[Federal Register Volume 59, Number 190 (Monday, October 3, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-24052]
[[Page Unknown]]
[Federal Register: October 3, 1994]
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Part II
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
21 CFR Part 314
Abbreviated New Drug Application Regulations; Patent and Exclusivity
Provisions; Final Rule
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 314
[Docket No. 85N-0214]
RIN 0905-AB63
Abbreviated New Drug Application Regulations; Patent and
Exclusivity Provisions
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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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
partners, or other parties.
New drug exclusivity is not a property right, but is rather a
statutory obligation on the agency. This statutory obligation is based
on data and information in an approved application. Although an
applicant may purchase an application or rights to data and information
in an application (i.e., exclusive rights to a new clinical
investigation), from which exclusivity would flow, there is no property
right to exclusivity itself that can be transferred separately and
apart from the application or data upon which exclusivity is based. The
agency does, however, permit the submission or approval of an ANDA when
the holder of the exclusivity permits FDA to receive or approve the
ANDA.
FDA notes that joint venture partners differ from licensees,
assignors, etc., because joint venture partners share in developing a
drug product. Consequently, FDA suggests that joint venture partners
carefully consider how they will seek approval of an application and
define their rights and interests in the application to avoid questions
regarding applicability of the exclusivity provisions of the act.
As stated above, FDA has revised the definition of the phrase,
``conducted or sponsored by the applicant,'' to construe a party who
has purchased exclusive rights to a study to have ``conducted or
sponsored'' the study. This change will enable a party who has acquired
exclusive rights to a study to seek exclusivity.
103. Four comments asked FDA to create a mechanism that would
determine whether a study was ``essential for approval'' either before
an application would be submitted or before the study began. Proposed
Sec. 314.108(a) stated that ``essential to approval'' with regard to an
investigation ``means that the application could not be approved by FDA
without that investigation, even with a delayed effective date.'' The
proposal, however, did not discuss the procedure by which FDA would
determine a study to be ``essential to approval.''
FDA declines to accept the comments. FDA cannot determine whether a
study is essential for approval until the application is approved.
Research goals and objectives often change during clinical
investigations. For example, the results from a study designed to
support a new indication could generate interest in a completely
different indication. The product ultimately approved may be a
different product from that characterized in the original application.
It is also possible that newly available data in the public domain will
obviate the need for the study prior to approval. Thus, FDA will decide
whether a study is essential for approval at the time of approval.
The agency has, however, amended the definition of ``essential to
approval'' to delete the reference to a delayed effective date. This
change is necessary because the agency no longer regards an application
with a delayed effective date as being approved. Instead, FDA considers
such applications as being tentatively approved (see 57 FR 17950 at
17953).
104. Proposed Sec. 314.108(b)(2) would provide 5 years of
exclusivity for a new chemical entity if a drug product containing the
new chemical entity was approved after September 24, 1984, in an
application submitted under section 505(b) of the act. One comment said
FDA should deny 5-year exclusivity to any section ``505(b)(2)
application for a new chemical entity that relies upon one or more
investigations that are essential for approval of the application but
which were not conducted or sponsored by the applicant * * *.'' The
comment explained that a 505(b)(2) applicant could assemble literature
demonstrating the safety and effectiveness of a drug product marketed
before 1962 (when the Federal Food, Drug, and Cosmetic Act was amended
to require new drugs to be safe and effective for their intended uses)
or 1938 (when the Food and Drugs Act was amended to require new drugs
to be safe for the conditions of their intended use) and, under the
rule, seek 5 years of new drug exclusivity. The comment said granting
exclusivity to such drugs would be inconsistent with statutory intent
and the legislative history.
Under the statute, a drug product may qualify for 5 years of
exclusivity if its active moiety has not been previously approved in
any other application (see section 505(c)(3)(D)(ii) and (j)(4)(D)(ii)
of the act). For some drug products marketed before 1938 or 1962, the
active moiety will have been the subject of an approved application
(under prior versions of the act or as part of a combination product
approved under the act), so the active moiety will be ineligible for 5-
year exclusivity.
FDA also notes that the statute provides 5-year exclusivity for
applications approved under section 505(b) of the act and that such
applications are submitted by persons who wish to introduce or deliver
for introduction into interstate commerce ``any new drug.'' (See
section 505(a) and (c)(3)(D)(ii).) The term ``new drug'' is defined in
section 201(p) of the act (21 U.S.C. 321(p)). Drug products with active
ingredients marketed before 1938 or 1962 may be ``new drugs,''
especially where there has been a change in the product's labeling,
composition, or manufacturer.
Products falling within the definition of a ``new drug'' must be
approved under section 505(b) of the act and, as a result, may qualify
for 5-year exclusivity under the language of the act and consistent
with legislative history.
105. One comment said that FDA should provide 5 years of
exclusivity for a single enantiomer of a previously approved racemate.
The comment asserted that FDA approval of a racemic drug mixture covers
the mixture rather than the enantiomers that compose the mixture.
The agency declines to revise the rule as requested by the comment.
As stated in the preamble to the proposed rule, the agency's position
is that ``a single enantiomer of a previously approved racemate
contains a previously approved active moiety and is therefore not
considered a new chemical entity'' (see 54 FR 28872 at 28898).
106. One comment asked FDA to interpret the phrase ``conditions of
approval'' in proposed Sec. 314.108(b)(4)(iv) narrowly to limit
exclusivity to studies conducted by the original applicant. Proposed
Sec. 314.108(b)(4) stated that if an application: (i) Was submitted
under section 505(b) of the act; (ii) was approved after September 24,
1984; (iii) was for a drug product that contains an active moiety that
has been previously approved in another application under section
505(b) of the act; and (iv) contained reports of new clinical
investigations (other than bioavailability studies) conducted or
sponsored by the applicant that were essential to approval of the
application, the agency will not make effective for a period of 3 years
after the date of approval of the application the approval of a
505(b)(2) application, or an ANDA for the conditions of approval of the
original application, or an ANDA submitted pursuant to an approved
petition under section 505(j)(2)(C) of the act that relies on the
information supporting the conditions of approval of an original NDA.
The comment said subsequent applicants who conduct their own studies to
obtain approval should not be subject to the original applicant's
exclusivity.
FDA believes that the comment misinterprets the scope of
exclusivity. As stated in the preamble to the proposed rule and the
preamble to this final rule, market exclusivity does 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 (see 54 FR 28872 at 28896). As
discussed earlier, the statute does not require that the original
applicant ``conduct'' the study to obtain exclusivity. FDA interprets
the act to allow for exclusivity where the applicant has supported the
study by providing more than 50 percent of the funding or by purchasing
exclusive rights to the study.
IV. Analysis of Impacts
FDA has examined the impacts of this rule under Executive Order
12866 and the Regulatory Flexibility Act (Pub. L. 96-354). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes that
this final rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. In addition, the final
rule is not a significant regulatory action as defined by the Executive
Order and so is not subject to review under the Executive Order.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact on small
entities. Title I of Pub. L. 98-417 eliminated unnecessary regulatory
barriers for generic drug products and has resulted in generic
competition on many important post-1962 drugs. Generic drug sales
account for a significant portion of total prescription drug sales, and
many of these sales would not have occurred in the absence of Pub. L.
98-417. This competition has saved consumers hundreds of millions of
dollars per year, and FDA concludes that this impact is directly
attributable to the statute. This rule will not affect the pace or
magnitude of this economic impact. The rule simply clarifies and
facilitates implementation of the act. Thus, FDA certifies that this
rule will not have a significant economic impact on a substantial
number of small entities. Therefore, under the Regulatory Flexibility
Act, no further analysis is required.
V. Environmental Impact
The agency has determined under 21 CFR 25.24(a)(8) that this action
is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.
VI. Paperwork Reduction Act of 1980
This final rule contains information collections which have been
submitted for approval to the Office of Management and Budget under the
Paperwork Reduction Act of 1980. The title, description, and respondent
description of the information collection are shown below with an
estimate of the annual reporting and recordkeeping burden. Included in
the estimate is the time for reviewing instructions, searching existing
data sources, gathering and maintaining the data needed, and completing
and reviewing the collection of information.
Title: Abbreviated New Drug Application Regulations; Patent and
Exclusivity Provisions.
Description: The information requirements collect information from
persons who must obtain FDA approval before marketing new human drug
products or generic versions of previously approved drug products.
These persons must submit information to FDA in the form of
applications, notices, and certifications. FDA will use this
information to determine whether patent information for a drug product
has been submitted and whether an applicant is seeking market
exclusivity for a particular drug product.
Description of Respondents: Businesses.
Estimated Annual Reporting and Recordkeeping Burden
----------------------------------------------------------------------------------------------------------------
No. of
Section No. of responses per Total annual Hours per Total hours
respondents respondent responses response
----------------------------------------------------------------------------------------------------------------
314.50(i)....................... 8 1 8 2 16
314.50(j)....................... 50 1 50 2 100
314.52.......................... 30 1 30 8 240
314.53.......................... 200 1 200 1 200
314.94(a)(12)................... 215 1 215 2 430
314.95.......................... 30 1 30 16 480
314.107......................... 10 1 10 10 10
---------------
Total....................... .............. .............. .............. .............. 1,476
----------------------------------------------------------------------------------------------------------------
There were no comments received on the Paperwork Reduction Act
clearance submission or on the burden estimates. The agency has,
however, revised the estimate for ANDA's under Sec. 314.94 based on its
latest figures for the number of ANDA's received.
VII. References
The following references have been placed on display in the Dockets
Management Branch (HFA-305), Food and Drug Administration, rm. 1-23,
12420 Parklawn Dr., Rockville, MD 20857, and may be seen by interested
persons between 9 a.m. and 4 p.m., Monday through Friday.
1. Letter dated September 28, 1992, from Jane E. Henney, Deputy
Commissioner for Operations, to Alan H. Kaplan and Richard S. Morey,
Kleinfeld, Kaplan and Becker (FDA Docket No. 90P-0455).
2. Letter dated December 8, 1987, from John M. Taylor, Associate
Commissioner for Regulatory Affairs, to Bruce J. Brennan, Senior
Vice President and General Counsel (FDA Docket No. 86P-0235/CP).
List of Subjects in 21 CFR Part 314
Administrative practice and procedure, Confidential business
information, Drugs, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
314 is amended as follows:
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN
ANTIBIOTIC DRUG
1. The authority citation for 21 CFR part 314 continues to read as
follows:
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701,
704, 721 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321,
331, 351, 352, 353, 355, 356, 357, 371, 374, 379e).
2. Section 314.50 is amended by redesignating existing paragraph
(h) as paragraph (k) and by adding new paragraphs (h), (i), and (j) to
read as follows:
Sec. 314.50 Content and format of an application.
* * * * *
(h) Patent information. The application is required to contain the
patent information described under Sec. 314.53.
(i) Patent certification--(1) Contents. A 505(b)(2) application is
required to contain the following:
(i) Patents claiming drug, drug product, or method of use. (A)
Except as provided in paragraph (i)(2) of this section, a certification
with respect to each patent issued by the United States Patent and
Trademark Office that, in the opinion of the applicant and to the best
of its knowledge, claims a drug (the drug product or drug substance
that is a component of the drug product) on which investigations that
are relied upon by the applicant for approval of its application were
conducted or that claims an approved use for such drug and for which
information is required to be filed under section 505 (b) and (c) of
the act and Sec. 314.53. For each such patent, the applicant shall
provide the patent number and certify, in its opinion and to the best
of its knowledge, one of the following circumstances:
(1) That the patent information has not been submitted to FDA. The
applicant shall entitle such a certification ``Paragraph I
Certification'';
(2) That the patent has expired. The applicant shall entitle such a
certification ``Paragraph II Certification'';
(3) The date on which the patent will expire. The applicant shall
entitle such a certification ``Paragraph III Certification''; or
(4) That the patent is invalid, unenforceable, or will not be
infringed by the manufacture, use, or sale of the drug product for
which the application is submitted. The applicant shall entitle such a
certification ``Paragraph IV Certification''. This certification shall
be submitted in the following form:
I, (name of applicant), certify that Patent No. ____________ (is
invalid, unenforceable, or will not be infringed by the manufacture,
use, or sale of) (name of proposed drug product) for which this
application is submitted.
The certification shall be accompanied by a statement that the
applicant will comply with the requirements under Sec. 314.52(a) with
respect to providing a notice to each owner of the patent or their
representatives and to the holder of the approved application for the
drug product which is claimed by the patent or a use of which is
claimed by the patent and with the requirements under Sec. 314.52(c)
with respect to the content of the notice.
(B) If the drug on which investigations that are relied upon by the
applicant were conducted is itself a licensed generic drug of a
patented drug first approved under section 505(b) of the act, the
appropriate patent certification under this section with respect to
each patent that claims the first-approved patented drug or that claims
an approved use for such a drug.
(ii) No relevant patents. If, in the opinion of the applicant and
to the best of its knowledge, there are no patents described in
paragraph (i)(1)(i) of this section, a certification in the following
form:
In the opinion and to the best knowledge of (name of applicant),
there are no patents that claim the drug or drugs on which
investigations that are relied upon in this application were
conducted or that claim a use of such drug or drugs.
(iii) Method of use patent. (A) If information that is submitted
under section 505 (b) or (c) of the act and Sec. 314.53 is for a method
of use patent, and the labeling for the drug product for which the
applicant is seeking approval does not include any indications that are
covered by the use patent, a statement explaining that the method of
use patent does not claim any of the proposed indications.
(B) If the labeling of the drug product for which the applicant is
seeking approval includes an indication that, according to the patent
information submitted under section 505 (b) or (c) of the act and
Sec. 314.53 or in the opinion of the applicant, is claimed by a use
patent, the applicant shall submit an applicable certification under
paragraph (i)(1)(i) of this section.
(2) Method of manufacturing patent. An applicant is not required to
make a certification with respect to any patent that claims only a
method of manufacturing the drug product for which the applicant is
seeking approval.
(3) Licensing agreements. If a 505(b)(2) application is for a drug
or method of using a drug claimed by a patent and the applicant has a
licensing agreement with the patent owner, the applicant shall submit a
certification under paragraph (i)(1)(i)(A)(4) of this section
(``Paragraph IV Certification'') as to that patent and a statement that
it has been granted a patent license. If the patent owner consents to
an immediate effective date upon approval of the 505(b)(2) application,
the application shall contain a written statement from the patent owner
that it has a licensing agreement with the applicant and that it
consents to an immediate effective date.
(4) Late submission of patent information. If a patent described in
paragraph (i)(1)(i)(A) of this section is issued and the holder of the
approved application for the patented drug does not submit the required
information on the patent within 30 days of issuance of the patent, an
applicant who submitted a 505(b)(2) application that, before the
submission of the patent information, contained an appropriate patent
certification is not required to submit an amended certification. An
applicant whose 505(b)(2) application is filed after a late submission
of patent information or whose 505(b)(2) application was previously
filed but did not contain an appropriate patent certification at the
time of the patent submission shall submit a certification under
paragraph (i)(1)(i) or (i)(1)(ii) of this section or a statement under
paragraph (i)(1)(iii) of this section as to that patent.
(5) Disputed patent information. If an applicant disputes the
accuracy or relevance of patent information submitted to FDA, the
applicant may seek a confirmation of the correctness of the patent
information in accordance with the procedures under Sec. 314.53(f).
Unless the patent information is withdrawn or changed, the applicant
must submit an appropriate certification for each relevant patent.
(6) Amended certifications. A certification submitted under
paragraphs (i)(1)(i) through (i)(1)(iii) of this section may be amended
at any time before the effective date of the approval of the
application. An applicant shall submit an amended certification as an
amendment to a pending application or by letter to an approved
application. If an applicant with a pending application voluntarily
makes a patent certification for an untimely filed patent, the
applicant may withdraw the patent certification for the untimely filed
patent. Once an amendment or letter for the change in certification has
been submitted, the application will no longer be considered to be one
containing the prior certification.
(i) After finding of infringement. An applicant who has submitted a
certification under paragraph (i)(1)(i)(A)(4) of this section and is
sued for patent infringement within 45 days of the receipt of notice
sent under Sec. 314.52 shall amend the certification if a final
judgment in the action is entered finding the patent to be infringed
unless the final judgment also finds the patent to be invalid. In the
amended certification, the applicant shall certify under paragraph
(i)(1)(i)(A)(3) of this section that the patent will expire on a
specific date.
(ii) After removal of a patent from the list. If a patent is
removed from the list, any applicant with a pending application
(including a tentatively approved application with a delayed effective
date) who has made a certification with respect to such patent shall
amend its certification. The applicant shall certify under paragraph
(i)(1)(ii) of this section that no patents described in paragraph
(i)(1)(i) of this section claim the drug or, if other relevant patents
claim the drug, shall amend the certification to refer only to those
relevant patents. In the amendment, the applicant shall state the
reason for the change in certification (that the patent is or has been
removed from the list). A patent that is the subject of a lawsuit under
Sec. 314.107(c) shall not be removed from the list until FDA determines
either that no delay in effective dates of approval is required under
that section as a result of the lawsuit, that the patent has expired,
or that any such period of delay in effective dates of approval is
ended. An applicant shall submit an amended certification as an
amendment to a pending application. Once an amendment for the change
has been submitted, the application will no longer be considered to be
one containing a certification under paragraph (i)(1)(i)(A)(4) of this
section.
(iii) Other amendments. (A) Except as provided in paragraphs (i)(4)
and (i)(6)(iii)(B) of this section, an applicant shall amend a
submitted certification if, at any time before the effective date of
the approval of the application, the applicant learns that the
submitted certification is no longer accurate.
(B) An applicant is not required to amend a submitted certification
when information on an otherwise applicable patent is submitted after
the effective date of approval for the 505(b)(2) application.
(j) Claimed exclusivity. A new drug product, upon approval, may be
entitled to a period of marketing exclusivity under the provisions of
Sec. 314.108. If an applicant believes its drug product is entitled to
a period of exclusivity, it shall submit with the new drug application
prior to approval the following information:
(1) A statement that the applicant is claiming exclusivity.
(2) A reference to the appropriate paragraph under Sec. 314.108
that supports its claim.
(3) If the applicant claims exclusivity under Sec. 314.108(b)(2),
information to show that, to the best of its knowledge or belief, a
drug has not previously been approved under section 505(b) of the act
containing any active moiety in the drug for which the applicant is
seeking approval.
(4) If the applicant claims exclusivity under Sec. 314.108(b)(4) or
(b)(5), the following information to show that the application contains
``new clinical investigations'' that are ``essential to approval of the
application or supplement'' and were ``conducted or sponsored by the
applicant:''
(i) ``New clinical investigations.'' A certification that to the
best of the applicant's knowledge each of the clinical investigations
included in the application meets the definition of ``new clinical
investigation'' set forth in Sec. 314.108(a).
(ii) ``Essential to approval.'' 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.
(iii) ``Conducted or sponsored by.'' If the applicant was the
sponsor named in the Form FDA-1571 for an investigational new drug
application (IND) under which the new clinical investigation(s) that is
essential to the approval of its application was conducted,
identification of the IND by number. If the applicant was not the
sponsor of the IND under which the clinical investigation(s) was
conducted, a certification that the applicant or its predecessor in
interest provided substantial support for the clinical investigation(s)
that is essential to the approval of its application, and information
supporting the certification. To demonstrate ``substantial support,''
an applicant must either provide a certified statement from a certified
public accountant that the applicant provided 50 percent or more of the
cost of conducting the study or provide an explanation of 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 or the applicant did not sponsor the investigational new drug.
A predecessor in interest is an entity, e.g., a corporation, that the
applicant has taken over, merged with, or purchased, or from which the
applicant has purchased all rights to the drug. Purchase of
nonexclusive rights to a clinical investigation after it is completed
is not sufficient to satisfy this definition.
* * * * *
3. New sections 314.52 and 314.53 are added to subpart B to read as
follows:
Sec. 314.52 Notice of certification of invalidity or noninfringement
of a patent.
(a) Notice of certification. For each patent which claims the drug
or drugs on which investigations that are relied upon by the applicant
for approval of its application were conducted or which claims a use
for such drug or drugs and which the applicant certifies under
Sec. 314.50(i)(1)(i)(A)(4) that a patent is invalid, unenforceable, or
will not be infringed, the applicant shall send notice of such
certification by registered or certified mail, return receipt requested
to each of the following persons:
(1) Each owner of the patent that is the subject of the
certification or the representative designated by the owner to receive
the notice. The name and address of the patent owner or its
representative may be obtained from the United States Patent and
Trademark Office; and
(2) The holder of the approved application under section 505(b) of
the act for each drug product which is claimed by the patent or a use
of which is claimed by the patent and for which the applicant is
seeking approval, or, if the application holder does not reside or
maintain a place of business within the United States, the application
holder's attorney, agent, or other authorized official. The name and
address of the application holder or its attorney, agent, or authorized
official may be obtained from the Division of Drug Information
Resources (HFD-80), Center for Drug Evaluation and Research, Food and
Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.
(3) This paragraph does not apply to a use patent that claims no
uses for which the applicant is seeking approval.
(b) Sending the notice. The applicant shall send the notice
required by paragraph (a) of this section when it receives from FDA an
acknowledgment letter stating that its application has been filed. At
the same time, the applicant shall amend its application to include a
statement certifying that the notice has been provided to each person
identified under paragraph (a) of this section and that the notice met
the content requirement under paragraph (c) of this section.
(c) Content of a notice. In the notice, the applicant shall cite
section 505(b)(3)(B) of the act and shall include, but not be limited
to, the following information:
(1) A statement that a 505(b)(2) application submitted by the
applicant has been filed by FDA.
(2) The application number.
(3) The established name, if any, as defined in section 502(e)(3)
of the act, of the proposed drug product.
(4) The active ingredient, strength, and dosage form of the
proposed drug product.
(5) The patent number and expiration date, as submitted to the
agency or as known to the applicant, of each patent alleged to be
invalid, unenforceable, or not infringed.
(6) A detailed statement of the factual and legal basis of the
applicant's opinion that the patent is not valid, unenforceable, or
will not be infringed. The applicant shall include in the detailed
statement:
(i) For each claim of a patent alleged not to be infringed, a full
and detailed explanation of why the claim is not infringed.
(ii) For each claim of a patent alleged to be invalid or
unenforceable, a full and detailed explanation of the grounds
supporting the allegation.
(7) If the applicant does not reside or have a place of business in
the United States, the name and address of an agent in the United
States authorized to accept service of process for the applicant.
(d) Amendment to an application. If an application is amended to
include the certification described in Sec. 314.50(i), the applicant
shall send the notice required by paragraph (a) of this section at the
same time that the amendment to the application is submitted to FDA.
(e) Documentation of receipt of notice. The applicant shall amend
its application to document receipt of the notice required under
paragraph (a) of this section by each person provided the notice. The
applicant shall include a copy of the return receipt or other similar
evidence of the date the notification was received. FDA will accept as
adequate documentation of the date of receipt a return receipt or a
letter acknowledging receipt by the person provided the notice. An
applicant may rely on another form of documentation only if FDA has
agreed to such documentation in advance. A copy of the notice itself
need not be submitted to the agency.
(f) Approval. If the requirements of this section are met, the
agency will presume the notice to be complete and sufficient, and it
will count the day following the date of receipt of the notice by the
patent owner or its representative and by the approved application
holder as the first day of the 45-day period provided for in section
505(c)(3)(C) of the act. FDA may, if the applicant amends its
application with a written statement that a later date should be used,
count from such later date.
Sec. 314.53 Submission of patent information.
(a) Who must submit patent information. This section applies to any
applicant who submits to FDA a new drug application or an amendment to
it under section 505(b) of the act and Sec. 314.50 or a supplement to
an approved application under Sec. 314.70, except as provided in
paragraph (d)(2) of this section.
(b) Patents for which information must be submitted. An applicant
described in paragraph (a) of this section shall submit information on
each patent that claims the drug or a method of using the drug that is
the subject of the new drug application or amendment or supplement to
it and with respect to which a claim of patent infringement could
reasonably be asserted if a person not licensed by the owner of the
patent engaged in the manufacture, use, or sale of the drug product.
For purposes of this part, such patents consist of drug substance
(ingredient) patents, drug product (formulation and composition)
patents, and method of use patents. Process patents are not covered by
this section and information on process patents may not be submitted to
FDA. For patents that claim a drug substance or drug product, the
applicant shall submit information only on those patents that claim a
drug product that is the subject of a pending or approved application,
or that claim a drug substance that is a component of such a product.
For patents that claim a method of use, the applicant shall submit
information only on those patents that claim indications or other
conditions of use of a pending or approved application.
(c) Reporting requirements--(1) General requirements. An applicant
described in paragraph (a) of this section shall submit the following
information for each patent described in paragraph (b) of this section:
(i) Patent number and the date on which the patent will expire.
(ii) Type of patent, i.e., drug, drug product, or method of use.
(iii) Name of the patent owner.
(iv) If the patent owner or applicant does not reside or have a
place of business within the United States, the name of an agent
(representative) of the patent owner or applicant who resides or
maintains a place of business within the United States authorized to
receive notice of patent certification under section 505(b)(3) and
(j)(2)(B) of the act and Secs. 314.52 and 314.95.
(2) Formulation, composition, or method of use patents--(i)
Original declaration. For each formulation, composition, or method of
use patent, in addition to the patent information described in
paragraph (c)(1) of this section the applicant shall submit the
following declaration:
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):
----------------------------------------------------------------------
(ii) Amendment of patent information upon approval. Within 30 days
after the date of approval of its application, if the application
contained a declaration required under paragraph (c)(2)(i) of this
section, the applicant shall by letter amend the declaration to
identify each patent that claims the formulation, composition, or the
specific indications or other conditions of use that have been
approved.
(3) No relevant patents. If the applicant believes that there are
no patents which claim the drug or the drug product or which claim a
method of using the drug product 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, it shall so declare.
(4) Authorized signature. The declarations required by this section
shall be signed by the applicant or patent owner, or the applicant's or
patent owner's attorney, agent (representative), or other authorized
official.
(d) When and where to submit patent information--(1) Original
application. An applicant shall submit with its original application
submitted under this part, including an application described in
section 505(b)(2) of the act, the information described in paragraph
(c) of this section on each drug (ingredient), drug product
(formulation and composition), and method of use patent issued before
the application is filed with FDA and for which patent information is
required to be submitted under this section. If a patent is issued
after the application is filed with FDA but before the application is
approved, the applicant shall, within 30 days of the date of issuance
of the patent, submit the required patent information in an amendment
to the application under Sec. 314.60.
(2) Supplements. (i) An applicant shall submit patent information
required under paragraph (c) of this section for a patent that claims
the drug, drug product, or method of use for which approval is sought
in any of the following supplements:
(A) To change the formulation;
(B) To add a new indication or other condition of use, including a
change in route of administration;
(C) To change the strength;
(D) To make any other patented change regarding the drug, drug
product, or any method of use.
(ii) If the applicant submits a supplement for one of the changes
listed under paragraph (d)(2)(i) of this section and existing patents
for which information has already been submitted to FDA claim the
changed product, the applicant shall submit a certification with the
supplement identifying the patents that claim the changed product.
(iii) If the applicant submits a supplement for one of the changes
listed under paragraph (d)(2)(i) of this section and no patents,
including previously submitted patents, claim the changed product, it
shall so certify.
(iv) The applicant shall comply with the requirements for amendment
of formulation or composition and method of use patent information
under paragraphs (c)(2)(ii) and (d)(3) of this section.
(3) Patent information deadline. If a patent is issued for a drug,
drug product, or method of use after an application is approved, the
applicant shall submit to FDA the required patent information within 30
days of the date of issuance of the patent.
(4) Copies. The applicant shall submit two copies of each
submission of patent information, an archival copy and a copy for the
chemistry, manufacturing, and controls section of the review copy, to
the Central Document Room, Center for Drug Evaluation and Research,
Food and Drug Administration, Park Bldg., rm. 2-14, 12420 Parklawn Dr.,
Rockville, MD 20857. The applicant shall submit the patent information
by letter separate from, but at the same time as, submission of the
supplement.
(5) Submission date. Patent information shall be considered to be
submitted to FDA as of the date the information is received by the
Central Document Room.
(6) Identification. Each submission of patent information, except
information submitted with an original application, and its mailing
cover shall bear prominent identification as to its contents, i.e.,
``Patent Information,'' or, if submitted after approval of an
application, ``Time Sensitive Patent Information.''
(e) Public disclosure of patent information. FDA will publish in
the list the patent number and expiration date of each patent that is
required to be, and is, submitted to FDA by an applicant, and for each
use patent, the approved indications or other conditions of use covered
by a patent. FDA will publish such patent information upon approval of
the application, or, if the patent information is submitted by the
applicant after approval of an application as provided under paragraph
(d)(2) of this section, as soon as possible after the submission to the
agency of the patent information. Patent information submitted by the
last working day of a month will be published in that month's
supplement to the list. Patent information received by the agency
between monthly publication of supplements to the list will be placed
on public display in FDA's Freedom of Information Staff. A request for
copies of the file shall be sent in writing to the Freedom of
Information Staff (HFI-35), Food and Drug Administration, rm. 12A-16,
5600 Fishers Lane, Rockville, MD 20857.
(f) Correction of patent information errors. If any person disputes
the accuracy or relevance of patent information submitted to the agency
under this section and published by FDA in the list, or believes that
an applicant has failed to submit required patent information, that
person must first notify the agency in writing stating the grounds for
disagreement. Such notification should be directed to the Drug
Information Services Branch (HFD-84), Center for Drug Evaluation and
Research, Food and Drug Administration, 5600 Fishers Lane, Rockville,
MD 20857. The agency will then request of the applicable new drug
application holder that the correctness of the patent information or
omission of patent information be confirmed. Unless the application
holder withdraws or amends its patent information in response to FDA's
request, the agency will not change the patent information in the list.
If the new drug application holder does not change the patent
information submitted to FDA, a 505(b)(2) application or an abbreviated
new drug application under section 505(j) of the act submitted for a
drug that is claimed by a patent for which information has been
submitted must, despite any disagreement as to the correctness of the
patent information, contain an appropriate certification for each
listed patent.
4. Section 314.54 is amended by adding new paragraph (a)(1)(vii) to
read as follows:
Sec. 314.54 Procedure for submission of an application requiring
investigations for approval of a new indication for, or other change
from, a listed drug.
(a) * * *
(1) * * *
(vii) If the applicant believes the change for which it is seeking
approval is entitled to a period of exclusivity, the information
required under Sec. 314.50(j).
* * * * *
5. Section 314.70 is amended by adding new paragraph (f) to read as
follows:
Sec. 314.70 Supplements and other changes to an approved application.
* * * * *
(f) Claimed exclusivity. If an applicant claims exclusivity under
Sec. 314.108 upon approval of a supplemental application for a change
to its previously approved drug product, the applicant shall include
with its supplemental application the information required under
Sec. 314.50(j).
6. Section 314.94 is amended by adding a new paragraph (a)(12) to
read as follows:
Sec. 314.94 Content and format of an abbreviated application.
(a) * * *
(12) Patent certification--(i) Patents claiming drug, drug product,
or method of use. (A) Except as provided in paragraph (a)(12)(iv) of
this section, a certification with respect to each patent issued by the
United States Patent and Trademark Office that, in the opinion of the
applicant and to the best of its knowledge, claims the reference listed
drug or that claims a use of such listed drug for which the applicant
is seeking approval under section 505(j) of the act and for which
information is required to be filed under section 505(b) and (c) of the
act and Sec. 314.53. For each such patent, the applicant shall provide
the patent number and certify, in its opinion and to the best of its
knowledge, one of the following circumstances:
(1) That the patent information has not been submitted to FDA. The
applicant shall entitle such a certification ``Paragraph I
Certification'';
(2) That the patent has expired. The applicant shall entitle such a
certification ``Paragraph II Certification'';
(3) The date on which the patent will expire. The applicant shall
entitle such a certification ``Paragraph III Certification''; or
(4) That the patent is invalid, unenforceable, or will not be
infringed by the manufacture, use, or sale of the drug product for
which the abbreviated application is submitted. The applicant shall
entitle such a certification ``Paragraph IV Certification''. This
certification shall be submitted in the following form:
I, (name of applicant), certify that Patent No. ____________ (is
invalid, unenforceable, or will not be infringed by the manufacture,
use, or sale of) (name of proposed drug product) for which this
application is submitted.
The certification shall be accompanied by a statement that the
applicant will comply with the requirements under Sec. 314.95(a) with
respect to providing a notice to each owner of the patent or their
representatives and to the holder of the approved application for the
listed drug, and with the requirements under Sec. 314.95(c) with
respect to the content of the notice.
(B) If the abbreviated new drug application refers to a listed drug
that is itself a licensed generic product of a patented drug first
approved under section 505(b) of the act, the appropriate patent
certification under paragraph (a)(12)(i) of this section with respect
to each patent that claims the first-approved patented drug or that
claims a use for such drug.
(ii) No relevant patents. If, in the opinion of the applicant and
to the best of its knowledge, there are no patents described in
paragraph (a)(12)(i) of this section, a certification in the following
form:
In the opinion and to the best knowledge of (name of applicant),
there are no patents that claim the listed drug referred to in this
application or that claim a use of the listed drug.
(iii) Method of use patent. (A) If patent information is submitted
under section 505(b) or (c) of the act and Sec. 314.53 for a patent
claiming a method of using the listed drug, and the labeling for the
drug product for which the applicant is seeking approval does not
include any indications that are covered by the use patent, a statement
explaining that the method of use patent does not claim any of the
proposed indications.
(B) If the labeling of the drug product for which the applicant is
seeking approval includes an indication that, according to the patent
information submitted under section 505(b) or (c) of the act and
Sec. 314.53 or in the opinion of the applicant, is claimed by a use
patent, an applicable certification under paragraph (a)(12)(i) of this
section.
(iv) Method of manufacturing patent. An applicant is not required
to make a certification with respect to any patent that claims only a
method of manufacturing the listed drug.
(v) Licensing agreements. If the abbreviated new drug application
is for a drug or method of using a drug claimed by a patent and the
applicant has a licensing agreement with the patent owner, a
certification under paragraph (a)(12)(i)(A)(4) of this section
(``Paragraph IV Certification'') as to that patent and a statement that
it has been granted a patent license.
(vi) Late submission of patent information. If a patent on the
listed drug is issued and the holder of the approved application for
the listed drug does not submit the required information on the patent
within 30 days of issuance of the patent, an applicant who submitted an
abbreviated new drug application for that drug that contained an
appropriate patent certification before the submission of the patent
information is not required to submit an amended certification. An
applicant whose abbreviated new drug application is submitted after a
late submission of patent information, or whose pending abbreviated
application was previously submitted but did not contain an appropriate
patent certification at the time of the patent submission, shall submit
a certification under paragraph (a)(12)(i) of this section or a
statement under paragraph (a)(12)(iii) of this section as to that
patent.
(vii) Disputed patent information. If an applicant disputes the
accuracy or relevance of patent information submitted to FDA, the
applicant may seek a confirmation of the correctness of the patent
information in accordance with the procedures under Sec. 314.53(f).
Unless the patent information is withdrawn or changed, the applicant
shall submit an appropriate certification for each relevant patent.
(viii) Amended certifications. A certification submitted under
paragraphs (a)(12)(i) through (a)(12)(iii) of this section may be
amended at any time before the effective date of the approval of the
application. However, an applicant who has submitted a paragraph IV
patent certification may not change it to a paragraph III certification
if a patent infringement suit has been filed against another paragraph
IV applicant unless the agency has determined that no applicant is
entitled to 180-day exclusivity or the patent expires before the
lawsuit is resolved or expires after the suit is resolved but before
the end of the 180-day exclusivity period. If an applicant with a
pending application voluntarily makes a patent certification for an
untimely filed patent, the applicant may withdraw the patent
certification for the untimely filed patent. An applicant shall submit
an amended certification by letter or as an amendment to a pending
application or by letter to an approved application. Once an amendment
or letter is submitted, the application will no longer be considered to
contain the prior certification.
(A) After finding of infringement. An applicant who has submitted a
certification under paragraph (a)(12)(i)(A)(4) of this section and is
sued for patent infringement within 45 days of the receipt of notice
sent under Sec. 314.95 shall amend the certification if a final
judgment in the action against the applicant is entered finding the
patent to be infringed. In the amended certification, the applicant
shall certify under paragraph (a)(12)(i)(A)(3) of this section that the
patent will expire on a specific date. Once an amendment or letter for
the change has been submitted, the application will no longer be
considered to be one containing a certification under paragraph
(a)(12)(i)(A)(4) of this section. If a final judgment finds the patent
to be invalid and infringed, an amended certification is not required.
(B) After removal of a patent from the list. If a patent is removed
from the list, any applicant with a pending application (including a
tentatively approved application with a delayed effective date) who has
made a certification with respect to such patent shall amend its
certification. The applicant shall certify under paragraph (a)(12)(ii)
of this section that no patents described in paragraph (a)(12)(i) of
this section claim the drug or, if other relevant patents claim the
drug, shall amend the certification to refer only to those relevant
patents. In the amendment, the applicant shall state the reason for the
change in certification (that the patent is or has been removed from
the list). A patent that is the subject of a lawsuit under
Sec. 314.107(c) shall not be removed from the list until FDA determines
either that no delay in effective dates of approval is required under
that section as a result of the lawsuit, that the patent has expired,
or that any such period of delay in effective dates of approval is
ended. An applicant shall submit an amended certification. Once an
amendment or letter for the change has been submitted, the application
will no longer be considered to be one containing a certification under
paragraph (a)(12)(i)(A)(4) of this section.
(C) Other amendments. (1) Except as provided in paragraphs
(a)(12)(vi) and (a)(12)(viii)(C)(2) of this section, an applicant shall
amend a submitted certification if, at any time before the effective
date of the approval of the application, the applicant learns that the
submitted certification is no longer accurate.
(2) An applicant is not required to amend a submitted certification
when information on a patent on the listed drug is submitted after the
effective date of approval of the abbreviated application.
* * * * *
7. New section 314.95 is added to subpart C to read as follows:
Sec. 314.95 Notice of certification of invalidity or noninfringement
of a patent.
(a) Notice of certification. For each patent that claims the listed
drug or that claims a use for such listed drug for which the applicant
is seeking approval and that the applicant certifies under
Sec. 314.94(a)(12) is invalid, unenforceable, or will not be infringed,
the applicant shall send notice of such certification by registered or
certified mail, return receipt requested to each of the following
persons:
(1) Each owner of the patent which is the subject of the
certification or the representative designated by the owner to receive
the notice. The name and address of the patent owner or its
representative may be obtained from the United States Patent and
Trademark Office; and
(2) The holder 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, or, if the application holder does
not reside or maintain a place of business within the United States,
the application holder's attorney, agent, or other authorized official.
The name and address of the application holder or its attorney, agent,
or authorized official may be obtained from the Division of Drug
Information Resources (HFD-80), Center for Drug Evaluation and
Research, Food and Drug Administration, 5600 Fishers Lane, Rockville,
MD 20857.
(3) This paragraph does not apply to a use patent that claims no
uses for which the applicant is seeking approval.
(b) Sending the notice. The applicant shall send the notice
required by paragraph (a) of this section when it receives from FDA an
acknowledgment letter stating that its abbreviated new drug application
is sufficiently complete to permit a substantive review. At the same
time, the applicant shall amend its abbreviated new drug application to
include a statement certifying that the notice has been provided to
each person identified under paragraph (a) of this section and that the
notice met the content requirements under paragraph (c) of this
section.
(c) Contents of a notice. In the notice, the applicant shall cite
section 505(j)(2)(B)(ii) of the act and shall include, but not be
limited to, the following information:
(1) A statement that FDA has received an abbreviated new drug
application submitted by the applicant containing any required
bioavailability or bioequivalence data or information.
(2) The abbreviated application number.
(3) The established name, if any, as defined in section 502(e)(3)
of the act, of the proposed drug product.
(4) The active ingredient, strength, and dosage form of the
proposed drug product.
(5) The patent number and expiration date, as submitted to the
agency or as known to the applicant, of each patent alleged to be
invalid, unenforceable, or not infringed.
(6) A detailed statement of the factual and legal basis of the
applicant's opinion that the patent is not valid, unenforceable, or
will not be infringed. The applicant shall include in the detailed
statement:
(i) For each claim of a patent alleged not to be infringed, a full
and detailed explanation of why the claim is not infringed.
(ii) For each claim of a patent alleged to be invalid or
unenforceable, a full and detailed explanation of the grounds
supporting the allegation.
(7) If the applicant does not reside or have a place of business in
the United States, the name and address of an agent in the United
States authorized to accept service of process for the applicant.
(d) Amendment to an abbreviated application. If an abbreviated
application is amended to include the certification described in
Sec. 314.94(a)(12)(i)(A)(4), the applicant shall send the notice
required by paragraph (a) of this section at the same time that the
amendment to the abbreviated application is submitted to FDA.
(e) Documentation of receipt of notice. The applicant shall amend
its abbreviated application to document receipt of the notice required
under paragraph (a) of this section by each person provided the notice.
The applicant shall include a copy of the return receipt or other
similar evidence of the date the notification was received. FDA will
accept as adequate documentation of the date of receipt a return
receipt or a letter acknowledging receipt by the person provided the
notice. An applicant may rely on another form of documentation only if
FDA has agreed to such documentation in advance. A copy of the notice
itself need not be submitted to the agency.
(f) Approval. If the requirements of this section are met, FDA will
presume the notice to be complete and sufficient, and it will count the
day following the date of receipt of the notice by the patent owner or
its representative and by the approved application holder as the first
day of the 45-day period provided for in section 505(j)(4)(B)(iii) of
the act. FDA may, if the applicant provides a written statement to FDA
that a later date should be used, count from such later date.
8. Section 314.101 is amended by revising paragraph (e) to read as
follows:
Sec. 314.101 Filing an application and an abbreviated antibiotic
application and receiving an abbreviated new drug application.
* * * * *
(e) The agency will refuse to file an application or abbreviated
antibiotic application or will consider an abbreviated new drug
application not to have been received if any of the following applies:
(1) The drug product is subject to licensing by FDA under the
Public Health Service Act (42 U.S.C. 201 et seq.) and subchapter F of
this chapter.
(2) In the case of a 505(b)(2) application or an abbreviated new
drug application, the drug product contains the same active moiety as a
drug that:
(i) Was approved after September 24, 1984, in an application under
section 505(b) of the act, and
(ii) Is entitled to a 5-year period of exclusivity under section
505(c)(3)(D)(ii) and (j)(4)(D)(ii) of the act and Sec. 314.108(b)(2),
unless the 5-year exclusivity period has elapsed or unless 4 years of
the 5-year period have elapsed and the application or abbreviated
application contains a certification of patent invalidity or
noninfringement described in Sec. 314.50(i)(1)(i)(A)(4) or
Sec. 314.94(a)(12)(i)(A)(4).
* * * * *
9. New sections 314.107 and 314.108 are added to subpart D to read
as follows:
Sec. 314.107 Effective date of approval of a 505(b)(2) application or
abbreviated new drug application under section 505(j) of the act.
(a) General. A drug product may be introduced or delivered for
introduction into interstate commerce when approval of the application
or abbreviated application for the drug product becomes effective.
Except as provided in this section, approval of an application or
abbreviated application for a drug product becomes effective on the
date FDA issues an approval letter under Sec. 314.105 for the
application or abbreviated application.
(b) Effect of patent on the listed drug. If approval of an
abbreviated new drug application submitted under section 505(j) of the
act or of a 505(b)(2) application is granted, that approval will become
effective in accordance with the following:
(1) Date of approval letter. Except as provided in paragraphs
(b)(3), (b)(4), and (c) of this section, approval will become effective
on the date FDA issues an approval letter under Sec. 314.105 if the
applicant certifies under Sec. 314.50(i) or Sec. 314.94(a)(12) that:
(i) There are no relevant patents; or
(ii) The applicant is aware of a relevant patent but the patent
information required under section 505 (b) or (c) of the act has not
been submitted to FDA; or
(iii) The relevant patent has expired; or
(iv) The relevant patent is invalid, unenforceable, or will not be
infringed.
(2) Patent expiration. If the applicant certifies under
Sec. 314.50(i) or Sec. 314.94(a)(12) that the relevant patent will
expire on a specified date, approval will become effective on the
specified date.
(3) Disposition of patent litigation. (i)(A) Except as provided in
paragraphs (b)(3)(ii), (b)(3)(iii), and (b)(3)(iv) of this section, if
the applicant certifies under Sec. 314.50(i) or Sec. 314.94(a)(12) that
the relevant patent is invalid, unenforceable, or will not be
infringed, and the patent owner or its representative or the exclusive
patent licensee brings suit for patent infringement within 45 days of
receipt by the patent owner of the notice of certification from the
applicant under Sec. 314.52 or Sec. 314.95, approval may be made
effective 30 months after the date of the receipt of the notice of
certification by the patent owner or by the exclusive licensee (or
their representatives) unless the court has extended or reduced the
period because of a failure of either the plaintiff or defendant to
cooperate reasonably in expediting the action; or
(B) If the patented drug product qualifies for 5 years of exclusive
marketing under Sec. 314.108(b)(2) and the patent owner or its
representative or the exclusive patent licensee brings suit for patent
infringement during the 1-year period beginning 4 years after the date
the patented drug was approved and within 45 days of receipt by the
patent owner of the notice of certification, the approval may be made
effective at the expiration of the 7\1/2\ years from the date of
approval of the application for the patented drug product.
(ii) If before the expiration of the 30-month period, or 7\1/2\
years where applicable, the court issues a final order that the patent
is invalid, unenforceable, or not infringed, approval may be made
effective on the date the court enters judgment;
(iii) If before the expiration of the 30-month period, or 7\1/2\
years where applicable, the court issues a final order or judgment that
the patent has been infringed, approval may be made effective on the
date the court determines that the patent will expire or otherwise
orders; or
(iv) If before the expiration of the 30-month period, or 7\1/2\
years where applicable, the court grants a preliminary injunction
prohibiting the applicant from engaging in the commercial manufacture
or sale of the drug product until the court decides the issues of
patent validity and infringement, and if the court later decides that
the patent is invalid, unenforceable, or not infringed, approval may be
made effective on the date the court enters a final order or judgment
that the patent is invalid, unenforceable, or not infringed.
(v) In order for an approval to be made effective under paragraph
(b)(3) of this section, the applicant must receive an approval letter
from the agency indicating that the application has received final
approval. Tentative approval of an application does not constitute
``approval'' of an application and cannot, absent a final approval
letter from the agency, result in an effective approval under paragraph
(b)(3) of this section.
(4) Multiple certifications. If the applicant has submitted
certifications under Sec. 314.50(i) or Sec. 314.94(a)(12) for more than
one patent, the date of approval will be calculated for each
certification, and the approval will become effective on the last
applicable date.
(c) Subsequent abbreviated new drug application submission.
(1) If an abbreviated new drug application contains a certification
that a relevant patent is invalid, unenforceable, or will not be
infringed and the application is for a generic copy of the same listed
drug for which one or more substantially complete abbreviated new drug
applications were previously submitted containing a certification that
the same patent was invalid, unenforceable, or would not be infringed
and the applicant submitting the first application has successfully
defended against a suit for patent infringement brought within 45 days
of the patent owner's receipt of notice submitted under Sec. 314.95,
approval of the subsequent abbreviated new drug application will be
made effective no sooner than 180 days from whichever of the following
dates is earlier:
(i) The date the applicant submitting the first application first
commences commercial marketing of its drug product; or
(ii) The date of a decision of the court holding the relevant
patent invalid, unenforceable, or not infringed.
(2) For purposes of paragraph (c)(1) of this section, the
``applicant submitting the first application'' is the applicant that
submits an application that is both substantially complete and contains
a certification that the patent was invalid, unenforceable, or not
infringed prior to the submission of any other application for the same
listed drug that is both substantially complete and contains the same
certification. A ``substantially complete'' application must contain
the results of any required bioequivalence studies, or, if applicable,
a request for a waiver of such studies.
(3) For purposes of paragraph (c)(1) of this section, if FDA
concludes that the applicant submitting the first application is not
actively pursuing approval of its abbreviated application, FDA will
make the approval of subsequent abbreviated applications immediately
effective if they are otherwise eligible for an immediately effective
approval.
(4) For purposes of paragraph (c)(1)(i) of this section, the
applicant submitting the first application shall, if sued for patent
infringement, notify FDA of the date that it commences commercial
marketing of its drug product. Commercial marketing commences with the
first date of introduction or delivery for introduction into interstate
commerce outside the control of the manufacturer of a drug product,
except for investigational use under part 312 of this chapter, but does
not include transfer of the drug product for reasons other than sale
within the control of the manufacturer or application holder. If an
applicant does not promptly notify FDA of such date, the effective date
of approval shall be deemed to be the date of the commencement of first
commercial marketing.
(d) Delay due to exclusivity. The agency will also delay the
effective date of the approval of an abbreviated new drug application
under section 505(j) of the act or a 505(b)(2) application if delay is
required by the exclusivity provisions in Sec. 314.108. When the
effective date of an application is delayed under both this section and
Sec. 314.108, the effective date will be the later of the 2 days
specified under this section and Sec. 314.108.
(e) Court actions. (1) References to actions of ``the court'' in
paragraphs (b) and (c) of this section are to the court that enters
final judgment from which no appeal can be or has been taken.
(2) For purposes of establishing the effective date of approval
based on a court judgment, the following dates shall be deemed to be
the date of the final decision of the court on the patent issues:
(i) If the district court enters a decision that the patent is
invalid, unenforceable, or not infringed, and the decision is not
appealed, the date on which the right to appeal lapses.
(ii) If the district court enters a decision that the patent is
invalid, unenforceable, or not infringed, and the decision is appealed,
the date of the first decision or order by a higher court holding or
affirming the decision of the district court that the patent is
invalid, unenforceable, or not infringed.
(iii) If the district court enters a decision that the patent is
infringed, and the decision is appealed, the date on which the district
court enters a judgment that the patent is invalid, unenforceable, or
not infringed pursuant to a mandate issued by a court of appeals.
(iv) The applicant shall submit a copy of the entry of the order or
judgment to the Office of Generic Drugs (HFD-600), or to the
appropriate division in the Office of Drug Evaluation I (HFD-100) or
Office of Drug Evaluation II (HFD-500), whichever is applicable, within
10 working days of a final judgment.
(f) Computation of 45-day time clock. (1) The 45-day clock
described in paragraph (b)(3) of this section begins on the day after
the date of receipt of the applicant's notice of certification by the
patent owner or its representative, and by the approved application
holder. When the 45th day falls on Saturday, Sunday, or a Federal
holiday, the 45th day will be the next day that is not a Saturday,
Sunday, or a Federal holiday.
(2) The abbreviated new drug applicant or the 505(b)(2) applicant
shall notify FDA immediately of the filing of any legal action filed
within 45 days of receipt of the notice of certification. If the
applicant submitting the abbreviated new drug application or the
505(b)(2) application or patent owner or its representative does not
notify FDA in writing before the expiration of the 45-day time period
or the completion of the agency's review of the application, whichever
occurs later, that a legal action for patent infringement was filed
within 45 days of receipt of the notice of certification, approval of
the abbreviated new drug application or the 505(b)(2) application will
be made effective immediately upon expiration of the 45 days or upon
completion of the agency's review and approval of the application,
whichever is later. The notification to FDA of the legal action shall
include:
(i) The abbreviated new drug application or 505(b)(2) application
number.
(ii) The name of the abbreviated new drug or 505(b)(2) application
applicant.
(iii) The established name of the drug product or, if no
established name exists, the name(s) of the active ingredient(s), the
drug product's strength, and dosage form.
(iv) A certification that an action for patent infringement
identified by number, has been filed in an appropriate court on a
specified date.
The applicant of an abbreviated new drug application shall send the
notification to FDA's Office of Generic Drugs (HFD-600). A 505(b)(2)
applicant shall send the notification to the appropriate division in
the Center for Drug Evaluation and Research reviewing the application.
A patent owner or its representative may also notify FDA of the filing
of any legal action for patent infringement. The notice should contain
the information and be sent to the offices or divisions described in
this paragraph.
(3) If the patent owner or approved application holder who is an
exclusive patent licensee waives its opportunity to file a legal action
for patent infringement within 45 days of a receipt of the notice of
certification and the patent owner or approved application holder who
is an exclusive patent licensee submits to FDA a valid waiver before
the 45 days elapse, approval of the abbreviated new drug application or
the 505(b)(2) application will be made effective upon completion of the
agency's review and approval of the application. FDA will only accept a
waiver in the following form:
(Name of patent owner or exclusive patent licensee) has received
notice from (name of applicant) under (section 505(b)(3) or
505(j)(2)(B) of the act) and does not intend to file an action for
patent infringement against (name of applicant) concerning the drug
(name of drug) before (date on which 45 days elapses. (Name of
patent owner or exclusive patent licensee) waives the opportunity
provided by (section 505(c)(3)(C) or 505(j)(B)(iii) of the act) and
does not object to FDA's approval of (name of applicant)'s
(505(b)(2) or abbreviated new drug application) for (name of drug)
with an immediate effective date on or after the date of this
letter.
Sec. 314.108 New drug product exclusivity.
(a) Definitions. The following definitions of terms apply to this
section:
Active moiety means the molecule or ion, excluding those appended
portions of the molecule that cause the drug to be an ester, salt
(including a salt with hydrogen or coordination bonds), or other
noncovalent derivative (such as a complex, chelate, or clathrate) of
the molecule, responsible for the physiological or pharmacological
action of the drug substance.
Approved under section 505(b) means an application submitted under
section 505(b) and approved on or after October 10, 1962, or an
application that was ``deemed approved'' under section 107(c)(2) of
Pub. L. 87-781.
Clinical investigation means any experiment other than a
bioavailability study in which a drug is administered or dispensed to,
or used on, human subjects.
Conducted or sponsored by the applicant with regard to an
investigation means that before or during the investigation, the
applicant was named in Form FDA-1571 filed with FDA as the sponsor of
the investigational new drug application under which the investigation
was conducted, or the applicant or the applicant's predecessor in
interest, provided substantial support for the investigation. To
demonstrate ``substantial support,'' an applicant must either provide a
certified statement from a certified public accountant that the
applicant provided 50 percent or more of the cost of conducting the
study or provide an explanation 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 or the applicant did
not sponsor the investigational new drug. A predecessor in interest is
an entity, e.g., a corporation, that the applicant has taken over,
merged with, or purchased, or from which the applicant has purchased
all rights to the drug. Purchase of nonexclusive rights to a clinical
investigation after it is completed is not sufficient to satisfy this
definition.
Date of approval means the date on the letter from FDA stating that
the new drug application is approved, whether or not final printed
labeling or other materials must yet be submitted as long as approval
of such labeling or materials is not expressly required. ``Date of
approval'' refers only to a final approval and not to a tentative
approval that may become effective at a later date.
Essential to approval means, with regard to an investigation, that
there are no other data available that could support approval of the
application.
FDA means the Food and Drug Administration.
New chemical entity means a drug that contains no active moiety
that has been approved by FDA in any other application submitted under
section 505(b) of the act.
New clinical investigation means an investigation in humans the
results of which have not been relied on by FDA to demonstrate
substantial evidence of effectiveness of a previously approved drug
product for any indication or of safety for a new patient population
and do not duplicate the results of another investigation that was
relied on by the agency to demonstrate the effectiveness or safety in a
new patient population of a previously approved drug product. For
purposes of this section, data from a clinical investigation previously
submitted for use in the comprehensive evaluation of the safety of a
drug product but not to support the effectiveness of the drug product
would be considered new.
(b) Submission of and effective date of approval of an abbreviated
new drug application submitted under section 505(j) of the act or a
505(b)(2) application. (1) [Reserved]
(2) If a drug product that contains a new chemical entity was
approved after September 24, 1984, in an application submitted under
section 505(b) of the act, no person may submit a 505(b)(2) application
or abbreviated new drug application under section 505(j) of the act for
a drug product that contains the same active moiety as in the new
chemical entity for a period of 5 years from the date of approval of
the first approved new drug application, except that the 505(b)(2)
application or abbreviated application may be submitted after 4 years
if it contains a certification of patent invalidity or noninfringement
described in Sec. 314.50(i)(1)(i)(A)(4) or Sec. 314.94(a)(12)(i)(A)(4).
(3) The approval of a 505(b)(2) application or abbreviated
application described in paragraph (b)(2) of this section will become
effective as provided in Sec. 314.107(b)(1) or (b)(2), unless the owner
of a patent that claims the drug, the patent owner's representative, or
exclusive licensee brings suit for patent infringement against the
applicant during the 1-year period beginning 48 months after the date
of approval of the new drug application for the new chemical entity and
within 45 days after receipt of the notice described at Sec. 314.52 or
Sec. 314.95, in which case, approval of the 505(b)(2) application or
abbreviated application will be made effective as provided in
Sec. 314.107(b)(3).
(4) If an application:
(i) Was submitted under section 505(b) of the act;
(ii) Was approved after September 24, 1984;
(iii) Was for a drug product that contains an active moiety that
has been previously approved in another application under section
505(b) of the act; and
(iv) Contained reports of new clinical investigations (other than
bioavailability studies) conducted or sponsored by the applicant that
were essential to approval of the application, the agency will not make
effective for a period of 3 years after the date of approval of the
application the approval of a 505(b)(2) application or an abbreviated
new drug application for the conditions of approval of the original
application, or an abbreviated new drug application submitted pursuant
to an approved petition under section 505(j)(2)(C) of the act that
relies on the information supporting the conditions of approval of an
original new drug application.
(5) If a supplemental application:
(i) Was approved after September 24, 1984; and
(ii) Contained reports of new clinical investigations (other than
bioavailability studies) that were conducted or sponsored by the
applicant that were essential to approval of the supplemental
application, the agency will not make effective for a period of 3 years
after the date of approval of the supplemental application the approval
of a 505(b)(2) application or an abbreviated new drug application for a
change, or an abbreviated new drug application submitted pursuant to an
approved petition under section 505(j)(2)(C) of the act that relies on
the information supporting a change approved in the supplemental new
drug application.
Dated: September 23, 1994.
William K. Hubbard,
Interim Deputy Commissioner for Policy.
[FR Doc. 94-24052 Filed 9-30-94; 8:45 am]
BILLING CODE 4160-01-P