where

applicable).''

FDA agrees with the comment, and has added Sec. 314.107(e)(2)(iv)

to require applicants to send a copy of a final decision to the Office

of Generic Drugs, or to the appropriate division in the Office of Drug

Evaluation I or the Office of Drug Evaluation II, whichever is

applicable.

87. Proposed Sec. 314.107(f) described how the 45-day period for

filing a patent infringement suit would be determined. In brief, under

proposed Sec. 314.107(f)(1), the 45-day period would begin on the day

after the date the patent owner or approved application holder, if an

exclusive patent licensee, received a notice of certification of

invalidity or noninfringement of the patent. Proposed

Sec. 314.107(f)(2) would require the 505(b)(2) applicant or ANDA

applicant to notify FDA whether an action for patent infringement had

been filed. Several comments objected to language in proposed

Sec. 314.107(f) that would consider notice to or actions by exclusive

licensees to be equivalent to notice to or actions by a patent owner.

The comments said that exclusive licensees do not always share the

patent owner's interests.

FDA agrees and has revised the rule to remove language that would

consider exclusive licensees to be equivalent to patent owners.

88. One comment objected to proposed Sec. 314.107(f)(1) because it

would start the 45-day period on the day after the date the patent

owner or the approved application holder, if an exclusive patent

licensee, received notice of invalidity or noninfringement of a patent.

The comment argued that the 45-day period should begin on the day after

the date that the patent owner and the approved application holder

received notice and, if these dates differed, the latest date should

mark the start of the 45-day period.

The agency agrees with the comment and has revised

Sec. 314.107(f)(1) to begin the 45-day period on the day after the date

the patent owner and the approved application holder have received the

applicant's notice of certification of invalidity or noninfringement of

a patent.

89. FDA received several comments on proposed Sec. 314.107(f)(2).

Absent a notice of an action for patent infringement, the proposal

would make the approval of an ANDA or 505(b)(2) application effective

immediately upon the expiration of the 45-day period for filing a

patent infringement suit or upon FDA's completion of the review and

approval process, whichever is later. The comments noted that the

regulation would have ANDA or 505(b)(2) applicants notify FDA whether a

patent infringement suit had been filed and asked FDA to permit, by

regulation, patent owners to notify FDA whether it had brought suit.

Alternatively, some comments would require the ANDA or 505(b)(2)

applicant certify that it had not been sued. The comments explained

that these changes were necessary because ANDA and 505(b)(2) applicants

would have no interest in notifying FDA whether suit had been filed

because, without such notice, they could immediately secure effective

approval of an application.

The agency has amended Sec. 314.107(f)(2) to permit patent owners

or their representatives to notify FDA whether a patent infringement

suit has been filed. The statute does not require applicants to certify

that they have not been sued, and the agency does not believe such a

burden to be necessary.

The agency has also made minor revisions to Sec. 314.107(f)(2) to

place more emphasis on an applicant's obligation to notify FDA

immediately of the filing of any legal action within 45 days of receipt

of a notice of certification.

Additionally, the agency has made a grammatical change in

Sec. 314.107(f)(2) to clarify that applicants must send the

notification to the Office of Generic Drugs or to the appropriate

division in the Center for Drug Evaluation and Research reviewing the

application.

90. One comment addressed the requirement in proposed

Sec. 314.107(f)(2) that a 505(b)(2) applicant or ANDA applicant notify

FDA whether an action for patent infringement had been filed ``before

the expiration of the 45-day time period or the completion of the

agency's review of the application, whichever occurs later.'' The

comment argued that a patent owner had 45 days to file a lawsuit after

receiving a notice of certification of invalidity or noninfringement of

a patent and, therefore, a party should have an additional time period

beyond the 45-day period for filing an action for patent infringement

for notifying the agency whether an action had been filed. The comment

would revise the rule to give a party an additional 15 days beyond the

45-day period to notify FDA whether an action for patent infringement

had been filed.

The agency declines to revise the rule as suggested. FDA believes

it is important to learn immediately if an action for patent

infringement is filed before the completion of the 45-day period to

avoid an erroneous approval with an immediate effective date.

FDA has, therefore, amended Sec. 314.107(f)(2) to require

applicants to notify FDA immediately whether any legal action has been

filed. The agency has also amended this subsection to clarify the

identity of the ``applicant.''

91. FDA has, on its own initiative, clarified its notification

requirements in Sec. 314.107(f)(2)(iii). As proposed,

Sec. 314.107(f)(2)(iii) would have required parties to identify a drug

by its established name, but would not have expressly required any

identification of the drug if no established name existed. The agency

has amended this provision to require identification of the drug

product by its established name or, if no established name exists, its

active ingredient(s).

92. One comment asked FDA to publish information regarding the

status and progress of patent infringement suits so other ANDA

applicants could decide whether to intervene in the suit ``and ask that

the 30-month period be shortened or lengthened in the event that it

feels that one or both of the litigants are not reasonably cooperating

in expediting the action.'' Alternatively, the comment asked FDA to

permit any interested party to petition the agency ``to remove an ANDA

from exclusivity considerations if it has not proceeded with due

diligence--either in prosecution of its ANDA or defense of an

infringement suit.''

FDA believes that ANDA applicants are capable of monitoring the

progress of patent litigation without imposing the additional burden of

acquiring and publishing information on patent litigation on FDA. The

agency, therefore, declines to adopt the comment.

FDA also declines to amend the rule to permit third parties to

petition the agency to deny exclusivity to an ANDA due to the ANDA

applicant's actions during litigation. Under the statute, the reduction

or enlargement of the 30-month period is left to the trial court's

discretion. Intervention by the agency is unwarranted.

93. One comment suggested replacing the words, ``action to

defend,'' in proposed Sec. 314.107(f)(2)(iv) with the words, ``action

for patent infringement.'' The comment said that ``action to defend''

was not a term of art.

FDA agrees and has adopted the comment.

94. FDA, on its own initiative, has modified the language regarding

waivers in Sec. 314.107(f)(3). The change is intended to clarify that

the patent owner does not object to FDA's approval of an ANDA or

505(b)(2) application with an immediate effective date and to account

for those situations where the ANDA applicant or 505(b)(2) applicant

and the patent owner have agreed to extend the 45-day period.

J. Section 314.108--New Drug Product Exclusivity

Proposed Sec. 314.108 was intended to implement the new drug

exclusivity provisions under section 505(c)(3)(D) and (j)(4)(D) of the

act. This section of the act provides specific time periods, known as

new drug product exclusivity or market exclusivity, during which the

effective date of approval for a 505(b)(2) application or an ANDA must

be delayed or, in some cases, a 505(b)(2) application or an ANDA cannot

be submitted. For example, section 505(c)(3)(D)(i) and (j)(4)(D)(i) of

the act grant a 10-year period of exclusivity to new chemical entities

that were approved during January 1, 1982, to September 24, 1984.

Section 505(c)(3)(D)(ii) and (j)(4)(D)(ii) of the act grant a 5-year

period of exclusivity to new chemical entities approved after September

24, 1984. These sections of the act expressly state that no 505(b)(2)

application or ANDA may be submitted during the exclusivity period

except that such applications may be submitted after 4 years if they

contain a certification of patent invalidity or noninfringement.

Section 505(c)(3)(D)(iii), (c)(3)(D)(iv), (j)(4)(D)(iii), and

(j)(4)(D)(iv) of the act grant a 3-year period of exclusivity to an

application or supplemental application that is approved after

September 24, 1984, and contains ``reports of new clinical

investigations (other than bioavailability studies) essential to the

approval'' of the application or supplemental application and

``conducted or sponsored by'' the person submitting the application or

supplemental application.

Section 505(c)(3)(D)(v) and (j)(4)(D)(v) of the act granted a 2-

year period of exclusivity to drugs that are not chemical entities or

for certain changes to already approved products that were approved

during January 1, 1982, to September 24, 1984. FDA did not propose any

regulations for this 2-year period because it expired on September 24,

1986.

The exclusivity provisions of the act do not provide any protection

from the marketing of a generic version of the same drug product if the

generic version is the subject of a full NDA submitted under section

505(b)(1) of the act.

95. Proposed Sec. 314.108(b)(4) would provide 3 years of

exclusivity to an application that was submitted under section 505(b)

of the act, was approved after September 24, 1984, was for a drug

product containing an active moiety that had been previously approved

in another application under section 505(b) of the act, and contained

reports of new clinical investigations (other than bioavailability

studies) conducted or sponsored by the applicant that were essential to

approval of the application. Proposed Sec. 314.108(b)(5) would provide

3 years of exclusivity to a supplemental application that was approved

after September 24, 1984, and contained reports of new clinical

investigations (other than bioavailability studies) conducted or

sponsored by the applicant that were essential to approval of the

application.

Several comments addressed the scope of new drug exclusivity. Two

comments said FDA should grant exclusivity for any change to an

approved drug product or, alternatively, should grant exclusivity based

on specific types of studies, such as studies intended to reduce drug

dosing or drug efficacy study implementation (DESI) upgrade studies.

One comment disagreed with the preamble to the proposed rule, which

stated, ``FDA expects that only those changes in an approved drug

product that affect its active ingredient(s), strength, dosage form,

route of administration or conditions of use would be granted

exclusivity'' (54 FR 28872 at 28899). Two comments asked FDA to clarify

whether a clinical investigation establishing new risks could be

eligible for exclusivity. The preamble to the proposed rule had

indicated that such studies would not qualify for exclusivity because

``protection of the public health demands that all products' labeling

contain all relevant warnings'' (see 54 FR 28872 at 28899). One comment

said FDA should accept an applicant's claim of exclusivity alone.

Two other comments sought to limit exclusivity or clarify its

scope. One comment argued that the rule was too broad, would confer

``an unearned windfall,'' and stifle generic competition. The comment

explained that some variations, such as reductions in dosage, require

little effort but would nevertheless qualify for exclusivity. The

comment suggested that the rule define what types of changes would

qualify for exclusivity. The second comment agreed with the preamble

that DESI upgrades should not qualify for exclusivity but asked FDA to

create a procedure whereby parties could contact FDA to determine

whether exclusivity information was accurate. The comment said this

would enable third parties to decide whether to challenge decisions to

grant or deny exclusivity.

FDA disagrees with those comments that would grant exclusivity for

any change to an approved drug product or accept, without question, an

applicant's claim that it is entitled to exclusivity. Under the statute

and this final rule, certain drugs or changes to drugs can receive 3

years of exclusivity if the application or supplement to an application

``contains reports of new clinical investigations (other than

bioavailability studies) essential to the approval * * *'' (see section

505(j)(4)(D)(iii) and (j)(4)(D)(iv) of the act). The phrase ``essential

to the approval'' suggests that the clinical investigations that

warrant exclusivity must be vital to the application or supplement. As

stated in the preamble to the proposed rule, ``to qualify for

exclusivity, there must not be published reports of studies other than

those conducted or sponsored by the applicant, or other information

available to the agency sufficient for FDA to conclude that a proposed

drug product or change to an already approved drug product is safe and

effective'' (see 54 FR 28872 at 28900). For example, the agency would

not consider studies to support a switch from prescription to over-the-

counter (OTC) status to be ``essential to approval'' if the agency

already had sufficient information to conclude that the OTC product

would be safe and effective. (In OTC switch situations, FDA encourages

applicants to consult FDA to determine whether clinical investigations

or any other actions are necessary to permit FDA to approve a switch in

a product's status.)

FDA declines to define in the regulation the kinds of supplemental

applications that, if supported by clinical investigations, would

warrant 3-year exclusivity. Although the preamble to the proposed rule

identified certain types of changes in a product that would normally

warrant exclusivity (changes in active ingredient, strength, dosage

form, route of administration, or conditions of use), the agency did

not intend to suggest that other types of changes would not qualify.

For example, changes in dosing regimen have resulted in grants of 3-

year exclusivity. Changes that would not warrant exclusivity are, as

discussed in the preamble to the proposed rule, changes in labeling

that involve warnings or other similar risk information that must be

included in the labeling of generic competitors. Applicants obtaining

approval for such changes in labeling would, in any event, have no

valid interest in precluding such information from the labeling of

other products. Furthermore, FDA does not consider a study to be

``essential to approval'' simply because the applicant conducted it and

submitted the study for agency review (Ref. 1).

FDA's interpretation is supported by statements that were made

during the congressional debates surrounding the 3-year exclusivity

provisions. Senator Orrin Hatch described the 3-year exclusivity

provisions upon approval of certain supplemental applications as

protecting ``some changes in strength, indications, and so forth, which

require considerable time and expense in FDA required clinical

testing'' (130 Congressional Record S10505, August 10, 1984) (statement

of Senator Hatch)). Representative Henry Waxman said 3-year exclusivity

was intended to ``encourage drugmakers to obtain FDA approval for

significant therapeutic uses of previously approved drugs'' (130

Congressional Record H9114, (September 6, 1984)). Thus, an applicant is

not entitled to 3-year exclusivity merely because it supplements an

approved application based in part on a clinical investigation or

because it certifies to FDA that the clinical investigation is

essential to approval of the application or supplement.

FDA also declines to create a new procedure whereby a party could

contact FDA to determine whether exclusivity information is accurate.

Interested parties can obtain information on exclusivity decisions

through the Freedom of Information Act process (21 CFR part 20).

Parties who wish to challenge an exclusivity decision can utilize the

citizen petition procedures (21 CFR 10.30).

96. One comment suggested that products whose labeling may not

include certain therapeutic indications (due to exclusivity or patent

protection) be listed in the Orange Book as not being therapeutically

equivalent to the innovator product.

FDA addressed this comment in its response to a citizen petition

submitted by the Pharmaceutical Manufacturers Association (PMA). The

response stated, in pertinent part:

In drafting the 1984 Amendments, the only mechanism that

Congress provided for enforcing the exclusivity accorded a new

indication is the requirement that ANDA's and 505(b)(2) applications

be given delayed effective approval for the exclusive indication.

During the period that ANDA's and 505(b)(2) applications may not be

made effective, pioneers thus have the exclusive right to promote

and label their products for the exclusive indication. Nothing in

the language of the amended statute or its legislative history,

however, suggests that Congress intended the granting of exclusivity

for a new indication to alter therapeutic equivalence ratings.

Moreover, it would be inconsistent with the established standards

for making therapeutic equivalence determinations to rate two

products as not therapeutically equivalent simply because one is

labeled with fewer than all the approved indications.

FDA's standards for therapeutic equivalence determinations * * *

have always been based upon scientific considerations relevant to

predicting the comparative pharmacological behavior of two products

in or on the human body. There is no scientific basis for concluding

that differences in recommended indications are relevant to this

prediction. For example, the fact that a particular brand of drug is

recommended in a medical journal article for an unlabeled use, does

not, from a scientific standpoint, render other brands of the same

drug therapeutically or biologically inequivalent. Similarly, the

fact that a pioneer drug is labeled with a protected indication does

not mean that generic copies of the same drug are not

therapeutically equivalent to the pioneer.

In absence of any suggestion in the statute or legislative

history that Congress intended FDA to alter the scientific basis of

therapeutic equivalence ratings to enforce exclusivity, FDA declines

to consider non-scientific criteria, i.e., the existence of

exclusive indications, in making therapeutic equivalence decisions.

(Ref. 2)

FDA has not changed this position and, therefore, declines to adopt the

comment.

97. Many comments objected to the definition of ``active moiety''

and the references to active moieties and new chemical entities

throughout proposed Sec. 314.108. The comments said the definitions

lacked statutory support and were contrary to two court decisions,

Abbott Laboratories v. Young, 691 F.Supp. 462 (D. D.C. 1988), remanded,

920 F.2d 984 (D.C. Cir. 1990), and Glaxo Operations UK Ltd. v. Quigg,

706 F.Supp. 1224 (E.D. Va. 1989), aff'd, 894 F.2d 392 (Fed. Cir. 1990).

Two comments added that the definition of ``active moiety'' was also

too restrictive because it excluded chelates, clathrates, and other

noncovalent derivatives. The comments, in general, would delete all

references to ``active moiety'' and ``new chemical entity'' and refer

only to ``active ingredients.'' Some comments would also define

``active ingredient'' as the active ingredient found in the finished

dosage form before the drug is administered to the patient.

Subsequent to the close of the comment period, the interpretation

of the act urged by the comments and adopted by the district court in

Abbott Laboratories v. Young (providing 10 years of exclusivity under

section 505(j)(4)(D)(i) of the act for products offering the same

therapeutic moiety in different active ingredient forms if the salt or

ester form was approved subsequent to the pure therapeutic moiety form)

was rejected by the United States Court of Appeals for the District of

Columbia. Noting that such an interpretation would award exclusivity to

both an active moiety and a salt if the application containing the

active moiety were submitted first, but would award exclusivity only to

the salt if the salt were submitted first, the court of appeals

rejected the interpretation as ``farfetched because it is not

consistent with any legislative goal'' (see Abbott Laboratories v.

Young, 920 F.2d 984, 989).

Although the court of appeals appeared to agree with the agency's

conclusion that exclusivity should be limited to the first approved

product containing the active moiety, the court found the agency's

parsing of the operative statutory phrase ``active ingredient

(including any salt or ester of the active ingredient)'' to be

linguistically impermissible as set forth in the agency's

administrative decision denying 10-year exclusivity to Abbott. Rather

than interpret the term ``active ingredient'' broadly to include the

concept of active moiety, the agency interpreted the term narrowly to

refer to the form of the moiety in the product, but interpreted the

parenthetical phrase ``(including any salt or ester of the active

ingredient)'' broadly to include all active ingredients that are

different but contain the same active moiety. Although the court noted

that the agency had, subsequent to the administrative decision, voiced

the more linguistically permissible construction (interpreting the term

``active ingredient'' to refer to active moiety), the court found that

it could not consider this construction because it was not relied upon

in the administrative decision. The court thus remanded the case to the

district court with instructions to remand the issue to the agency for

further consideration.

The agency has concluded that the term ``active ingredient,'' as

used in the phrase ``active ingredient (including any salt or ester of

the active ingredient),'' means active moiety. Thus, the agency

declines to adopt the comments suggesting removal of the definition of,

and references to, ``active moiety'' from Sec. 314.108.

FDA disagrees with the assertion that the definition of ``active

moiety'' should not exclude chelates, clathrates, and other noncovalent

derivatives. As stated in the preamble to the proposed rule,

exclusivity is intended to provide incentives for innovation (see 54 FR

28872 at 28898 and 28899). The addition of a chelate, clathrate, or

other noncovalent derivative generally does not affect the active

moiety of a drug product. The agency, therefore, does not believe that

providing exclusivity for chelates, clathrates, and other noncovalent

derivatives of a previously approved active moiety would be consistent

with the statutory intent.

98. FDA received a number of comments regarding the term

``substantial support'' in the definition of ``conducted or sponsored

by the applicant'' in proposed Sec. 314.108(a). The proposed rule

stated, ``Ordinarily, substantial support will mean providing 50

percent or more of the cost of conducting the study'' (see 54 FR 28872

at 28930). The comments said the 50 percent figure was unrealistic,

unnecessary, or unauthorized by law and argued that cost should not be

a controlling factor in determining new drug exclusivity. Other

comments said the rule should permit firms to buy studies because there

is no basis to grant exclusivity to a firm that purchases an NDA and to

deny exclusivity to a firm that purchases a study. One comment asked

how FDA would treat a publicly funded study.

The 50-percent contribution requirement reflects a reasonable

interpretation of section 505 (j)(4)(D)(iii) and (j)(4)(D)(iv) of the

act. A study can be conducted by or for only one applicant. Exclusivity

based on less than 50-percent funding would allow multiple parties to

claim exclusivity against ANDA applicants as well as each other.

Moreover, the legislative history indicates that Congress created 3-

year exclusivity to protect products whose development required a

significant time commitment and ``an investment of some magnitude''

(see 130 Congressional Record S10504 (August 10, 1984) (statement of

Senator Hatch); 130 Congressional Record H9124-H9125 (September 6,

1984) (statement of Representative Waxman)). Obviously, if a sponsor

provided 50 percent or more funding to a study, its investment

represents a substantial portion of the study's funding.

FDA acknowledges that there may be some rare circumstance in which

less than 50-percent funding could constitute ``substantial support''

and merit exclusivity. FDA has, therefore, revised the rule to require:

(1) A certified statement from a Certified Public Accountant that the

applicant provided 50 percent or more of the cost of conducting the

study; or (2) an explanation from the applicant why FDA should consider

the applicant to have conducted or sponsored the study if the

applicant's financial contribution to the study is less than 50 percent

if the applicant did not sponsor the investigational new drug

application. The agency has made a corresponding change to

Sec. 314.50(j)(4)(iii).

With regard to studies that the applicant has purchased and

publicly funded studies, FDA agrees that an applicant who has purchased

exclusive rights to a study should be able to obtain new drug

exclusivity. FDA, therefore, has revised the definition of ``conducted

or sponsored by the applicant'' to state that the purchase of

nonexclusive rights to an investigation does not satisfy the

definition. FDA emphasizes that the applicant must have exclusive

rights to the purchased study in order to be deemed to have sponsored a

study. The purchase of nonexclusive rights by different parties could

result in multiple claims of exclusivity for the same study. For these

reasons, FDA also believes that most, if not all, publicly funded

studies will not qualify for exclusivity. These studies are usually

publicly available, so FDA will not give one applicant exclusive rights

based on a study that, by virtue of its funding, belongs to the general

public and is publicly available.

99. The agency, on its own initiative, has amended the definition

of ``date of approval'' to note that the date of approval ``refers only

to a final approval and not to a tentative approval that may become

effective at a later date.'' This change reflects FDA's position that

drug products with delayed effective dates of approval are not listed

drugs and that an ``approval with a delayed effective date is tentative

and does not become final until the effective date'' (see 57 FR 17950

at 17953).

100. One comment said proposed Sec. 314.108(a) failed to correspond

to proposed Sec. 314.50(j)(4)(i), which states that Sec. 314.108(a)

defines ``new'' and ``clinical investigations.'' Proposed

Sec. 314.50(j)(4)(i) contained an error. The proposed rule does not

contain separate definitions for ``new'' and ``clinical

investigations''; it does, however, define ``new clinical

investigations'' at Sec. 314.108(a). FDA has corrected

Sec. 314.50(j)(4)(i) accordingly.

101. One comment objected to the last sentence in the definition of

``new clinical investigation.'' The comment claimed that the definition

would ``unnecessarily, and contrary to the Statute, ``expand and award

an exclusivity for a previously submitted study; and it unjustifiably

distinguishes between safety and effectiveness.''

Under the statute, 3-year exclusivity is awarded if the application

or supplemental application contained reports of new clinical

investigations that were conducted or sponsored by the applicant and

were essential to the approval of the application or supplemental

application (see section 505(j)(4)(D)(iii) and (j)(4)(D)(iv) of the

act). The legislative history indicates that 3-year exclusivity is for

investigations requiring a considerable investment of time and money

and that are necessary for approval of important innovations (see 54 FR

28872 at 28899). Thus, FDA interprets ``new clinical investigation'' as

a clinical investigation whose data have not been relied upon by FDA to

demonstrate substantial evidence of effectiveness of a previously

approved drug for any indication or safety in a new patient population

and do not duplicate the results of another investigation relied upon

by FDA to demonstrate a previously approved drug's effectiveness or

safety in a new patient population. An applicant is not limited to

recently conducted clinical investigations; a clinical investigation

that provides a ``new'' basis for drug approval can qualify for

exclusivity.

102. Two comments recommended revising the rule to address

transfers of new drug exclusivity between an applicant and all

predecessors in interest, including licensors, assignors, joint venture

p

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