[Federal Register: June 18, 2003 (Volume 68, Number 117)]
[Rules and Regulations]
[Page 36675-36712]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr18jn03-17]
[[Page 36675]]
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Part III
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Part 314
Applications for FDA Approval To Market a New Drug: Patent Submission
and Listing Requirements and Application of 30-Month Stays on Approval
of Abbreviated New Drug Applications Certifying That a Patent Claiming
a Drug Is Invalid or Will Not Be Infringed; Final Rule
[[Page 36676]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 314
[Docket No. 02N-0417 ]
RIN 0910-AC48
Applications for FDA Approval to Market a New Drug: Patent
Submission and Listing Requirements and Application of 30-Month Stays
on Approval of Abbreviated New Drug Applications Certifying That a
Patent Claiming a Drug Is Invalid or Will Not Be Infringed
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending its patent
submission and listing requirements for new drug applications (NDAs).
The final rule clarifies the types of patents that must and must not be
submitted and revises the declaration that NDA applicants must provide
regarding their patents to help ensure that NDA applicants submit only
appropriate patents. The final rule also revises the regulations
regarding the effective date of approval for certain abbreviated new
drug applications (ANDAs) and certain other new drug applications,
known as 505(b)(2) applications, submitted under the Federal Food,
Drug, and Cosmetic Act (the act). In certain situations, Federal law
bars FDA from making the approval of certain ANDA and 505(b)(2)
applications effective for 30 months if the applicant has certified
that the patent claiming a drug is invalid or will not be infringed,
and the patent owner or NDA holder then brings suit for patent
infringement. The final rule also states that there is only one
opportunity for a 30-month stay in the approval date of each ANDA and
505(b)(2) application. The final rule will make the patent submission
and listing process more efficient as well as enhance the ANDA and
505(b)(2) application approval processes.
DATES: Effective Date: This final rule is effective on August 18, 2003.
Compliance Date: The compliance date is December 18, 2003, for the
submission of information on polymorph patents.
FOR FURTHER INFORMATION CONTACT: Jarilyn Dupont, Office of Policy and
Planning (HF-11), Food and Drug Administration, 5600 Fishers Lane,
Rockville, MD 20857, 301-827-3360.
SUPPLEMENTARY INFORMATION:
I. Introduction
This final rule revises implementing regulations in part 314 (21
CFR part 314) for certain statutory amendments to the act, 21 U.S.C.
301 et seq., relating to new drug applications and generic drug
approvals. The statutory provisions were added to the act through the
Drug Price Competition and Patent Term Restoration Act of 1984 (Public
Law 98-417 (21 U.S.C. 355, 360cc; 35 U.S.C. 156, 271, 282) (``Hatch-
Waxman Amendments'')). These statutory provisions reflect an attempt to
balance two competing interests: Promoting competition between ``brand-
name'' or ``innovator drugs'' and ``generic'' drugs, and encouraging
research and innovation. The act promotes competition by creating a
process to expedite the filing and approval of ANDA and 505(b)(2) drug
applications (applications submitted under the provisions of section
505(b)(2) of the act) and for resolving challenges to patents in court
before marketing begins. At the same time, the act encourages research
and innovation by protecting the patent interests of the patent owner
and innovator drug company.
The final rule maintains a balance between the innovator companies'
intellectual property rights and the desire to get generic drugs on the
market in a timely fashion. The final rule limits to one per ANDA or
505(b)(2) application the maximum number of statutory 30-month stays of
approval to which an innovator will be entitled when it submits
multiple patents for the same NDA. Eliminating multiple 30-month stays
will speed up the approval and market entry of generic drugs. The final
rule also clarifies patent submission and listing requirements, which
will reduce confusion and help curb attempts to take advantage of this
process. Specifically, patents claiming packaging, intermediates, or
metabolites must not be submitted for listing. Patents claiming a
different polymorphic form of the active ingredient described in the
NDA must be submitted if the NDA holder has test data demonstrating
that a drug product containing the polymorph will perform the same as
the drug product described in the NDA.
A. What Are the Statutory Provisions Which Affect Patent Submissions
and the Approval of New Drugs?
To explain why we (FDA) issued the proposal, we first describe how
Federal law requires NDA applicants to file patent information and how
that patent information can affect the approval of ANDA and 505(b)(2)
applications. (We will refer to these as ``ANDA and 505(b)(2)
applicants'' or ``ANDA or 505(b)(2) applicants'' and refer to their
applications as ``ANDA and 505(b)(2) applications'' or ``ANDA or
505(b)(2) applications'' throughout the remainder of the preamble of
this document.)
Section 505(b)(1) of the act (21 U.S.C. 355(b)(1)) requires all NDA
applicants to file, as part of the NDA, ``the patent number and the
expiration date of any patent which claims the drug for which the
applicant submitted the application or which claims a method of using
such drug and with respect to which a claim of patent infringement
could reasonably be asserted if a person not licensed by the owner
engaged in the manufacture, use, or sale of the drug.'' Section
505(c)(2) of the act (21 U.S.C. 355(c)(2)) imposes a similar patent
submission obligation on holders of approved NDAs when the NDA holder
could not have submitted the patent information with its application.
Under section 505(b)(1) of the act, we publish patent information
after approval of an NDA application in our approved drug products list
entitled ``Approved Drug Products With Therapeutic Equivalence
Evaluations.'' This list is known popularly as the ``Orange Book''
because of its orange-colored cover. If patent information is submitted
after NDA approval, section 505(c)(2) of the act directs us to publish
the information upon its submission.
The act also requires ANDA or 505(b)(2) applicants to make
certifications regarding each of the listed patents pertaining to the
drug they intend to reference (see sections 505(b)(2)(A)(i) through
(b)(2)(A)(iv) and 505(j)(2)(A)(vii)(I) through (j)(2)(A)(vii)(IV) of
the act (21 U.S.C. 355(b)(2)(A)(i) through (b)(2)(A)(iv) and 21 U.S.C.
355(j)(2)(A)(vii)(I) through (j)(2)(A)(vii)(IV)). In brief, these
certifications state that:
[sbull] Patent information has not been filed,
[sbull] The patent has expired,
[sbull] The patent will expire on a specific date, or
[sbull] The patent is invalid or will not be infringed.
If the ANDA or 505(b)(2) applicant certifies that the patent is
invalid or will not be infringed (a certification known as a
``paragraph IV'' certification because it is the fourth type of patent
certification described in the act\1\), the act requires the applicant
to notify the
[[Page 36677]]
NDA holder and patent owner (see sections 505(b)(3) and 505(j)(2)(B) of
the act (21 U.S.C. 355(b)(3) and 355(j)(2)(B)). The notice states that
an ANDA or 505(b)(2) application containing a paragraph IV
certification to a listed patent has been submitted for the NDA
holder's approved drug product (known as the ``listed drug''). The
notice also includes 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'' (id.). If the NDA holder or patent owner brings an
action for patent infringement within 45 days after notice of the
paragraph IV certification has been received, then we may not make the
approval of an ANDA or 505(b)(2) application effective for 30 months,
or such shorter or longer period as a court may order, or until the
date of a court decision (see sections 505(c)(3)(C) and
505(j)(5)(B)(iii) of the act (21 U.S.C. 355(c)(3)(C) and
355(j)(5)(B)(iii)). (We will refer to the date the approval of an ANDA
or 505(b)(2) application is made effective as the ``approval date''
throughout the remainder of this preamble.)
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\1\ Paragraph IV throughout also refers to paragraph iv, the
comparable provision in section 505(b)(2)(A) of the act.
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B. What Did the Proposed Rule Say?
In the Federal Register of October 24, 2002 (67 FR 65448), we
published a proposed rule (proposed rule) that would address:
[sbull] The types of patents that must and must not be submitted by
NDA applicants and NDA holders or patent owners (for purposes of this
preamble, an NDA applicant is someone who is seeking FDA approval of a
specific new drug application or supplement, whereas an NDA holder is
someone whose NDA we have approved);
[sbull] The types of patents that we will list in the Orange Book;
[sbull] The patent declaration that NDA applicants must submit as
part of an NDA, an amendment, a supplement, or when submitting
information on a newly issued patent; and
[sbull] The 30-month stay of the effective date of approval for an
ANDA or 505(b)(2) application.
The preamble to the proposed rule noted that, on occasion, we have
seen NDA holders submit new patents for listing shortly before other
listed patents for the same drug were to expire (see 67 FR 65448 at
65449). We explained that, in some disputes over recently listed
patents, the parties had questioned whether particular patents met the
regulatory requirements for submission and listing in the Orange Book.
These disputes sometimes resulted in judicial decisions that are
inconsistent with our regulatory policies or our interpretation of our
own regulations (id.). We proposed to clarify our regulatory policies
regarding patent submission, listing, certification, and notice. We
also issued the proposal to respond, in part, to concerns raised by the
Bureau of Competition and the Policy Planning Staff of the Federal
Trade Commission (FTC). On May 16, 2001, the FTC submitted a citizen
petition to FDA (FDA docket number 01P-0248) (``FTC Citizen Petition'')
asking for guidance concerning the criteria that a patent must meet
before it is listed in the Orange Book. The FTC Citizen Petition asked
us to clarify several patent listing issues and indicated that the FTC
was conducting an extensive study of generic drug competition.
In July 2002, the FTC published the results of the study in a
report entitled ``Generic Drug Entry Prior to Patent Expiration: An FTC
Study'' (``FTC Report''). The FTC Report focused on the procedures used
to facilitate a generic drug's entry into the market before the
expiration of a patent or patents that claim the brand-name drug
product. The FTC also recommended changing Federal law to ``permit only
one automatic 30-month stay per drug product per ANDA to resolve
infringement disputes over patents listed in the Orange Book prior to
the filing date of the generic applicant's ANDA'' (see FTC Report at
page ii). The FTC Report explained ``To permit only one 30-month stay
per drug product per ANDA should eliminate most of the potential for
improper Orange Book listings to generate unwarranted 30-month stays''
(id. at page v (footnote omitted)). In an appendix to its report, the
FTC asked us to issue a regulation or guidance clarifying whether an
NDA holder could submit various types of patents for listing in the
Orange Book. The types of patents for which the FTC sought
clarification were patents that claimed metabolites, polymorphs,
intermediates, product-by-process patents, and double patents (see FTC
Report at pages A-39-A-45).
C. What Does This Final Rule Do?
The comments received expressed both support for, and opposition
to, various provisions of the proposed rule. After careful review of
these comments, we are making final most of the provisions of the
proposed rule with certain modifications. The final rule:
[sbull] Allows a full opportunity for only one 30-month stay per
ANDA or 505(b)(2) application;
[sbull] Prohibits the submission of patents claiming packaging,
intermediates, or metabolites;
[sbull] Requires the submission of certain patents claiming a
different polymorphic form of the active ingredient described in the
NDA;
[sbull] Adds a requirement that for submission of polymorph patents
the NDA holder must have test data demonstrating that a drug product
containing the polymorph will perform the same as the drug product
described in the NDA;
[sbull] Makes changes to the patent information required to be
submitted and provides declaration forms for submitting that
information to FDA, both with the NDA and after NDA approval; and
[sbull] Does not require claim-by-claim listing on the declaration
form except for method-of-use patents claiming approved methods of use.
II. Comments on the Proposed Rule
We received over 35 comments on the proposed rule. The comments
represented a diverse range of interests such as: Health insurance
programs, brand name pharmaceutical companies, generic pharmaceutical
companies, law firms, consumer organizations, pharmacy associations,
the FTC, the New York Department of Health, large corporations, and
individuals. In general, most comments supported the rule, either in
whole or in part, and believed that the rule would help reduce
prescription drug costs by making generic drugs available more quickly.
However, other comments opposed the rule because they felt we had
misinterpreted the act or because they felt that new legislation,
rather than a regulation, was necessary. We describe the comments, and
our responses to the comments, in this section. To make it easier to
identify the comments and our responses, the word ``Comment'' in
parentheses, will appear before the description of the comment, and the
word ``Response'' in parentheses, will appear before our response. We
also have numbered each comment to make it easier to identify a
particular comment. The number assigned to each comment is only for
organizational purposes. It does not signify the comment's value,
importance, or the order in which we received it.
A. Comments on Specific Aspects of the Proposed Rule
1. What Patents Must and Must Not Be Submitted? (Section 314.53(b))
Proposed Sec. 314.53(b) would require NDA applicants and holders
or patent owners to submit information on the following types of
patents for listing in the Orange Book. In brief, the proposed
[[Page 36678]]
rule would clarify that we would list only patents that claim:
[sbull] The drug substance (ingredient);
[sbull] The drug product (formulation and composition); and
[sbull] Method of use.
Proposed Sec. 314.53(b) would not allow listing of process patents
and patents claiming packaging, metabolites, or intermediates.
a. Patents Claiming a Drug Substance--Must Patents that Claim the
``Same'' Active Ingredient Be Submitted and Listed? For patents that
claim a drug substance, the proposal stated that an applicant ``shall
submit information only on those patents that claim the form of the
drug substance that is the subject of the pending or approved
application or that claim a drug substance that is the same as the
active ingredient that is the subject of the approved or pending
application.'' We explained that an NDA applicant or holder would
determine whether the drug substance was the ``same'' as the active
ingredient in the NDA by considering ``whether the drug substances can
be expected to perform the same with respect to such characteristics as
dissolution, solubility, and bioavailability'' (see 67 FR 65448 at
65452).
Drug substances that are the same active ingredient, but that are
in different physical forms, are often called ``polymorphs.'' For
example, the different crystalline forms of a drug substance are
sometimes known collectively as polymorphs, and drug substances with
different waters of hydration are sometimes referred to as
``polymorphs'' as well. (For purposes of this final rule, polymorphs
include chemicals with different crystalline structures, different
waters of hydration, solvates, and amorphous forms.) Under the proposed
rule, an NDA applicant or holder would be required to submit a patent
claiming a different polymorph from that of the drug substance
described in the NDA if a drug product containing the polymorph will
perform the same as the drug product described in the NDA with respect
to dissolution, solubility, and bioavailability.
The proposed rule would make the patent listing standards generally
consistent with the ANDA approval standards. For ANDA approval
purposes, the active ingredient in a generic drug product can be the
``same'' as that in the reference listed drug notwithstanding
differences in the physical forms of their active ingredient if the
drug product performs the same. Thus, we stated that it would be
consistent to interpret ``drug substance'' for patent submission and
listing purposes as including certain drug substances having different
physical forms if they would be considered the same active ingredient
for ANDA approval purposes (id.).
We invited comment on whether we should revise the codified
language to require an NDA holder to submit additional information
regarding the basis for its assertion that the drug substances are the
``same'' active ingredient. We also invited comment on the potential
impact of the change (allowing the submission of patents claiming
different polymorphs) on the submission of ANDA and 505(b)(2)
applications.
(Comment 1) Several comments disagreed with our proposal to allow
listing of patents claiming different polymorphs of the active
ingredient in the listed drug. Some comments stated that section
505(b)(1) of the act requires the patent to claim the drug substance
that is the subject of the NDA. Several comments asserted that a patent
claiming a polymorph that was not the subject of an NDA did not satisfy
section 505(b)(1) of the act. Other comments argued that ``sameness''
for ANDA approval purposes differed from ``sameness'' in patent law, so
we did not have to develop an identical interpretation of the two
concepts. Several comments maintained that no such patents could exist
if the active ingredients were truly the ``same'' because a subsequent
patent for the ``same'' active ingredient should not have been issued.
Some comments agreed that patents claiming different polymorphs of the
same active ingredient should be listed, but only with submission of
additional information such as clinical trial data required for FDA
approval or proof that ``sameness'' is beneficial. A few comments
maintained that the proposal did not change our pre-existing position
because we have permitted NDA holders and applicants to submit patents
claiming different polymorphs of the active ingredient. In response to
our request for comment on the impact on ANDA and 505(b)(2)
applications, one comment expressed the belief that listing patents
claiming different polymorphs of the active ingredient would reduce the
ability of generic manufacturers to ``design around'' the existing
patents, an option which was contemplated by the Hatch-Waxman
Amendments.
(Response) We decline to modify our position taken in the proposed
rule which would require patents to be submitted for listing that claim
different polymorphs of the active ingredient described in the NDA. If
the NDA applicant or holder is able to establish that a polymorph
claimed in a patent is the ``same'' active ingredient (i.e., that a
drug product containing the polymorph will perform the same as the drug
product described in the NDA with respect to such characteristics as
dissolution, solubility, and bioavailability), the NDA applicant or
holder must submit the patent to us for listing. We acknowledge that
there may be some legitimate confusion regarding our prior position
concerning submission of such patents for listing, which resulted in
the listing of some polymorph patents in the Orange Book. The
uncertainty over our policy resulted from certain court decisions, our
response to those court decisions, and other public statements. The FTC
Citizen Petition highlighted the need for clarification and is one
reason we decided to implement this final rule and clarify our
position. For the reasons explained in the preamble to the proposed
rule (see 67 FR 65448 at 65452 to 65453), it is appropriate to have a
consistent interpretation of the ``sameness'' principle in the patent
listing and ANDA approval contexts. Accordingly, we will not treat
polymorphs differently for patent submission and listings and ANDA
approval. The argument that certain polymorph patents should never have
been issued is not a matter for us to address. The Patent and Trademark
Office (PTO) is responsible for reviewing and issuing patents. We will
not question whether the PTO should have issued a particular patent,
nor will we conduct a ``patent law'' or other analysis to determine
``sameness.''
We agree with the comments that suggested we needed to take
additional steps to help ensure that the submitted patents claim the
``same'' active ingredient as that described in the NDA. A polymorph
patent must claim the drug substance (active ingredient) to meet the
statutory requirements for submission. We have modified the declaration
requirement and created forms to help ensure that the NDA applicant or
holder or patent owner confirms that the patent does claim the ``same''
active ingredient. The final rule and the declaration forms require
that the NDA applicant or holder or patent owner certify that test data
exist demonstrating that a drug product containing the polymorph will
perform the same as the drug product described in the NDA. If a patent
claims more than one polymorph, each polymorph for which the required
test data are available must be identified by claim or description in
the declaration forms.
[[Page 36679]]
The final rule does not require these tests to be submitted to FDA at
the time of patent submission, nor does it require the NDA applicant or
holder to conduct the tests itself. The testing requirements, however,
will ensure that only relevant polymorphs are submitted for listing.
Whether two different polymorphs are the ``same'' active ingredient
for purposes of drug approval is a scientific determination based upon
the specific characteristics of the forms of the drug substance
involved. Only with testing can the scientific determination be made
that the drug product containing the polymorph will perform the same as
the drug product described in the NDA. The test data that the NDA
applicant or holder or patent owner must certify exist at the time of
patent submission are similar to the type of information required under
Sec. Sec. 314.50 and 314.94. The following explains more fully the
required tests or data that would support the statement in the
declaration forms:
[sbull] A full description of the polymorphic form of the drug
substance, including its physical and chemical characteristics and
stability; the method of synthesis (or isolation) and purification of
the drug substance; the process controls used during manufacture and
packaging; and such specifications and analytical methods as are
necessary to assure the identity, strength, quality, and purity of the
polymorphic form of the drug substance;
[sbull] The executed batch record for a drug product containing the
polymorphic form of the drug substance and documentation that the batch
was manufactured under current good manufacturing practice
requirements;
[sbull] Demonstration of bioequivalence between the executed batch
of the drug product that contains the polymorphic form of the drug
substance and the drug product as described in the NDA;
[sbull] A list of all components used in the manufacture of the
drug product containing the polymorphic form and a statement of the
composition of the drug product; a statement of the specifications and
analytical methods for each component; a description of the
manufacturing and packaging procedures and in-process controls for the
drug product; such specifications and analytical methods as are
necessary to assure the identity, strength, quality, purity, and
bioavailability of the drug product, including release and stability
data complying with the approved product specifications to demonstrate
pharmaceutical equivalence and comparable product stability; and
[sbull] Comparative in vitro dissolution testing on 12 dosage units
each of the executed test batch and the NDA product.
This test data requirement corresponds to the test data required of
ANDA applicants to demonstrate the drug product containing the
polymorph described in the ANDA will perform the same as the drug
product described in the NDA. In addition to the data requirements
described in our regulations cited above (Sec. Sec. 314.50 and
314.94), we have published guidance documents describing the test data
ANDA applicants may use to demonstrate that the drug product will
perform the same as the drug product described in the NDA. (See
``Guidance for Industry: Changes to an Approved NDA or ANDA'' (November
1999) and ``Guidance for Industry: Immediate Release Solid Oral Dosage
Forms CMS 5'' (November 1995); these guidances are available at
http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=www.fda.gov/opacom/morechoices/industry/guidedc.htm.)
The stringency of these requirements regarding ``sameness'' also
should address the concerns that the submission of polymorph patents
might lead to submission of other patents claiming components which are
not, but might be, included in a drug described in an NDA. Given the
narrow legal and scientific basis for submission of polymorph patents,
the final rule does not open the door to submission of any patents
claiming formulations or inactive ingredients not contained in the drug
product described in the NDA.
We believe that these changes will help deter submission of
inappropriate polymorph patents. The assumption that a product
containing a polymorph will perform the same as the product containing
a different polymorph and described in the NDA will have to be
substantiated.
b. Product-by-Process Patents--Should These Patents Be Listed?
Proposed Sec. 314.53(b) would allow an NDA applicant or holder or
patent owner to submit information on product-by-process patents. The
act requires that NDA holders submit patents that claim the drug
product. However, NDA applicants or holders must not submit patents
that claim a process for making that product.
We explained that a product-by-process patent claims a product by
describing or listing process steps to wholly or partially define the
claimed product. In a product-by-process patent, the patented, novel
invention is the product and not the process that is used to make the
product. We recognized that the distinction between a product-by-
process patent and a process patent might not be readily apparent to
persons who are unfamiliar with patent law. We sought comment on ways
to ensure that only appropriate product-by-process patents are listed
in the Orange Book.
(Comment 2) Several comments argued that product-by-process patents
must not be listed. Some comments stated that product-by-process
patents ``closely resemble'' process patents and that the act does not
allow listing of process patents. One comment asserted that listing
product-by-process patents would have a ``profound negative effect'' on
generic drug approvals because NDA applicants and holders or patent
owners would attempt to list any product-by-process patent, whether or
not the process defined in the patent was actually used to manufacture
the drug product approved in the NDA.
Similarly, other comments sought to limit the type of product-by-
process patents that could be listed. Several comments would revise the
rule to require the product-by-process patent to claim a ``novel''
product, so that if the drug product described by the product-by-
process patent was a ``known'' drug product or the product already had
been listed in the Orange Book, we would not list the product-by-
process patent. In other words, the comments sought to ensure that the
product-by-process patent covered a product that was ``new and
patentably distinct'' from previously-approved drug products. One
comment suggested adding a new paragraph to the patent declaration to
read as follows:
F. For each drug substance or drug product claim that was (1)
identified as listable in subparts B and C and (2) is drafted in
product-by-process format, please provide the following information:
1. Is the product of the recited process novel? [If the answer
to question F.1 is ``no,'' stop. The patent cannot be listed. If
yes, please identify the claim(s) by number.]
Another comment thought that few drugs would be the subject of a
product-by-process patent. The comment recommended that we investigate
any product-by-process patents that were listed in the Orange Book to
see if these related to the NDA drug product. Yet another comment would
amend the patent declaration to identify the product-by-process claims
in the patent, the effective filing date of the patent application,
whether the product has been previously sold, and, if the product had
been previously sold, whether such sales occurred more than 1 year
before the effective filing date of the patent application. The comment
explained that if the drug's active ingredient has been previously sold
for more than 1 year before the effective filing date of the product-
by-process patent
[[Page 36680]]
application, the patent would be ineligible for listing because the
patent would violate a specific provision in patent law.
In contrast, three comments supported listing product-by-process
patents. These comments agreed that product-by-process patents are a
form of a product patent. Two comments stated that we did not need to
revise the rule to distinguish between product-by-process patents
(which must be listed) and process patents (which must not be listed).
The comment suggested revising Sec. 314.53(b) to replace its mention
of product-by-process patents with ``patents that claim the drug
substance or drug product at least in part in terms of its method of
manufacture (product-by-process patents).''
(Response) We agree that, to be submitted for listing, the product-
by-process patent must claim the drug product that is the subject of
the NDA. We explained in the proposed rule why a product-by-process
patent is a type of product patent (see 67 FR 65448 at 65452). We also
agree that the declaration should be clear enough to ensure that the
patents that are submitted for listing are product-by-process patents
and not process patents. In the response to comment 12 in section II.A
of this document we detail the changes we have made to the declaration
(including declaration forms) to help ensure that the patents submitted
for listing are patents that claim the drug product that is the subject
of the NDA and do not claim the process that is used to manufacture the
drug product.
The declaration forms include a question which requires the NDA
applicant or holder or patent owner to certify whether the patent being
submitted is a product-by-process patent in which the product claimed
is novel. Although we do not adopt the wording suggested by several
comments, we agree that a requirement to identify the product as novel
will help ensure that the patent is a product-by-process patent. We
acknowledge that when the PTO issues a patent, the PTO necessarily
determines that some aspect of the patent claims is ``novel.'' We want
to make sure that the NDA applicant or holder or patent owner is
identifying the product claim as the novel aspect. This clarification
should eliminate the submission of patents that may be mistakenly
identified as product-by-process patents but, in reality, are process
patents which cannot be submitted for listing.
We expect that product-by-process patents will not be submitted
often. Drug products approved under section 505 of the act typically
are capable of being described by their chemical formula. Most such
drug products approved are not of the type that can be described only
in terms of the process used to produce the product. We decline to add
any additional questions to the declaration relating to the patented
product's length of time in the commercial market or other related
questions, as we believe that the declaration questions we have added
will accomplish the clarification necessary to prevent the submission
of process patents.
c. Patents Claiming Packaging--Do We Consider Containers and
Delivery Systems to be ``Packaging?'' Proposed Sec. 314.53(b) would
not have allowed an applicant to list a patent that claimed packaging.
(Comment 3) Most comments agreed that patents claiming packaging
should not be submitted for listing. However, some comments stated that
patents claiming devices or containers that are ``integral'' to the
drug product or require prior FDA approval should be submitted and
listed. These comments distinguished between packaging and devices such
as metered dose inhalers and transdermal patches, which are drug
delivery systems used and approved in combination with a drug.
(Response) We agree that patents claiming a package or container
must not be submitted. Such packaging and containers are distinct from
the drug product and thus fall outside of the requirements for patent
submission. However, we have clarified the rule to ensure that if the
patent claims the drug product as defined in Sec. 314.3, the patent
must be submitted for listing.
Section 314.3 defines a ``drug product'' as ``* * * a finished
dosage form, for example, tablet, capsule, or solution, that contains a
drug substance, generally, but not necessarily, in association with one
or more other ingredients.'' The appendix in the Orange Book lists
current dosage forms for approved drug products. The list includes
metered aerosols, capsules, metered sprays, gels, and pre-filled drug
delivery systems. The key factor is whether the patent being submitted
claims the finished dosage form of the approved drug product. Patents
must not be submitted for bottles or containers and other packaging, as
these are not ``dosage forms.'' The revised declaration requirements,
described in the response to comment 12 in section II.A of this
document, detail the information required for submission.
d. Patents Claiming Metabolites--Are Any Patents Claiming
Metabolites Eligible for Submission and Listing? The proposed rule
would prohibit submission and listing of a patent claiming a metabolite
of the approved drug. A metabolite is the chemical compound that
results after the active ingredient of the drug has broken down inside
the body. We explained that a patent claiming a metabolite does not
claim the approved drug, as required by the act, because the metabolite
exists only after the approved drug has been broken down inside the
body (see 67 FR at 65451).
(Comment 4) Most comments agreed with our exclusion of patents
claiming a metabolite. One comment, however, asked whether we would
list ``a patent that claims a method of using an approved drug to
administer a metabolite.'' The comment distinguished a method-of-use
patent from a patent that claimed the metabolite.
(Response) The final rule prohibits submission of patents claiming
metabolites when the metabolite is not the active ingredient described
in the NDA. The submission of a metabolite patent does not meet the
legal requirements for patent submissions as discussed in the proposed
rule (see 67 FR 65448 at 65451). By contrast, if a patent submitted for
listing claimed an approved method of using an approved drug to
administer a metabolite, the submission of the patent would be
permissible as long as all the conditions for submitting ``method-of-
use'' patents are met. We describe the requirements for submission of
method-of-use patents in the response to comment 7 in section II.A of
this document. Briefly, if a method of use is described in the labeling
for the drug product, and there is a patent claiming that method of
use, the patent must be submitted for listing in the Orange Book, the
method-of-use claim must be identified in the declaration forms, and
the labeling language related to the method-of-use claim must be
provided in the declaration forms.
e. Patents Claiming Intermediates--Must We Allow Them to Be
Submitted? The proposed rule would not allow the submission of patents
that claimed an intermediate. We explained that intermediates are
materials that are produced during preparation of the active ingredient
and are not present in the finished drug product. We consider
intermediates to be ``in-process materials'' rather than drug
substances or components in the finished drug product (see 67 FR 65448
at 65451 to 65452).
(Comment 5 and Response) The comments that addressed this issue
agreed with the proposal. Consequently,
[[Page 36681]]
the final rule does not allow submission of patents that claim
intermediates for the reasons explained in the proposal.
f. ``Double'' Patents--What Are They, and Must We Allow Them to Be
Submitted? The proposal did not discuss ``double'' patents.
(Comment 6) One comment suggested that we prohibit the listing of
patents that contain a terminal disclaimer over a patent that had
already been listed. The comment explained that patent law generally
prevents an inventor from double patenting--that is, extending the term
of the patent ``by the subsequent patenting of variations that are not
patentably distinct from the first-patented invention.'' The comment
stated that this ``double patenting'' can be cured if the patent holder
files a ``terminal disclaimer'' which ``acts to disclaim the term of
the later patent that extends beyond the term of the original patent,
so that both patents expire on the same day.'' The comment expressed
concern that NDA holders could list a later patent and have an
opportunity to obtain a 30-month stay even if the later listed patent
had a terminal disclaimer. In other words, the terminal disclaimer
would prevent the inventor from enjoying a longer term of patent
protection, but it would not prevent the imposition of another 30-month
stay if the NDA holder or patent owner sued to enforce the later
patent. The comment noted that, for the drugs PAXIL and FOSAMAX, the
NDA holder had submitted earlier patents and a later-issued patent that
had a terminal disclaimer. The patents were listed in the Orange Book,
paragraph IV certifications were required for both patents and the NDA
holder sued ANDA applicants on both patents, triggering 30-month stays.
(Response) We acknowledge that the ``double patenting'' described
by the comment may, indeed, provide an NDA holder an opportunity to
obtain an additional 30-month stay under the prior interpretation of
the act. Under the final rule, there is no opportunity for multiple 30-
month stays if patents with terminal disclaimers are submitted for
listing. If such a patent is submitted after an ANDA applicant has
filed a paragraph IV certification to a previously filed patent, and
one full opportunity was provided for the 30-month stay, no notice need
be given for a subsequent paragraph IV certification and no additional
30-month stay for that ANDA applicant can result under the final rule.
The act expressly contemplates listing of patents after NDA
approval. It does not prevent an NDA holder or patent owner from
submitting a patent with a terminal disclaimer. As long as the patent
meets the statutory requirements, the patent must be submitted, even if
it contains a terminal disclaimer. Again, we note that the PTO is
responsible for the issuance of such patents. We defer to the PTO on
matters of patent issuance.
g. Method-of-Use Patents--Must the ``Use'' Be Approved in the
Approved Drug Product? The preamble to the proposed rule mentioned that
patents claiming a method of use would be able to be submitted, but did
not address such patents except to confirm our position that patents
may not be submitted for listing if they claim methods of use that are
not approved for the listed drug or are not the subject of a pending
application.
(Comment 7) Comments disagreed as to whether the method-of-use
claim in a patent submitted for listing must be a use approved in the
NDA. Several comments urged us to list only those patents claiming
methods of use approved in the NDA or that required clinical trials.
One comment argued that listing only patents for approved uses was the
only way to stop NDA holders from claiming broad uses or indications
not in the approved labeling. In contrast, other comments argued that
the act did not prevent NDA applicants or holders or patent owners from
submitting patents for listing that claimed uses not approved by FDA.
Some comments stated that patent infringement is not limited to
approved uses. Other comments stated that section 505(b)(1) of the act
contemplates the listing of patents claiming unapproved uses if a claim
of patent infringement could reasonably be asserted, citing Purepac
Pharm. Co. v. Thompson, 238 F. Supp. 2d 191 (D.D.C. 2002) (Purepac).
(Response) If an NDA applicant or holder or patent owner intends to
submit information on a patent that claims a method of use, the patent
must claim a use that is described in the NDA. If we have already
approved the NDA, the patent must claim a method of use that is in the
labeling of the approved NDA. This has been our position since before
we issued the final patent information rule in 1994 (see 59 FR 50338,
50363-50364 (Oct. 3, 1994)). The pre-existing requirement can be found
at Sec. 314.53(b) and (c)(2).
Sections 505(b) and (c) of the act support our position that only
patents claiming approved methods of use be submitted for listing.
Section 505(b)(1) of the act provides that the NDA applicant ``shall
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 * * * .'' The
corresponding language in section 505(c)(2) of the act is nearly
identical. Only method-of-use patents ``which claim the drug for which
the applicant submitted the application'' must be listed. ``Drug'' is
an ambiguous term, one which, for many years, we have consistently
interpreted in the Hatch-Waxman Amendments to refer to the drug
product. One court has said that:
The meaning of the word ``drug'' in 21 U.S.C.Sec. 355(b)(1)
cannot be determined apart from its context. Neither the FDA nor
this court disputes that the definition of drug in Sec. 321(g)
covers both drug products and active ingredients. The relevant
statutory section in this case, however, modifies the word ``drug''
by attaching the phrase ``for which the applicant submitted the
application.'' In that context the FDA's interpretation of drug as
meaning drug product is consistent with and indeed required by the
statute.
(See Pfizer, Inc. v. FDA, 753 F. Supp. 171, 176 (D. Md. 1990).) All of
the benefits afforded NDA holders under the Hatch-Waxman Amendments,
such as the 30-month stay, derive from obtaining our approval of a
particular drug product. Accordingly, only method-of-use patents that
claim a use of the drug product in the pending or approved application
must be submitted. Method-of-use patents for uses that the NDA holder
``has not chosen to make available to the public'' (id. at 177) must
not be submitted for listing.
This construction of the statute is also supported by the more
recent case law. Since we issued the proposed rule, there have been
several judicial opinions discussing method-of-use patents. In Purepac
Pharm. Co. v. Thompson, 238 F. Supp. 2d 191 (D.D.C. 2002), and in the
related case TorPharm, Inc. v. Thompson, Civ. No. 03-0254 (D.D.C. April
25, 2003) (appeal pending for both Purepac and TorPharm), the district
court held that, where a patent did not claim a use approved in the
NDA, an ANDA applicant could not be required to certify to that patent,
and the agency could properly find that no ANDA applicant was entitled
to 180-day exclusivity on that patent. In Warner-Lambert Co. v. Apotex
Corp., 316 F.3d 1348 (Fed. Cir. 2003), the Federal Circuit held that an
ANDA applicant does not need to certify to a patent claiming a use not
covered by the applicable NDA, and there is no cause of action against
an ANDA applicant for patent infringement under 35 U.S.C. 271(e)(2)(A)
for patents that claim an unapproved use. In Allergan, Inc. v. Alcon
Labs., Inc., 324 F.3d 1322 (Fed.
[[Page 36682]]
Cir. 2003), the Federal Circuit issued a per curium opinion that held
that a method-of-use patent holder does not have an infringement action
against an ANDA applicant when the use claimed in the patent is not FDA
approved and the ANDA applicant is not seeking approval of that use.
These decisions are consistent with our position that sponsors must not
submit method-of-use patents that do not claim an approved use for
listing in the Orange Book. They also highlight the need for an
improved declaration that will clarify the claimed scope of the method-
of-use patents being submitted.
We have modified the required declaration relating to method-of-use
patents submitted. Although we agree, as discussed in the response to
comment 11 of section II.A of this document, that each individual claim
of a patent does not need to be listed on the declaration forms for
drug substance and drug product patents, we do require identification
of individual claims for method-of-use patents. The declarant must
describe each individual method of use for which a patent is submitted
for listing, and identify the corresponding language found in the
labeling of the approved NDA that corresponds to that method of use.
This information will expedite our review of ANDA and 505(b)(2)
applications that do not seek approval for all the approved uses. In
determining whether an ANDA applicant can ``carve out'' the method of
use, rather than certify to the listed patent, we will rely on the
description of the approved use provided by the NDA holder or patent
owner in the patent declaration and listed in the Orange Book.
The need for accurate and detailed information related to the
approved methods of use claimed in the patent being submitted for
listing is underscored by the decision in Purepac Pharm. Co. v.
Thompson, 238 F. Supp. 2d 191 (D.D.C. 2002). In that case, the NDA
holder submitted information on a patent claiming what was later
determined to be an unapproved use of the approved drug product. This
submission was accompanied by the required signed declaration from the
NDA holder that the patent covered the method of use for the approved
product. Accordingly, we listed the patent and the use code information
submitted with the patent. Years later, well after litigation over this
patent was underway, the NDA holder clarified to FDA that the patent
did not, in fact, claim the use for which the NDA was approved.
This submission of inappropriate patent information led to
confusion and then to litigation over an ANDA applicant's obligation to
submit either a paragraph IV certification under section
505(j)(2)(A)(vii)(IV) of the act or a ``section viii'' statement under
section 505(j)(2)(A)(viii) of the act. The section viii statement,
which is also applicable to 505(b)(2) applications, permits the ANDA or
505(b)(2) applicant to avoid certifying to a patent by stating that it
is not seeking approval for the use claimed in the listed patent. A
section viii statement does not carry the requirement for notice to the
NDA holder and patent owner, and the related opportunity for a 30-month
stay.
We have implemented the section viii provisions of the act by
deferring to the NDA holder's or patent owner's assertion that the
method-of-use patent claims an approved use of the drug product. When
the NDA holder or patent owner submits a method-of-use patent for an
approved NDA, we rely upon the requirements in the regulations and the
required declaration as the evidence that the patent claims an approved
use. Therefore, when an ANDA applicant has sought to duplicate the
labeling for which the innovator has submitted the patent, and not to
specifically omit, or ``carve out'' labeling, we require the ANDA
applicant to submit a certification to that patent. A section viii
statement would not be appropriate because the ANDA applicant is
seeking approval for exactly the same labeling as that in the NDA for
which the patent was submitted.
Our position has been that, for an ANDA applicant to file a section
viii statement, it must ``carve out'' from the proposed ANDA labeling,
the labeling protected by the listed patent. Unless the ANDA applicant
can show that it is carving out certain method-of-use labeling, a
section viii statement is not a correct submission for the listed
patent. In Purepac, the court rejected our reliance on the regulations
and the general declaration as a reasonable basis for this approach to
implementation. The court specifically pointed to the patent
submissions in the case, and noted that the NDA holder had not complied
with the requirement that NDA holders submit only those patents
claiming an approved use for the drug. Although the court noted that
the facts in Purepac were unique (the NDA holder later admitted that it
made its submission ``without regard'' to FDA's regulations), there may
be other cases in which NDA holders have submitted patents claiming
unapproved uses of approved drug products.
Following the Purepac decision, we have two options for
implementing the section viii statement provisions under sections
505(b)(2)(B) and 505(j)(2)(A)(viii) of the act that intersect with the
patent submission considerations described in the proposed rule. One
approach would be to permit each ANDA and 505(b)(2) applicant to make
its own independent decision on whether a listed method-of-use patent
claims the use for which the ANDA applicant seeks approval, and then to
submit a paragraph IV certification or section viii statement as the
applicant sees fit. The second approach would be to require the NDA
applicant or holder to identify specifically the approved uses claimed
by the method-of-use patent, with reference to the approved labeling,
and declare under penalty of perjury that the patent claims an approved
use. This would permit ANDA and 505(b)(2) applicants, and us, to assess
whether the ANDA or 505(b)(2) applicant is seeking approval for a use
the sponsor states is claimed in the listed patent, and thus determine
whether the applicant must submit a patent certification or may submit
a section viii statement under section 505(b)(2)(B) or
505(j)(2)(A)(viii) of the act.
In the absence of explicit statutory language, we believe an
approach that requires the NDA applicant or holder or patent owner to
identify the approved methods of use protected by the patent is most
consistent with the general balance adopted in Hatch-Waxman. This
approach permits the NDA applicant or holder to determine which patents
claim its approved drug product and then, when appropriate, to resolve
disputes over infringement of those patents through patent litigation.
If ANDA and 505(b)(2) applicants could always avoid the possibility of
a 30-month stay by asserting in a section viii statement that certain
labeling for which the applicant is seeking approval is not protected
by a listed method-of-use patent--despite the NDA holder's assertion to
the contrary--there would be little reason for any applicant to submit
a paragraph IV certification for a method-of-use patent. This approach
would essentially eliminate the certification, notice, and litigation
process as to any listed method-of-use patent, producing an outcome
that is inconsistent with the act.
To effectively implement the certification and section viii
statement provisions set out in the statute, we must have adequate
information concerning method-of-use patents. Since 1994, we have
requested, but not required, that NDA applicants submit to FDA
information on the approved use claimed by the patent. Since the
[[Page 36683]]
Purepac case and other instances have raised questions about what
aspects of the approved drug are claimed by a listed use patent, we
believe that it is necessary that an NDA holder submit more specific
information on the approved methods of use protected by a submitted
patent. Only with this information can we determine what submission is
required of the ANDA and 505(b)(2) applicants referencing the approved
drug.
We further note that we list methods of use for approved products
in the Orange Book in the section on use codes. Due to the limitations
of our database system and software constraints, we are limited to
using 240 total characters for the use code description in the Orange
Book. Traditionally, we have created the use code description for the
Orange Book from the information submitted by the NDA applicant or
holder. After considering the comments, and in light of the previously
described litigation, we have determined that it is more efficient and
accurate to ask the NDA holder to give us the exact use code
description to be published in the Orange Book. Use codes are intended
to alert ANDA and 505(b)(2) applicants to the existence of a patent
that claims an approved use. They are not meant to substitute for the
applicant's review of the patent and the approved labeling. We
understand that in some cases 240 characters may not fully describe the
use as claimed in the patent. The declaration, which includes the
complete description of the method-of-use claim and the corresponding
language in the labeling of the approved drug, will be publicly
available after NDA approval.
h. Miscellaneous Patent Listing Comments. i. Should We Create an
Administrative Process to Challenge Patent Listings or to De-List
Patents or to Review the Listability of Patents? The proposed rule did
not propose an administrative process for challenging patent listings
or for seeking removal of a patent from the Orange Book, nor did we
propose a new process to internally review the patents for listability.
(Comment 8) Several comments stated that parties, such as generic
drug companies and even third parties, need a method for challenging
patent listings or for de-listing patents in the Orange Book. Some
comments explained that the lack of an administrative procedure for
challenging patent listings either encouraged NDA applicants to submit
inappropriate patent information, or did not deter the practice, to
delay generic competition. A number of comments maintained that FDA has
more than a ministerial role and should review patents to determine if
they meet the requirements for listing. Several comments contend that
we have the authority to determine the attributes of the approved drug
and thus to determine the appropriate patent listings. Various
administrative mechanisms were suggested through which FDA could
conduct a review of patents. These suggestions ranged from hiring
patent lawyers to review submitted patents to development of a full
administrative hearing process.
One comment stated that patent owners need an administrative
process to enforce the listing of their patents because an NDA holder
might ``fail'' to list eligible patents.
(Response) A fundamental assumption of the Hatch-Waxman Amendments
is that the courts are the appropriate mechanism for the resolution of
disputes about the scope and validity of patents. The courts have the
experience, expertise, and authority to address complex and important
issues of patent law. This final rule supports that assumption in two
ways. First, the final rule clarifies what patents must and must not be
submitted for listing. This will make it easier for NDA applicants and
holders and patent owners to avoid inadvertently submitting patents
that do not meet the statutory and regulatory requirements. The
clarification will reduce the pressure on us to intercede in patent
listing disputes and will allow the courts and parties to focus on the
ultimate issue of patent invalidity or non-infringement. Second, the
final rule requires NDA applicants or holders or patent owners to
submit detailed information and to certify to its correctness. This
should further ensure that only patents meeting the statutory
requirements will be submitted for listing.
We decline to create an additional administrative process for
challenging patent listings beyond that already established in Sec.
314.53(f). We also decline to create a new process for de-listing
patents or for internal FDA review of patents beyond the limited review
of the patent declaration described in this final rule. Section
505(b)(1) of the act directs NDA applicants to submit certain patent
information. It requires that ``[u]pon approval of the application, the
Secretary shall publish'' the patent information (emphasis added). In
section 505(j)(7)(A)(ii) and (iii) the statute mandates that we publish
revisions to this information every 30 days. These short time frames do
not contemplate a substantive agency review of the scope of the patent
and its application to the approved drug product. Indeed, the
requirement of prompt publication (``upon submission''), combined with
the 30-day timeframe for updating the Orange Book, are strong evidence
that Congress did not intend us to undertake anything other than a
ministerial action.
In addition to the absence of any statutory basis for a substantive
agency review of patents, we have long observed that we lack expertise
in patent matters. An administrative process for reviewing patents,
assessing patent challenges, and de-listing patents would involve
patent law issues that are outside both our expertise and our
authority. Although we will continue to relay questions about the
accuracy of a patent submission to the NDA holder (see Sec.
314.53(f)), our patent listing role remains ministerial. Courts have
upheld our determination that our role with respect to patent listing
is ministerial. (See aai Pharma v. Thompson, 296 F.3d 227, 242-43 (4th
Cir. 2002), cert. denied, 123 S. Ct. 1582 (2003); American Biosci.,
Inc. v. Thompson, 269 F.3d 1077, 1084 (D.C. Cir. 2001); In re Buspirone
Patent Litigation, 185 F. Supp. 2d 363, 371 (S.D.N.Y. 2002); Watson
Pharm., Inc. v. Henney, 194 F. Supp. 2d 442, 445-446 (D. Md. 2001);
Mylan Pharm., Inc. v. Thompson, 139 F. Supp. 2d 1, 10-11 (D.D.C.),
rev'd on other grounds, 268 F.3d 1323 (Fed. Cir. 2001).) We recognize
that one court has held that parties have no private right of action to
seek de-listing of patents (see Mylan Pharmaceuticals, Inc. v.
Thompson, 268 F.3d 1323 (Fed. Cir. 2001)). Nevertheless, it would be
inappropriate and impractical for us to create regulatory mechanisms
for reviewing patent listings or permitting third parties to submit
patents for listing. We lack both the resources and the expertise to
resolve such matters.
Furthermore, even if we were to establish an administrative process
for patent review, our decisions on these patent listing matters would
inevitably lead to disputes and increased litigation against us. This
litigation could question whether such an administrative process was
within our legal authority. Even if the courts were to decide that we
may review submitted patents, there would be repeated litigation over
individual patent listing decisions. Given the uncertainty of the
listing status of the challenged patent during the litigation, there is
no assurance that, if we reviewed submitted patents, ANDAs or 505(b)(2)
applications would be approved sooner and generic drugs would enter the
market any more rapidly.
[[Page 36684]]
We agree that there have been a few cases in which legitimate
concerns have been raised about whether specific submitted patents meet
the statutory requirements for submission and listing. We believe that
these concerns will be adequately and efficiently addressed by the
clarification of the types of patents that must and must not be
submitted and by improvements to the patent information required. We
further believe that even if legally permissible, it is not necessary
for us to develop a patent review mechanism. The final rule permits us
to allocate our limited resources to public health activities, while
leaving questions of patent law to the courts, which are better able to
handle such questions. This division of responsibility is fully
consistent with the process established in the Hatch-Waxman Amendments.
(Comment 9) One comment suggested that we create an administrative
mechanism to ensure timely patent infringement litigation if no
statutory notice is provided to the NDA holder.
(Response) We decline to amend the proposed rule as suggested by
the comment. The act does not contemplate that we will play an active
role in determining the timing of patent infringement litigation. In
the absence of the 45-day timetable imposed when notice is given for a
paragraph IV certification, a decision on whether and when to file suit
for patent infringement may depend on multiple variables. For example,
did the NDA holder or patent owner have sufficient information to
decide whether to sue the ANDA or 505(b)(2) applicant for patent
infringement? An ANDA applicant and the NDA holder may disagree on when
the NDA holder had sufficient information to decide to file suit. The
parties may also disagree as to what constitutes ``timely'' litigation.
For example, an NDA holder who defers filing a lawsuit on a later-filed
patent until a 30-month stay has elapsed may feel that the subsequent
litigation is still ``timely,'' given the information available to the
NDA holder. The ANDA or 505(b)(2) applicant may view this latter
lawsuit as an obstacle to marketing its drug product. Given the limits
of our statutory authority as well as complex issues of patent
litigation strategy that lie outside our expertise, we decline to
create a mechanism to ensure ``timely'' patent litigation in situations
where the NDA holder and patent owner did not receive notice of
subsequent paragraph IV certifications.
ii. Should There Be Time Limits on Patent Submissions or
Certifications? The proposed rule did not specify when patent
information would need to be submitted, or whether ANDA or 505(b)(2)
applicants would need to provide certifications for patents listed
after they had filed an ANDA or 505(b)(2) application.
(Comment 10) Several comments suggested revising the rule to create
time limits relating to the submission of patent information or patent
certifications. For example, one comment asserted that ``abuse'' occurs
when NDA holders submit non-meritorious patent information to us
shortly before an earlier-submitted patent is to expire. Another
comment suggested that we limit the time during which NDA holders can
submit patent information to a defined time period after we have
approved their NDAs. Another comment said we should not require ANDA
applicants to submit amended patent certifications if the patent was
submitted after the first ANDA had been filed.
Similarly, one comment asserted that a patent submitted after NDA
approval cannot claim the approved drug product because the later-
submitted patent would be invalid. The comment explained that, under
patent law, a person cannot obtain a patent if the subject of the
patent is known and therefore ``anticipated'' under patent law.
(Response) We decline to amend the proposed rule as suggested by
the comments. The act clearly contemplates the submission of additional
patent information after an NDA has been filed. For example, section
505(b)(1) of the act instructs applicants to amend their NDAs to
include information on a patent issued after the NDA has been filed,
but before the NDA has been approved, which claims the drug or a method
of using the drug that is the subject of the application. Section
505(c)(2) of the act directs NDA holders to submit patent information
if the patent issued after we have approved the NDA. We do not
interpret the act as permitting us to refuse to accept submissions of
new patents either after an NDA has been filed or approved, or after an
ANDA has been submitted.
Section 505(c)(2) of the act also instructs NDA holders to submit
information on patents issued after NDA approval no later than 30 days
after the date the patent issued. This deadline ensures prompt public
notice that the NDA holder believes the patent claims the approved drug
product and permits legal issues regarding these later-issued patents
to be resolved as early as possible. Under Sec. 314.94(a)(12)(vi), we
do not require an ANDA or 505(b)(2) applicant with a pending
application to certify to a patent issued after NDA approval but not
submitted to us within 30 days after issuance. However, the patent will
be listed in the Orange Book upon submission of a complete declaration,
and ANDA and 505(b)(2) applications filed after the patent is listed
will be required to contain a certification to the patent. This
longstanding interpretation is consistent with the statutory language
describing patent submission deadlines, the notice concept inherent in
patent publication, and early judicial resolution of patent disputes.
We are not persuaded by the comments that we should change our
interpretation.
We believe that removing the possibility of multiple 30-month stays
per ANDA will diminish the incentive to obtain additional patents late
in the patent life of the product described in the NDA. As described in
the FTC Report, of the patents reviewed by FTC, many of the patents
submitted well after NDA approval, and usually after an ANDA
application was filed, were ultimately found to be invalid. Therefore,
in the absence of the 30-month stay, these patents would have been
unlikely to serve as a basis for a preliminary injunction precluding
market entry of generic drugs.
We also decline to amend the proposed rule to exempt ANDA
applicants from submitting patent certifications if the patent was
listed after the ANDA was filed. Our pre-existing regulations do not
require ANDA applicants to amend their patent certifications if:
[sbull] The NDA holder failed to provide the required patent
information within 30 days after the issuance of the patent; and
[sbull] The ANDA had already been submitted and had contained an
appropriate patent certification before the submission of new patent
information (see Sec. 314.94(a)(12)(vi)).
However, if the NDA holder has submitted patent information in a
timely manner, consistent with section 505(c)(2) of the act, then
section 505(j)(2)(A)(vii) of the act requires the ANDA applicant to
certify to that patent. Section 505(j)(2)(A)(vii) of the act requires
ANDA applicants to provide a certification with respect to ``each
patent which claims the listed drug,'' not only patents that are listed
at the time the ANDA is submitted. The act contemplates the submission
of patent certifications even if the patent was listed after the ANDA
or 505(b)(2) application had been submitted.
We do not have the authority to declare any patent to be invalid.
We leave questions regarding the issuance
[[Page 36685]]
and validity of patents to the PTO and the courts.
iii. What Should the Patent Declaration Say? (Proposed Sec.
314.53(c)). Proposed Sec. 314.53(c) would require a patent declaration
for NDA applicants and holders and patent owners to complete as part of
the NDA, an amendment, a supplement, or for information on a later-
issued patent. The proposed revised declaration in the proposal was a
``checklist'' that focused on individual patent claims. The proposed
declaration required information on each claim to help ensure that
applicants submit only appropriate patent information, and that they
stand behind the accuracy of the information. The proposed requirement
to identify claims was intended to help all parties focus on the same
claim and help prevent arguments as to whether a particular claim
claimed the approved drug product.
(1) Should the Declaration Identify Individual Patent Claims?
(Comment 11) Several comments objected to identifying patent claims
as part of the declaration. The comments stated that a claim-by-claim
listing:
[sbull] Would be ``unnecessarily onerous'' because patents may
contain many claims;
[sbull] Could threaten the patent holder's legitimate rights if the
NDA applicant failed to list a patent claim because the failure to list
that claim could be used as an admission against the NDA holder's or
patent owner's interests in litigation;
[sbull] Could expose the NDA holder to criminal and civil liability
if the claim cited in the declaration is later found not to claim the
drug; or,
[sbull] Is irrelevant to patent listing because the patent, and not
the patent claims, is what we must list in the Orange Book.
Other comments supported the claim-by-claim listing. Some comments
requested that we impose a 30-month stay only if the specific claims
submitted in the patent declaration were the subject of the patent
litigation filed within the 45-day time period.
(Response) We have re-examined our rationale for proposing a claim-
by-claim listing and have concluded that submission of a claim-by-claim
declaration for all patents is not warranted. Such detailed information
is not explicitly required by the act and is not necessary for a patent
to be listed in the Orange Book. Section 505(b)(1) of the act requires
that the patent be one that ``claims the drug for which the applicant
submitted the application or which claims a method of using such drug
and with respect to which a claim of patent infringement could
reasonably be asserted * * *.'' The number of claims contained within a
particular patent does not affect the ability of the patent to be
listed as long as there is at least one claim that meets the two
required elements.
Individual patent claims are relevant for purposes of the Orange
Book only in the context of method-of-use patents. The specific method-
of-use claims are essential to our review because sections
505(j)(2)(A)(viii) and 505(b)(2)(B) of the act allow ANDA and 505(b)(2)
applicants to file statements which assert that the method-of-use
patent does not claim a use for which the applicant is seeking
approval. The ANDA or 505(b)(2) applicant does not have to seek
approval for all uses approved for the reference listed drug. Thus, the
claim-by-claim listing of method-of-use patents will permit ANDA and
505(b)(2) applicants to assess whether they are seeking approval for a
use claimed in the listed patent, and thus determine whether to submit
a patent certification or a section viii statement. Additionally, we
can verify that the certification or statement is correct, and that
only the appropriate methods of use are included in the proposed
labeling for the ANDA or 505(b)(2) drug product.
We decline to adopt the recommendation made in some comments to
require all claims to be listed and then provide a 30-month stay only
for litigation involving a claim listed in the Orange Book. This
suggestion would require us to significantly exceed our ministerial
responsibility in listing patents because we would be obliged to
evaluate patent lawsuits and their relation to individual patent
claims. We discuss our ministerial role in the response to comment 8.
Removing the proposed requirement of a claim-by-claim listing in the
final rule should not be detrimental to ANDA or 505(b)(2) applicants.
In fact, several generic companies, the FTC and the Generic
Pharmaceutical Association (GPhA), stated in their comments that no
``prudent generic company'' would rely solely on Orange Book listings
to evaluate patent information for litigation exposure, particularly
when all patents cannot be listed in the Orange Book. Thus, we believe
that identification of the relevant patent(s), as opposed to the
individual patent claims (other than for method-of-use patents),
satisfies the act's explicit requirements, provides sufficient
information to potential applicants to determine if a more thorough
patent search or analysis is warranted, and will help to ensure
appropriate patent submissions.
(2) Should the Declaration Be Expanded or Modified? The proposed
rule would revise Sec. 314.53(c)(2) and would replace the existing,
general declaration with a more detailed declaration. The proposed
declaration would be a ``checklist'' that required information on the
approved drug product including trade name, active ingredient(s),
strength(s), dosage form(s), and approval date. For each patent
submitted, each claim of a patent which applied to the drug substance
(active ingredient), drug product (formulation or composition), and
method of use would need identification. A ``yes'' or ``no'' check-off
would be required as to each individual applicable patent claim. The
proposed Sec. 314.53 would require the NDA applicant or holder or
patent owner to state in the declaration that the information was
provided for an NDA submitted under section 505 of the act.
(Comment 12) Several comments supported our proposed changes to the
declaration but also suggested additions to the declaration. These
comments would add the following information to the declaration:
[sbull] Specific exclusions of patents for forms of the active
ingredient not marketed, such as acids, freebases, salts, and isomers;
[sbull] Exclusion of patents claiming labeling matters such as
business methods, registries, titration/dosing schedules, or ornamental
designs;
[sbull] Exclusion of a patent claiming a drug substance claimed in
conjunction with another active ingredient or method of using the
combination which is not the claimed drug substance;
[sbull] Various forms of statements indicating or certifying the
submitter has filed accurate information;
[sbull] Identification of the NDA applicant's pending patent
applications; and
[sbull] Additional information for product-by-process patents.
The comments suggested that it was necessary to identify each of
the excluded patents in the declaration form and the codified text.
Several comments suggested requiring a sworn statement and an
acknowledgement that a false statement was subject to criminal
penalties. For example, one comment suggested that the declaration
include the statement: ``The undersigned declares that all of the above
information has been provided in accordance with Title 28, section
1746, entitled `Unsworn declarations under penalty of perjury',''
followed by the signature, date, title, and telephone
[[Page 36686]]
number. The comment also would require additional information on
patents in the declaration form to identify that the product in the
product-by-process patent was a novel product.
(Response) We agree, in part, with the comments that the
information that would be required in the declaration should be
modified. Also, we have created standardized declaration forms which
will encompass the required patent declaration information.
The final rule changes the general requirements in pre-existing
Sec. 314.53(c)(1) by requiring that the patent information which must
be submitted must be provided on the declaration forms in full. In
final Sec. 314.53(c)(2), we substitute declaration forms which must be
used in place of the checklist described in the proposed rule. Each
declaration form is a standard form that must be used by all NDA
applicants or holders or patent owners for submission of patent
information at the time of initial NDA or supplement filing, and upon
and after NDA or supplement approval.
For several years our Internet Web site has included a sample
format which can be used in submitting patent information required
under pre-existing regulations. Although use of the sample format is
purely voluntary, it is used extensively to submit patent information
to us. Based on this experience, and given the additional information
required in the final rule, we concluded that mandatory declaration
forms are appropriate to obtain the patent information. We, thus,
require use of forms in the final rule. Since we determined that forms
are appropriate, we have consolidated information currently required by
pre-existing regulations with the new required information. For
example, we require a response on whether there are relevant patents
related to the drug product, information currently required under pre-
existing Sec. 314.53(c)(3). This was not contained in the proposal
but, for administrative efficiency, and to lessen the burden on NDA
applicants or holders or patent owners, we have included in the
declaration forms all of the required information relating to the
patent submission.
The NDA applicant must provide a declaration form when an NDA,
amendment, or supplement to an NDA is filed. The NDA holder must also
submit another declaration form after NDA or supplement approval to
provide information on all patents relevant to the approved NDA or
supplement, whether or not information on any such patent was
previously submitted. The declaration forms filed with us must be
attested to as to the accuracy of the patent information being
submitted. Examples of the two declaration forms, FDA Form 3542 and
3542a, are provided in the Appendix found at the end of this document.
The declaration forms will be available on the Internet at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov
by searching for the word ``forms''.
The final rule also revises pre-existing Sec. 314.53(c)(2)(ii) and
(c)(3) to conform to the changes we made to the patent information
required on the declaration forms. The final rule requires a
declaration form to be filed with us within 30 days after NDA approval;
this is consistent with the pre-existing requirement. This form must
also be used to file patent information on any patents submitted or
issued after NDA approval. This declaration form requires the NDA
holder or patent owner to provide the patent information applicable to
the approved NDA. It is similar to the declaration form filed upon the
filing of an NDA, supplement, or amendment. However, the declaration
form filed upon or after NDA approval requires information on the
approved product and a description of the approved methods of use for
the use code listing in the Orange Book. This description will be
limited to 240 characters as discussed in the response to comment 7.
The final rule describes other information required for the
declaration forms not identified in the proposed rule. Some of the
additional information will allow us to more easily determine the
eligibility of the patent for listing, while other information will
provide more complete information related to the responsibilities of
the NDA holders or ANDA applicants. For example, we require the issue
date of the patent in order to determine whether the patent has been
submitted to us within the required 30 days. We require information on
whether the patent being submitted has been submitted previously for
the NDA or supplement referenced in the declaration. For example, an
earlier listed patent may have included several method-of-use claims
but only one method of use previously approved and submitted. A second
method of use may be approved in a supplement and must be submitted for
listing. Such information will assist the Orange Book staff with its
administrative listing responsibilities. The address and contact
information of the patent owner required in the declaration forms will
assist in the required notification to the patent owner of a paragraph
IV certification. We have elaborated on the requirement for asserting
that the polymorph is the ``same'' as the active ingredient approved in
the NDA. We require information on whether the patents submitted claim
metabolites or intermediates to help ensure that the patents prohibited
from submission under final Sec. 314.53(b) are not submitted.
Similarly, we require information on patents claiming the drug product
to prevent the submission of patents claiming packaging.
The final rule also requires information on product-by-process
patents as discussed in the response to comment 2 of section II.A of
this document. We have added a requirement that the NDA applicant or
holder or patent owner state whether the patent being submitted is a
product-by-process patent in which the product claimed is novel. This
is to help ensure that process patents are not submitted for listing.
We agree that the attestation in the declaration form should be
revised in the final rule. In the proposal, we stated that we had
revised the declaration so that applicants would ``make careful and
well-considered representations'' and ``stand behind the accuracy of
that information'' (see 67 FR 65448 at 65453). In the final rule, we
revise the statement to be more specific about the need to ensure the
information is accurate. We adopt the attestation statement contained
in 28 U.S.C. 1746 for unsworn declarations and include attestations in
the declaration forms. The attestation statements in the declaration
forms read as follows:
(Declaration Form 3542a submitted with NDA, amendment or
supplement.)
The undersigned declares that this is an accurate and complete
submission of patent information for the NDA, amendment, or
supplement pending under section 505 of the Federal Food, Drug, and
Cosmetic Act. This time-sensitive patent information is submitted
pursuant to 21 CFR 314.53. I attest that I am familiar with 21 CFR
314.53 and this submission complies with the requirements of the
regulation. I verify under penalty of perjury that the foregoing is
true and correct.
(Declaration Form 3542 submitted upon or after NDA approval.)
The undersigned declares that this is an accurate and complete
submission of patent information for the NDA or supplement approved
under section 505 of the Federal Food, Drug, and Cosmetic Act. This
time-sensitive patent information is submitted pursuant to 21 CFR
314.53. I attest that I am familiar with 21 CFR 314.53 and this
submission complies with the requirements of the regulation. I
verify under penalty of perjury that the foregoing is true and
correct.
We also include a warning statement in the declaration forms to alert
the submitter that a willfully and knowingly false statement is a
criminal offense under 18 U.S.C. 1001.
[[Page 36687]]
We decline to revise the proposed rule to list every excluded type
of patent as requested by some comments. Based on our experience, we
believe that if we attempted to include questions on all types of
patents, such as ``business method'' or ``registry'' patents, or
specifically list all exclusions in the final rule, there would be
disagreements over whether the examples are all-inclusive or whether
other types of patents were excluded as well. We believe the patent
information requested is sufficient to ensure only eligible patents are
submitted for listing.
We also decline to revise the declaration to require identification
of an NDA applicant or NDA holder's patent applications that are under
review by the PTO. The act does not contain any references to pending
patents. In contrast, sections 505(b) and 505(c)(2) of the act contain
requirements for patent information to be submitted after the patent is
issued. Section 505(b) of the act requires that the information
submitted on any patent claiming the drug include the patent number and
expiration date of the patent. We publish that information when we list
the patent in the Orange Book. A patent number and expiration date are
available only when the PTO issues a patent and are not available for
pending patent applications. Accordingly, we will not require
submission of information regarding pending patent applications.
Although we do not require submission of information concerning
pending patent applications, we understand that pending patent
applications are generally publicly disclosable by the PTO if pending
for more than 18 months at the PTO or foreign patent offices. In
addition, information concerning pending patents would not provide any
useful information if the PTO never issued the patent.
We note that we will not evaluate a patent to assess whether the
declaration is accurate or whether the patent has been appropriately
submitted for listing (see our response to comment 8). We will,
however, review the declaration for completeness and to determine that
the information given by the NDA applicant or holder or patent owner
indicates that the patent is eligible for listing.
Although section 505(b)(1) of the act requires submission of patent
information upon the filing of an NDA, we will rely only on the
declaration form filed upon or after NDA approval under Sec.
314.53(c)(2)(ii) to list patent information in the Orange Book. Patent
information for newly approved NDAs, NDA supplements, or newly issued
patents will not be published in the Orange Book unless and until we
receive a complete declaration submitted post-NDA approval indicating
the patent is eligible for listing.
We interpret the statute to permit listing of only those patents
claiming the approved drug product and its approved uses. Even though
the NDA applicant must submit patent information prior to NDA approval,
it is not until the NDA or supplement has been approved that the scope
of that approval is known. For example, we might approve only one of
two indications proposed in an NDA and, thus, patents on an unapproved
indication or use, although submitted with the original NDA, could not
be listed. Therefore, as a way of confirming or amending the original
patent information, a declaration form must be submitted after
approval. If the declaration form submitted after NDA approval is
incomplete or indicates a patent is not eligible for listing, we will
notify the NDA holder and indicate the reason. The NDA holder must
resubmit the declaration form with complete information indicating that
the patent is eligible for listing. If the declaration form is
incomplete or indicates the patent is not eligible for listing, we will
refuse to list the patent until an appropriate declaration form has
been submitted.
For patents newly issued by the PTO after the NDA is approved,
section 505(c)(2) of the act requires that the NDA holder submit the
patent information to us within 30 days to be considered timely filed.
All such patent information must be contained in a complete declaration
submitted post-NDA approval indicating that the patent is eligible for
listing. A patent is considered listed in the Orange Book as of the
date it is received in the Central Document Room as required in Sec.
314.53(d)(4) and (d)(5), if it is accompanied by a declaration form
that is both complete and contains information indicating that the
patent is eligible for listing. If we must notify an NDA holder that a
declaration form is incomplete or the patent is not eligible for
listing, and the NDA holder then submits an acceptable declaration
within 15 calendar days, we will consider the patent timely filed. So,
for example, suppose an NDA holder submits information on a new patent
to us 20 days after the patent is issued by PTO, and we notify the NDA
holder 5 days later that the declaration is incomplete. If the NDA
holder submits an adequate declaration within 15 calendar days of the
notification, we will consider the patent information to have been
submitted as of the date we originally received it, that is, within the
30 day period allowed by the statute. If the NDA holder submits the
adequate declaration more than 15 calendar days after notification, we
will consider the patent information to have been submitted on the day
the revised declaration form is received, which may be more than 30
days after the date of patent issuance. Such patents will be subject to
patent certification only as described in Sec. 314.94(a)(12)(vi). If
the NDA holder does not submit an adequate declaration for the newly
issued patent, we will not list the patent in the Orange Book. This
approach is appropriate because it gives the NDA holder who promptly
submits information on a newly-issued patent a reasonable period of
time to correct a mistake in a patent declaration, while at the same
time ensuring that there are adequate declarations and minimal delays
for listed patents. We will accept certifications to any patent only
from the date an acceptable declaration is submitted.
The process established in Sec. 314.53(f) for patent listing
challenges is not altered by our requirements for patent information
and declaration forms. Interested parties may still rely on that
process if they believe a patent has been submitted and listed in
error.
We are aware of NDA holders that have submitted patents for listing
that have been listed in the Orange Book and then, at a later time,
been removed from the Orange Book at the NDA holder's request. If,
after the patent has been removed from the Orange Book, the NDA holder
again seeks to submit the patent for listing, we will require
resubmission of the patent information and the filing of an
accompanying patent declaration before the patent will be relisted.
Such resubmission will be governed under the final rule. If the
resubmission of a previously listed patent takes place after the
effective date of this rule, the final rule applies as described in
section IV of this document.
The final rule does not require us to review or evaluate patents,
but will simplify and clarify the submission process for NDA applicants
and holders and patent owners, and will promote administrative
efficiency. The additional information required by the declaration form
will help ensure that only appropriate patents are submitted for
listing.
[[Page 36688]]
2. How Many Times Can an ANDA or Sec. 505(b)(2) Application's Approval
Date Be Delayed by 30-Month Stays?
The proposed rule offered an interpretation of the act that would
limit the number of 30-month stays to only one possible stay per ANDA
or 505(b)(2) application. The proposed interpretation in the proposed
rule differed from our previous interpretation of the act (which
allowed for multiple 30-month stays). Under our proposed
interpretation, the ANDA or 505(b)(2) applicant would continue to file
the appropriate certifications as required under section
505(j)(2)(A)(vii)(I) through (j)(2)(A)(vii)(IV) or section
505(b)(2)(A)(i) through (b)(2)(A)(iv) of the act. However, under the
proposed interpretation in the proposed rule, the notice to the NDA
holder and patent holder of the paragraph IV certification is required
only when a paragraph IV certification is included in the initial ANDA
or 505(b)(2) application or when such an application is amended to
include, for the first time, a paragraph IV certification. Notice to
the NDA holder and patent owner is one of the requirements for a 30-
month stay; if the ANDA or 505(b)(2) applicant is not obliged to
provide a subsequent notice to the patent owner and NDA holder, no
successive 30-month stay is possible.
a. When Must Notice Be Provided and What Is a Full Opportunity for
a 30-Month Stay? The proposed rule would require an ANDA or 505(b)(2)
applicant to provide notice to NDA holders and patent owners only when
the applicant files a paragraph IV certification with the initial
application or amends the application to include a paragraph IV
certification for the first time. If the application were amended to
add additional paragraph IV certifications, no notice to the NDA holder
and patent owner would be required.
(Comment 13) Several comments claimed that the lack of notice for
subsequent paragraph IV certifications would delay initiation of patent
litigation. To avoid this ``delay,'' the comments suggested that, if we
retained our proposed interpretation allowing only one 30-month stay
per ANDA or 505(b)(2) application, we should amend the rule to:
[sbull] Give the ANDA applicant the ``option'' to provide voluntary
notification;
[sbull] Give the ANDA applicant the ``option'' to provide
notification and be subject to an ``optional'' additional 30-month
stay;
[sbull] Require us to notify the NDA holder as to a subsequent
paragraph IV certification.
Similarly, several comments expressed concerns that ANDA and
505(b)(2) applicants could manipulate the rule to avoid even a single
30-month stay. The comments explained that in the absence of notice for
all paragraph IV certifications, there could be several scenarios in
which an ANDA or 505(b)(2) applicant could take advantage of the
regulations to avoid a meaningful 30-month stay under our revised
interpretation. For example, an ANDA or 505(b)(2) applicant could file
a paragraph IV certification on a narrow patent or a narrow patent
claim and provide notice to the NDA holder and patent owner on that
certification, thereby satisfying the regulatory requirements, while
providing a paragraph III certification on broader patents or claims.
The NDA holder or patent owner could bring a patent infringement suit
within the 45 days, triggering a 30-month stay, or decide not to bring
suit on the narrow claim or patent. The comments argued that, after
suit was filed, or after the 45 days expired with no suit initiated,
the ANDA or 505(b)(2) applicant could change the paragraph IV
certification to a paragraph III. If suit had been filed, the applicant
could seek dismissal of the patent infringement suit and avoid the 30-
month stay. At a later date, the ANDA or 505(b)(2) applicant could
change its paragraph III certification on the broader patent or claim
to a paragraph IV certification, but because there had already been an
opportunity for a 30-month stay, no further 30-month stay would be
possible.
The comments maintained that we should not allow such manipulation
and that it could be avoided by treating the new or revised
certification as though it relates back to, and substitutes for, the
original certification so that the notification requirements for
original applications, and not those for amendments, apply. Under this
suggested approach, the changed paragraph III certification would be
treated as if the original application had contained the paragraph IV
certification. The new certification, thus, would require notice to the
NDA holder and patent owner and have the potential to trigger a 30-
month stay. The comment cited Sec. 314.94(a)(12)(viii) which relates
to amended certifications to support this approach. In this instance,
it was argued that there should be the opportunity for at least one 30-
month stay when the ANDA or 505(b)(2) applicant ``alters or amends'' a
patent certification for reasons other than the listing of a patent
subsequent to the filing of an ANDA.
(Response) We decline to modify the proposed rule as suggested. We
conclude, however, that clarification of the proposed rule is required
in the final rule to ensure that our revised interpretation allows for
one full opportunity for a 30-month stay after notice of a paragraph IV
certification.
Our long experience with administering the Hatch-Waxman Amendments
convinces us that any regulatory scheme in this area will be complex,
and that any advantage that a party can find in manipulating the
regulatory program will be pursued. Despite our conviction that the
final rule will substantially reduce such manipulation, we do not
believe we can completely prevent attempts at ``creative compliance''
by the parties.
Our revised interpretation of the statute reads all three
subparagraphs of section 505(j)(2)(B) of the act as a coherent whole.
We believe that Congress considered the first paragraph IV
certification, notice and the opportunity for a single 30-month stay,
to be part of an inter-connected process. In the final rule we keep
these provisions operating together, as much as possible, requiring
that certifications be made and notification provided in such a way
that there always will be one full opportunity for a 30-month stay.
The notice requirement in the final rule depends on whether the
ANDA or 505(b)(2) application contained a paragraph IV certification
before the submission of an amendment containing a paragraph IV
certification. We note three potentially confusing situations
concerning applicability of that principle and describe how these will
be treated under the final rule.
First, an ANDA or 505(b)(2) applicant who filed a paragraph IV
certification could change to a paragraph III certification after
notice is given but before the 45 days for filing suit has run and
before a suit is filed. In this situation, because the opportunity for
a 30-month stay has not vested (the 45 days has not expired or patent
litigation has not yet been initiated), under the final rule, this ANDA
or 505(b)(2) application will not be considered to have ever included a
paragraph IV certification. If a paragraph IV certification is
submitted later, the notice obligation and one full opportunity for a
30-month stay will attach. This ensures that, consistent with the
statute, for at least one paragraph IV certification, the NDA holder or
patent owner has a full 45 days to determine whether to exercise the
right to sue for patent infringement
[[Page 36689]]
and to obtain a 30-month stay on ANDA or 505(b)(2) approval. The phrase
``one full opportunity for a 30-month stay'' used throughout this
preamble means a notice of a paragraph IV certification followed by
either the full 45 day period, or notice followed by the initiation of
patent litigation before the 45 days expire.
Only where both the 45 days have not run and the ANDA or 505(b)(2)
applicant has not been sued for patent infringement will this exception
apply. If the NDA holder brings suit before the 45 days, and the ANDA
or 505(b)(2) applicant then changes its application to omit any
paragraph IV certifications, the court where suit is pending can
determine how to proceed.
For effective enforcement of this provision of the regulations,
notice of the first paragraph IV certification(s) must be given by the
ANDA or 505(b)(2) applicant either: (1) When the applicant receives
from us an acknowledgement that the ANDA or 505(b)(2) application is
sufficiently complete to permit substantive review, or (2) at the same
time that the amendment to the ANDA or 505(b)(2) application is
submitted to us. These requirements are already contained in our
regulations at Sec. 314.95(b) and (d) and Sec. 314.52(b) and (d).
(These also apply to a second notice of a paragraph IV certification
when the first notice did not result in a full opportunity for a 30-
month stay.) The importance of ANDA and 505(b)(2) applicants providing
this notice was recently reaffirmed in TorPharm, Inc. v. Thompson, Civ.
No. 03-0254 (D.D.C. April 25, 2003) (appeal pending). ANDA and
505(b)(2) applicants shall submit proper documentation of notice to us
as required by Sec. Sec. 314.95(e) and 314.52(e).
Second, an applicant who filed a paragraph IV certification with
its original ANDA or 505(b)(2) application could change its paragraph
IV certification (generally to a paragraph III certification) after a
patent infringement suit is filed and after the 30-month stay has
commenced. Such a change could occur, for example, as a result of a
court order after a finding of infringement in the patent litigation.
In this circumstance, an application that previously contained a
paragraph IV certification would no longer do so. If such an
application is subsequently amended to add a new paragraph IV
certification, the notice obligation will not be triggered for the new
certification. The notice requirement and one full opportunity for 30-
month stay will have been exhausted when the first patent lawsuit was
filed and a 30-month stay was imposed.
The third situation could occur when an applicant withdraws an ANDA
or 505(b)(2) application that contained a paragraph IV certification
after it has provided notification to the NDA holder and patent owner.
If an ANDA or 505(b)(2) applicant were to reactivate its withdrawn
application, it might contend that the notice that it provided prior to
withdrawal of the ANDA or 505(b)(2) application was the only notice
that could trigger a 30-month stay, regardless of whether the 45 day
period had run, whether patent infringement litigation was initiated,
or whether that litigation was terminated because of withdrawal of the
application.
Our pre-existing regulations prevent an applicant from using
withdrawal to defeat the opportunity for one 30-month stay. Under
Sec. Sec. 314.52(b) and 314.95(b), the applicant is not to give notice
until it receives an acknowledgement letter from us stating that its
application is sufficiently complete to permit review. Any notice sent
prior to receipt of such letter will not constitute the notice that
creates the full opportunity for the single 30-month stay.
Once the review period begins, an application may not be withdrawn
and then ``reactivated.'' If the ANDA or 505(b)(2) application is
withdrawn during the review period, we ``will treat the resubmission as
a new application or abbreviated application'' under Sec. 314.100(b).
If the applicant wishes to have the withdrawn ANDA or 505(b)(2)
application reviewed, it must submit it as a new ANDA or 505(b)(2)
application. The ``decision to withdraw the application is without
prejudice to refiling'' as noted in Sec. 314.65. However, we will
treat the new ANDA or 505(b)(2) application in the same manner as any
other original application. The applicant will be required to provide
notice for paragraph IV certifications contained in the new ANDA or
505(b)(2) application, with the possibility of a single 30-month stay.
If the new ANDA or 505(b)(2) application contains no paragraph IV
certification, notice must be provided if it is later amended to
include such a certification. In short, withdrawal of an ANDA or
505(b)(2) application will not defeat the opportunity for a 30-month
stay of approval for the resubmitted ANDA or 505(b)(2) application.
We do not agree that Sec. 314.94(a)(12)(viii) supports a
``relation back'' theory. The provision does provide that when an ANDA
or 505(b)(2) applicant changes a certification in its application,
``the application will no longer be considered to contain the prior
certification,'' but it cannot be read to suggest that the application
will be considered to have contained only the changed certification
retroactively to the date that the original certification was filed. If
interpreted in that manner, an ANDA or 505(b)(2) applicant could amend
certifications to other patents and make them paragraph IV
certifications. Among other difficulties, an applicant could then argue
that, by virtue of relating back, such a paragraph IV certification was
the ``first'' application with a paragraph IV certification,
potentially entitling the applicant to exclusivity under section
505(j)(5)(B)(iv) of the act. This theory would lead to absurd results
in the application of 180-day exclusivity.
Furthermore, we note that ANDA applicants have substantial
incentives to avoid manipulation of the patent certification process.
The 180-day marketing exclusivity provided in section 505(j)(5)(B)(iv)
of the act is a significant incentive for ANDA applicants to file
legitimate paragraph IV certifications. Exclusivity as to each listed
patent is available only to the first ANDA applicant filing a paragraph
IV certification. Frequently, there is a race to submit the first
paragraph IV certification. Consequently, given this incentive, we do
not anticipate that ANDA applicants will manipulate their patent
certification filings, because they could jeopardize their chances of
obtaining the valuable 180-day exclusivity.
We encourage ANDA and 505(b)(2) applicants to resolve their
concerns about commencing litigation quickly by providing voluntary
notice to the NDA holder and patent owner as they wish. There is
nothing in the final rule to prevent ANDA or 505(b)(2) applicants from
providing notice on their own initiative, nothing to prevent NDA
holders or patent owners from responding with patent litigation, and
nothing to prevent ANDA or 505(b)(2) applicants from not marketing
during the litigation. To the extent that ANDA or 505(b)(2) applicants
seek resolution of outstanding patent issues before entering the
market, we note that the applicant can file a declaratory judgment
action (as discussed below) and enter into a stipulated preliminary
injunction pursuant to which the ANDA or 505(b)(2) applicant will not
enter the market during the course of the litigation. Such a
stipulation, of course, must be consistent with FTC precedent and
established antitrust requirements. Information on pertinent FTC
consent orders may be obtained from the FTC or its Internet Web site.
The interpretation we are adopting in the final rule allows only
one 30-month stay per ANDA or 505(b)(2) application;
[[Page 36690]]
it does not permit multiple 30-month stays. Revising the rule to impose
additional 30-month stays would be contrary to our interpretation of
the act and the reasons for the rulemaking. Furthermore, requiring
notice and imposing a second full opportunity for an additional 30-
month stay under the circumstances described would be inconsistent with
our legal basis for a single 30-month stay since we permit notice and
one full opportunity for a 30-month stay per ANDA or 505(b)
application. Multiple 30-month stays increase the delay in approval of
generic drugs and result in increased costs to consumers because the
cost of individual drugs is reduced when generic drugs enter the
marketplace and compete with the NDA drug.
b. Should All Paragraph IV Certifications Be Made Public and Should
the Notice Requirements Be Modified? The proposed rule would limit when
a notice of a paragraph IV certification is provided to NDA holders and
patent owners but did not address the content or format of the notice.
The proposed rule did not address whether or not paragraph IV
certifications were subject to public disclosure. We invited comment on
whether our regulations regarding the notice by ANDA and 505(b)(2)
applicants to the NDA holder and patent owner could and should be
amended (67 FR 65454).
(Comment 14) Several comments suggested that we should post all
paragraph IV certifications on our Web site because, these comments
argued, there is no basis to exempt the paragraph IV certifications
from public disclosure. The comments also suggested that we disclose
all paragraph IV certifications.
(Response) We decline to amend the proposed rule to make public all
paragraph IV certifications or otherwise provide notice of paragraph IV
certifications to NDA holders and patent owners. Under current
practice, paragraph IV certifications are subject to public disclosure
under the Freedom of Information Act (FOIA) and FDA's public disclosure
regulations once the notice of the paragraph IV certification has been
provided to the NDA holder and patent owner. Because the notice to the
NDA holder or patent owner of the paragraph IV certification is
considered a public disclosure after notice has been given, the
certification is available under FOIA. The final rule requires notice
only for the first paragraph IV certification of an ANDA or 505(b)(2)
application if that notice results in a full opportunity for a 30-month
stay. Notice for a subsequent paragraph IV certification will be
required only if the full opportunity did not result. Only the
paragraph IV certifications for which notice is required will be
routinely subject to public disclosure prior to approval. All other
certifications in an application would be considered confidential,
commercial information. Unless the ANDA or 505(b)(2) applicant makes
the subsequent certification public on its own accord, we are
prohibited from any disclosure that would reveal the applicant's
identity, contents of the application, or the timing of the application
(see Sec. Sec. 20.61(b) and 314.430). We do not believe that amending
our FOIA regulations to permit the release of information typically
considered confidential, commercial information, i.e. information that
could cause competitive harm is appropriate, without deciding at this
time that we could even do so.
Although parties are free to make paragraph IV certifications
public themselves, we will continue to adhere to our pre-existing FOIA
and public disclosure requirements as applicable to paragraph IV
certifications. We also intend to publish on our Internet Web site, for
each drug, the number of paragraph IV certifications filed to patents
submitted after the effective date of this final rule, if it can be
done in a manner that is consistent with FOIA. To avoid any
inappropriate public identification, we will not publish the number of
subsequent paragraph IV certifications if there is only one ANDA or
505(b)(2) application containing a paragraph IV certification because
such publication would be tantamount to a public disclosure of that
applicant's confidential, commercial information.
The NDA holder and patent owner also have other means to determine
whether subsequent paragraph IV certifications have been filed. If a
lawsuit is filed after notice of the paragraph IV certification, the
NDA holder or patent owner can use the litigation process to discover
the ANDA or 505(b)(2) applicant's certifications to subsequent patents.
Furthermore, additional public information is available if we issue a
tentative approval letter to the ANDA or 505(b)(2) applicant with a
paragraph IV certification. These letters are publicly available before
the ANDA or 505(b)(2) applicant receives an approval and note the
applicable patents, patent certifications, and exclusivities affecting
the timing of the approval of the ANDA or 505(b)(2) application.
We note that comments concerning public disclosure of paragraph IV
certifications and the need for quick resolution of patent issues were
submitted both by brand name or innovator firms and their trade
associations and by generic drug firms or related interests. We believe
such mutual interests will encourage the voluntary disclosure of
paragraph IV certifications.
(Comment 15) Several comments responded to our request for comments
on whether our regulations concerning the certifications filed by ANDA
and 505(b)(2) applicants and the notice to NDA holders and patent
owners could or should be modified. Most comments agreed that we had
the authority to modify both the certifications and the notice. One
comment suggested that we ``clarify the elements of a proper paragraph
IV notification'' to ``ensure that paragraph IV notifications
communicate meaningful information regarding the basis for an assertion
that a listed patent is invalid or not infringed'' and that
``adequate'' information is provided. Another comment suggested that
the notice provided to the NDA holder and patent owner of a paragraph
IV certification should include an explanation of the relationship
between the patent claims as construed by the ANDA or 505(b)(2)
applicant and the drug product. Another comment said we should require
the NDA holder and patent owner to identify an ``agent for service''
and require service by registered mail to ensure that the notice will
reach its ``proper location within the corporation in a timely
manner.''
(Response) In reviewing the current notification requirements at
Sec. 314.95(c), we do not believe that the suggested solutions for
clarification or more detailed explanations would improve upon the
current regulation. The current regulation requires specific
information in a notice that explains in full, and in detail, the
nature of the claim that the listed patent is invalid or, unenforceable
or will not be infringed. Our regulations, at Sec. Sec. 314.52(a) and
314.95(a), require notification by registered or certified mail, return
receipt requested. Our regulations also require documentation of a
receipt establishing that the notice was received by the listed NDA
holder and patent owner (see Sec. 314.52(e) and Sec. 314.95(e)). A
receipt other than a return receipt or a letter from the recipient
acknowledging receipt can be provided only with advance FDA agreement.
We do not believe it would be appropriate to further limit delivery
of the notice, nor do we believe it is appropriate to require ``agents
for service.'' We are not persuaded that such agents would solve the
comment's problem that ``notice is not reaching its
[[Page 36691]]
proper location within the corporation in a timely manner.'' In
addition, the individual listed as the ``agent for service'' could
change, resulting in confusion and delay in providing notice.
(Comment 16) Another comment suggested we require ANDA and
505(b)(2) applicants to file a new complete application for every drug
product listed separately in the Orange Book rather than allow
applicants to file supplements to approved applications. This comment
would require new applications for each drug strength listed in the
Orange Book as a separate product.
(Response) We decline to adopt the comment's suggestions. Our
current policies regarding supplements to ANDA and 505(b)(2)
applications allow for significant administrative efficiencies and
reduced application review times. Requiring separate ANDA or 505(b)(2)
applications would substantially increase costs for applicants, as well
as the agency, to accommodate the burden of creating, submitting,
processing, and reviewing multiple, complete applications. Our policy
regarding supplemental ANDAs for multiple strengths of a drug has been
a major factor in reducing ANDA review times. Before 1991 (when
applicants had to submit separate ANDAs for different strengths of a
drug), the median approval time for an ANDA was 33 months. Today it is
approximately 18 months. A key purpose of this final rule is to help
expedite the approval of generic products so that they can more quickly
be introduced to the marketplace. If we adopted the suggestion, the
probable effect would be to delay the introduction of generic drugs
into the market because the review times would increase. Requiring
multiple applications would not provide any additional value to our
review of ANDA applications. Consequently, we decline to require
separate applications as suggested by the comment.
c. Should the Single 30-Month Stay Be Further Limited?
(Comment 17) Many comments agreed with our determination that the
delay in approval of ANDA or 505(b)(2) applications could be limited to
one 30-month stay per application. Other comments agreed with the
limitation but stated that the single 30-month limitation was or should
be:
[sbull] Per drug;
[sbull] Per ANDA, for all patents submitted before any ANDA filing;
or
[sbull] Limited only to patents submitted within 30 days of NDA
approval.
(Response) We decline to adopt the additional limitations as
suggested by the comments. The act requires a certification for each
listed patent for each application filed under sections 505(b)(2) or
505(j) of the act. We construe section 505(c)(2) of the act to require
submission of patent information after NDA approval, without regard to
when an ANDA or 505 (b)(2) application has been filed. We decline to
limit the 30-month stay resulting from a paragraph IV certification to
only those patents submitted before any ANDA or 505(b)(2) filing, or
those filed only within 30 days of NDA approval, or per listed drug
instead of per application.
d. Will the Application of Only One 30-Month Stay Affect
Declaratory Judgment Actions Under the Act?
(Comment 18) Several comments supported the single 30-month stay
but expressed concern that limiting the notice requirement and 30-month
stays to the first paragraph IV certification could affect the ability
of ANDA and 505(b)(2) applicants to file a declaratory judgment action
to resolve patent infringement issues. Some comments believed that in
the absence of both notice to the NDA holder and patent owner and the
ensuing 45-day period within which a patent infringement suit could be
initiated, a declaratory judgment action could not be brought. Other
comments opposed the single 30-month stay and also expressed concern
about the ability to pursue a declaratory judgment action under the
proposal. Some comments questioned whether a declaratory judgment
action could be filed under other statutory provisions; the comments
explained that the Hatch-Waxman Amendments created the act of patent
infringement and, if litigation were bought ``outside'' the act, there
would be no ``case or controversy'' required by those provisions. One
comment cited Cordis Corp. v. Medtronic, Inc., 835 F.2d 859, 862 (Fed.
Cir. 1987), noting that ``when the generic cannot meet the subjective
standard of proving a reasonable apprehension of a suit by the brand
company,'' the case may be dismissed because there was no ``case or
controversy.'' Another comment cited Teva Pharmaceuticals, USA, Inc. v.
FDA, 182 F.3d 1003 (D.C. Cir. 1999), to claim that if no notification
were received, arguably no declaratory action could be brought. Other
comments suggested that limiting NDA holders to a single 30-month stay
per ANDA or 505(b)(2) application would encourage the delay of
litigation designed to resolve patent issues and thus would reduce
``certainty'' for ANDA applicants.
(Response) We appreciate the desire to resolve patent issues
quickly, but believe the concerns expressed about the ability to pursue
declaratory judgment actions are unwarranted. Section 505(j)(5)(B)(iii)
of the act provides: ``Until the expiration of forty-five days from the
date the notice made under paragraph (2)(B)(i) is received, no action
may be brought under section 2201 of title 28, United States Code, for
a declaratory judgment with respect to the patent.'' We interpret this
particular section as creating an exception to the general right of a
party to bring a declaratory judgment action at any time that
jurisdictional requirements are satisfied under title 28, United States
Code. The general rule allowing declaratory judgments under 28 U.S.C.
2201 would be applicable as long as a party can satisfy the ``case or
controversy'' requirement that is necessary to file a declaratory
judgment action. The exception created in section 505(j) of the act
restricts the timing when a declaratory judgment action may be filed
under certain limited circumstances. Under the act, if notice of a
paragraph IV certification is required, no declaratory judgment action
can be filed until 45 days after that notice is given to the NDA holder
and patent owner. However, if no notice is required to be provided to
the NDA holder and patent owner, the exception created in section
505(j) of the act no longer applies, and the general rule permitting
declaratory judgments to be filed at any time under 28 U.S.C. 2201
would apply.
We also disagree with the conclusions drawn from the cases cited in
the comments that, in the absence of the notice of subsequent paragraph
IV certifications, there would be no case or controversy on which to
base a declaratory judgment action. A case or controversy can exist
where first, there is reasonable fear of a lawsuit and, second, the
plaintiff has actually produced the product in question or is prepared
to produce the product. (See Cordis Corp. v. Medtronic, Inc., 835 F.2d
859 (Fed. Cir. 1987)). In Vanguard Research, Inc. v. PEAT, Inc., 304
F.3d 1249, 1255 (Fed. Cir. 2002), the court found that fear of a
lawsuit existed when the competitor was engaged in activity subject to
a patent infringement charge, and the patent holder already had sued
the competitor to protect its technology. The court noted that:
``[f]iling a lawsuit for patent infringement would be just another
logical step in its quest to protect its technology.'' This is similar
to the
[[Page 36692]]
situation in which an ANDA or 505(b)(2) applicant has filed an initial
paragraph IV certification and the NDA holder or patent owner has filed
a lawsuit to protect the patent and obtain a 30-month stay. There is
little reason to doubt that an NDA holder or patent owner who had
submitted a second patent to us for listing would bring another lawsuit
to protect the second patent if an ANDA or 505(b)(2) applicant were to
manufacture the drug, even if no notice of a subsequent paragraph IV
certification was provided. In other words, the NDA holder or patent
owner should have an incentive to protect the patented invention
regardless of whether the ANDA or 505(b)(2) applicant provided notice.
We acknowledge that the court in Jervis B. Webb Co. v. Southern
Systems, Inc., 742 F.2d 1388 (Fed. Cir. 1984), found that a case or
controversy did not exist when the plaintiff had not produced a product
(a device) at the time of the declaratory judgment counterclaim.
However, an ANDA or 505(b)(2) applicant is engaged in ``producing'' a
product at the time the ANDA or 505(b)(2) application is filed.
Although 35 U.S.C. 271(e)(1) makes it an act of non-infringement to use
a patented invention for uses related to submitting an ANDA or
505(b)(2) application (such as testing and producing sample batches of
drug product), 35 U.S.C. 271(e)(2) expressly makes it an act of
infringement to submit an ANDA or 505(b)(2) application seeking
approval of the drug product before a patent expires. This statutory
provision does not require that the NDA holder or patent owner receive
formal notice of a paragraph IV certification for the submission of the
application to be an act of infringement. Thus, unlike the plaintiff in
Jervis B. Webb Co. v. Southern Systems, Inc., the second element of the
case or controversy test would be satisfied.
In another case cited in the comments, Teva Pharmaceuticals, USA,
Inc. v. FDA, 182 F.3d 1003 (D.C. Cir. 1999), the court explained that a
case or controversy did not exist in the underlying declaratory
judgment action. There was no reasonable apprehension of suit--the
first element of the case or controversy test--because the patent owner
had disavowed an intent to sue. A disavowal of the intent to sue is an
unusual circumstance that we do not expect to occur in many cases. In
any event, the availability of a declaratory judgment action is less
important when the innovator or patent owner disavows an intent to sue
because the ANDA applicant will face less risk in marketing its
competing product. We are not aware of any other Hatch-Waxman patent
infringement case in which a court has found no reasonable apprehension
of suit.
In response to the comments arguing that a single 30-month stay
would create uncertainty regarding litigation and later-submitted
patents, we note that a firm's inability to predict whether it will or
will not be sued for patent infringement is a matter outside the scope
of this final rule. A decision by the NDA holder or patent owner on
whether to file suit for patent infringement may depend on many
factors. For example, litigation decisions could be affected by the
strength of the underlying patent, the party's resources, licensing
agreements if the patented invention is made under a license, or other
factors. We also note that some patent infringement suits may be
initiated after the 45 day period available to obtain a 30-month stay
has expired. The act only requires the initiation of a patent
infringement suit within a specific time if the NDA holder or patent
owner wishes to get the benefit of a 30-month stay in the approval of
an ANDA or 505(b)(2) application; the NDA holder or patent owner can
bring suit at a later time, but loses the opportunity to obtain a 30-
month stay of approval.
In addition, there are various types of patents which must not be
submitted for listing in the Orange Book. These patents are not subject
to the certification, notice, and 30-month stay provisions. The fact
that such patents must not be listed does not prevent the NDA holder or
patent owner from defending those patents in litigation as it deems
appropriate.
e. Is the Correct Legal Interpretation Applied to Provide Only One
30-Month Stay?
(Comment 19) Numerous comments challenged our proposed
interpretation of the act to permit only one 30-month stay per ANDA or
505(b)(2) application. Some comments advanced a legal analysis
different than the one we described in the preamble to the proposal to
support a single 30-month stay. The comments asserted that their legal
theories were either better than ours or were the only appropriate
legal arguments possible.
In contrast, other comments maintained that section
505(j)(2)(B)(iii) of the act requires that notice be provided to the
NDA holder and patent owner each time a new paragraph IV certification
is added to an ANDA. These comments maintained that multiple 30-month
stays are clearly required if the notices result in patent litigation.
Several comments contended that the plain meaning of ``include'' or
``amended to include'' is to ``contain'' or ``comprise as part of a
whole,'' and that our interpretation of section 505(j)(2)(B)(iii) of
the act is not reasonable. The comments also argued that our
interpretation of ``include'' in this provision differs from its use
elsewhere in section 505 of the act. One comment stated that the
meaning of ``include'' in sections 505(j)(7)(A)(ii) and (iii) of the
act cannot be reconciled with our interpretation of that term in
section 505(j)(2)(B)(iii) of the act. Section 505(j)(2)(B)(iii) of the
act states that ``If an application is amended to include a
certification described in subparagraph (A)(vii)(IV), the notice
required by clause (ii) shall be given when the amended application is
submitted.'' The comment noted that section 505(j)(7)(A)(ii) of the act
provides that the Secretary ``shall revise the list [Orange Book] to
include each drug which has been approved . . . during the
[intervening] thirty-day period'' and, when that updated drug
information is recorded ``in revisions made under clause (ii), [shall]
include such [patent] information for such drug.''
Several comments questioned whether the legislative history of the
Hatch-Waxman Amendments supported our proposed interpretation of
section 505(j)(2)(B)(iii) of the act. One comment contended that House
Report language (see 67 FR 65448 at 65456) we had cited should be read
as supporting multiple 30-month stays. The comments also argued that
our interpretation failed to consider the importance of the final
compromise that led to a 30-month, rather than 18-month, stay to ensure
that patent litigation was resolved before a generic drug was approved.
Finally, other comments criticized our failure to consider other
language from a House Report that allegedly shows that Congress
intended the availability of multiple 30-month stays. This language,
found at H. Rept. 98-857, Part 1, 98th Cong., 2d Sess. at 28, states:
``In the case where the patent certification is amended in an ANDA to
allege invalidity or non-infringement of a patent, the FDA may not make
the approval effective within the 45 day period that an action for
patent infringement may be brought.''
(Response) We agree that section 505(j)(2)(B)(iii) of the act can
be read to permit multiple 30-month stays. Indeed, this has been our
position since the enactment of the Hatch-Waxman Amendments. The
proposal put forth a different interpretation, one that we believe is
equally reasonable and more in line with the intent of the Hatch-
[[Page 36693]]
Waxman Amendments--to maintain a balance between the rights of the NDA
holders and patent owners, and the desire to have more rapid
availability of generic drugs. Our revised interpretation of section
505(j)(2)(B)(iii) of the act accomplishes two statutory objectives: (1)
It closes a possible loophole that would have allowed ANDA applicants
to avoid any 30-month stay and (2) it prevents multiple 30-month stays
per ANDA application. A similar conclusion applies to the parallel
provisions of section 505(b)(2) of the act.
We based our change in position on a reevaluation of the statutory
text and concluded that the act is ambiguous on this issue of multiple
30-month stays. We note that certain other legal interpretations or
theories may support a single 30-month stay, but we believe that the
position we have taken in the final rule is the most appropriate.
The preamble to the proposed rule explained the rationale for our
different interpretation (see 67 FR 65448 at 65454 to 65456). In brief,
after reviewing the text of section 505(j)(2)(B)(i) through (iii) of
the act, we believe that these provisions may be reasonably interpreted
so that notice and the opportunity for a 30-month stay do not flow from
all paragraph IV certifications. However, one notice of a paragraph IV
certification and one full opportunity for a 30-month stay will always
be required. This outcome--the opportunity for one 30-month stay during
which patent rights can be litigated, but no multiple 30-month stays
per ANDA or 505(b)(2) application to unreasonably delay approvals of
competitor drugs--is a reasonable and balanced interpretation of the
act.
We disagree with the comments that claimed that notice and 30-month
stays are required only for paragraph IV certifications contained in
original ANDAs because the notice provision at section 505(j)(2)(B)(ii)
references only section 505(j)(2)(B)(i) of the act. This interpretation
would eliminate the opportunity for a 30-month stay in any situation
where an ANDA applicant waits until an amendment to submit a paragraph
IV certification. As we explained in the proposed rule (see 67 FR 65448
at 65455 to 65456), section 505(j)(2)(B)(iii) of the act specifically
requires ANDA applicants to give notice if they amend their
applications to include their first paragraph IV certification. For
these reasons, we do not interpret the act to require that only
paragraph IV certifications contained in original ANDA applications
will trigger the notice requirements and the possibility of a 30-month
stay.
Our interpretation ensures that the NDA holder and patent owner
will receive notice of at least one paragraph IV certification and have
one full opportunity for a 30-month stay. However, we also disagree
that every paragraph IV certification requires notice and an
opportunity for a 30-month stay. We will require notice to the NDA
holder and patent owner of a later paragraph IV certification if: (1)
The ANDA or 505(b)(2) application did not previously contain a
paragraph IV certification, but is amended to include a paragraph IV
certification; or (2) a previous notice of a paragraph IV certification
did not result in one full opportunity for the 30-month stay under the
act.
This approach is consistent with the statutory language. By its
terms, section 505(j)(2)(B)(i) of the act, and the nearly identical
language applicable to 505(b)(2) applicants, requires that the ANDA
applicant submitting a paragraph IV certification in its original ANDA
``include in the application'' that it will provide the required
notice. Section 505(j)(2)(B)(ii) of the act sets forth the required
content of the notice referred to in clause (i). Under section
505(j)(5)(B)(iii) of the act, we are prohibited from approving an
application with a paragraph IV certification if an action has been
brought within 45 days of the date the notice under section
505(j)(2)(B)(i) is received. The text of section 505(j)(5)(B)(iii)
refers multiple times to ``the notice provided [or made] under
paragraph (2)(B)(i).'' Thus, at a minimum, it cannot be said the
statute clearly applies the notice requirement to all paragraph IV
certifications, whether in original or amended ANDAs.
By contrast, section 505(j)(2)(B)(iii) of the act refers to
amended, not original, ANDAs. It addresses the question of notice when
an ANDA is amended to include a paragraph IV certification. Our
interpretation eliminates the possibility that an ANDA applicant could
evade any notice that could lead to a 30-month stay by omitting any
paragraph IV certification in an original ANDA, and then later amending
the application to include such a certification. By providing one full
opportunity for the 30-month stay, we reduce the opportunity for
intentional manipulation of the filing of paragraph IV certifications.
We do not agree that the act's language governing the operation of
paragraph IV certifications, notice, and 30-month stays is clear and
unambiguous. As the multiple interpretations advanced by the comments
demonstrate, the statutory language may plausibly be read in different
ways. It is certainly reasonable to interpret ``include'' as used in
the act to mean ``contain.'' That is the meaning we understood the word
to have when we issued the proposed rule (see 67 FR 65448 at 65455).
Thus, it is a reasonable construction of the act to conclude that when
an application is amended to contain a paragraph IV certification (when
it did not previously contain such a certification), it is thus amended
to include such a certification; and, that once an application contains
such a certification, adding a new one does not amend or change the
application to include or contain one, since it already contained such
a certification. In any event, reliance on words in isolation is
misplaced. As Judge Learned Hand observed, ``Words are not pebbles in
alien juxtaposition; they have only a communal existence; and not only
does the meaning of each interpenetrate the other, but all in their
aggregate take their purport from the setting in which they are used *
* *.'' NLRB v. Federbush Co., 121 F.2d 954, 957 (2d Cir. 1941). Our
interpretation of the 30-month stay provision is fully consistent with
this principle.
We also reject the view that our interpretation of the statutory
language ``amended to include'' is inconsistent with the use of the
word ``include'' elsewhere in the statute. We do not agree that the use
of ``include'' in section 505(j)(7)(A)(ii) and (j)(7)(A)(iii) of the
act cannot be squared with our interpretation of that term in section
505(j)(2)(B)(iii) of the act. Sections 505(j)(7)(A)(ii) and
(j)(7)(A)(iii) of the act, which relate to updating the Orange Book
every 30 days to take into account drug approvals and patent listings,
provide that the Secretary ``shall revise the list to include each drug
which has been approved * * * during the [intervening] thirty-day
period'' and when that updated drug information is recorded, ``in
revisions made under clause (ii), [shall] include such [patent]
information for such drug.'' That language requires publication of
revisions to include something that was not previously contained in the
Orange Book, i.e., approved drugs and patents that were not listed in
the version of the Orange Book that existed immediately before the
amendments were filed. The Secretary would publish nothing, under this
statutory directive, if in the preceding 30 days, no new drugs were
approved or patent listings filed. Similarly, when an ANDA or 505(b)(2)
application is amended to include a paragraph IV certification, when no
such certification is contained in the
[[Page 36694]]
application prior to the amendment of the application, section
505(j)(2)(B)(iii) of the act applies. But when an ANDA or 505(b)(2)
application contained a paragraph IV certification prior to the
amendment and one full opportunity arose for a 30-month stay, no notice
obligation is triggered for subsequent paragraph IV certifications.
We do not agree with the comment that the legislative history
indicates that Congress changed the 18-month stay to a 30-month stay
because it intended that patent litigation be resolved before a generic
application could be approved. The House Judiciary Committee rejected
an ``amendment [that] would have required that either the patent expire
before approval, or that there be a final decision by a Federal
District Court that the patent in question was not valid'' (see H.
Rept. 98-857, Part 2, 98th Cong. 2d Sess., 9 (1984)). It appears that
the amendment was rejected because the effect ``would have been to
substantially delay generics from getting onto the market when they
seek to challenge the validity of a patent'' (id. at 10). Congress
explicitly rejected amendments to prohibit generic entry before
judicial resolution of the patent issues prior to approval, but
accepted a 30-month stay period, whether or not litigation was finally
resolved, because, as a practical matter, it was believed the time
period would not affect when generic manufacturers would begin to
market their drugs (see 130 Congressional Record H9118 (September 6,
1984) (remarks of Rep. Waxman)).
We also believe that the legislative history quoted in the comments
is ambiguous at most and can be interpreted in a way that does not
undercut our changed interpretation. The report states: ``In the case
where the patent certification is amended in an ANDA to allege
invalidity or non-infringement of a patent, the FDA may not make the
approval effective within the 45 day period that an action for patent
infringement may be brought.'' Although this language does not
distinguish explicitly between situations when an application already
contained a paragraph IV certification and those when it did not, it
would not be unreasonable to interpret it to apply only when invalidity
or non-infringement of a patent is alleged for the first time. Language
describing when an ANDA is ``amended * * * to allege invalidity or non-
infringement of a patent'' can be read in another way as ``amended to
include'' a paragraph IV certification. When an ANDA or 505(b)(2)
application is amended to include an allegation of invalidity or non-
infringement of a listed patent for the first time, we cannot approve
the application for 45 days, and notification of the paragraph IV
certification will be required. For additional paragraph IV
certifications, when a patent has already resulted in a paragraph IV
certification and a full opportunity for a 30-month stay, no notice is
required and we do not need to wait for 45 days to approve an ANDA or
505(b)(2) application if it is otherwise ready for approval.
f. Is There a Sufficient Basis to Adopt the Change in Legal
Interpretation? In the preamble to the proposed rule, we detailed the
factual basis for our decision to reevaluate our legal interpretation
of the maximum number of 30-month stays per ANDA or 505(b)(2)
application (see 67 FR 65448 at 65455). We noted that our impression
that multiple 30-month stays were increasing was confirmed by the FTC
Report. In addition, the FTC Report found that there was an increase in
submission of later-issued patents, many of which ``do not appear to
claim the approved drug product or an approved use of the drug'' (id.).
(Comment 20) Several comments questioned the factual basis for what
they called our ``dramatic change in position'' and argued that the
information used in the FTC Report was already known to us. Since there
was no ``new information,'' the comments maintained that the facts did
not provide an ``adequate'' basis for our adoption of a single 30-month
stay per ANDA or 505(b)(2) application.
(Response) We disagree with the contention that our factual basis
underlying our rule was inadequate. At the outset, we note that the
comments proceed from a false premise to a flawed conclusion. The
``newness'' of the underlying data is not the appropriate legal
standard for evaluating the reasonableness of our different
interpretation. An agency must consider ``the wisdom of its policy on a
continuing basis'' ``with or without a change in circumstances'' (see
Chevron, U.S.A., Inc. v. Natural Resources Defense Council, Inc., 467
U.S. 837, 863, 104 S. Ct. 2778, 2792 (1984); Motor Vehicle
Manufacturers Ass'n v. State Farm Mut. Automobile Ins. Co., 463 U.S.
29, 57, 103 S. Ct. 2856, 2873 (1983)). Our pre-existing regulations
permitting multiple 30-month stays have led to protracted delays in
generic drug approvals and, therefore, need to be changed.
If ``newness'' of the underlying data were the test, the data here
would satisfy it. Over the last several years, there has been an
increasing number of multiple 30-month stays for a single drug product.
These stays have caused significant delays in the approval of generic
versions of frequently prescribed drugs. We anticipate that if we do
not address the current situation, these multiple 30-month stays and
resulting delays in generic drug approvals would continue to increase.
There will be an increasing number of patents expiring in the next few
years covering innovator drugs currently on the market. According to
our records, over 500 drug patents will expire between 2003 and 2009.
We have identified 26 top-selling drugs subject to patents with
expiration dates between 2003 and 2005. These 26 drugs had combined
2001 retail sales exceeding $38 billion (over 25 percent of all 2001
prescription drug expenditures) and include 7 of the top 10 best
selling drugs. The pressure on NDA holders and innovator companies to
protect their market share and delay generic competition into the
market will continue to increase. We would expect to see an increase in
the conduct documented in FTC Report if our regulations remained the
same.
The FTC's comprehensive and discerning analyses of the data it
collected substantiated the seriousness of the problem. The FTC
analyzed the relationship between patent listings and multiple 30-month
stays, conducted an extensive review of various lawsuits involving
multiple 30-month stays (including lawsuits in which we were not a
party) and analyzed the outcome of the litigation. Although we provided
some raw data to the FTC to assist its investigations (and thus that
information was not ``new'' to us), we did not have all of the data
that the FTC collected nor had we analyzed the data in the manner done
by the FTC.
We have concluded that our regulations permitting multiple 30-month
stays have led to considerable delays in the approval of generic drugs.
This consequence was not intended either by Congress or by FDA. Thus,
we have changed our regulations to address this problem.
B. Miscellaneous Comments
1. Do We Need Legislation to Accomplish Our Goals?
The preamble to the proposed rule did not discuss any legislative
efforts to enhance the availability of generic drugs.
(Comment 21) Several comments said that legislation would be better
than rulemaking or that we should support legislation. In general, the
comments felt that legislation would:
[sbull] Better resolve intellectual property issues than our rule;
[[Page 36695]]
[sbull] Give us clear legal authority to act or be less vulnerable
to judicial review; or,
[sbull] Result in timely and predictable access to generic drugs.
One comment noted that Congress had considered several bills to
address 30-month stays. The comment declared that such proposed
legislative action indicated both that we lacked authority to issue the
rule and that new legislation was needed. Another comment suggested
that we support legislation to allow only one 30-month stay and only
for patents that are listed within 30 days of an NDA's initial
approval.
(Response) We believe that, under our existing regulations, there
have been delays in generic drugs reaching the market, as well as
confusion over certain patent listing requirements. This rule is
intended to help ensure that lower cost, safe and effective generic
drugs become available to Americans without any inappropriate delays,
while still preserving incentives to innovate. These changes can be
achieved through rulemaking, using our existing legal authority. We
cannot predict whether, if at all, legislation addressing these issues
will be enacted. The possibility that there could be legislation to
address problems associated with 30-month stays and generic drug
approvals cannot, and should not, preclude us from using our existing
authority to address these problems. We also note that those comments
favoring legislative solutions over regulatory ones apparently assume
that legislative changes would necessarily lead to less litigation than
a rule. Based on our past experience in defending statutory
interpretations, we question whether such a presumption is appropriate
here. We recognize that a regulation may not always be a perfect
solution due to limits on our statutory authority, but that recognition
does not mean that we cannot use our existing legal authority to engage
in rulemaking to improve our regulatory approach.
Additionally, we disagree with the comments that claimed we lack
authority to issue the rule. The preamble to the proposed rule
discussed our legal authority (see 67 FR 65448 at 65457). We will not
repeat that discussion here. The fact that Congress has considered, or
is currently considering, bills on the 30-month stay issue does not
preclude us from exercising our existing authority, nor demonstrate
that we presently lack that authority. As the Supreme Court has
explained:
We have stated * * * that failed legislative proposals are a
particularly dangerous ground on which to rest an interpretation of
a prior statute. Congressional inaction lacks persuasive
significance because several equally tenable inferences may be drawn
from such inaction, including the inference that existing
legislation already incorporated the offered change.
(See Central Bank of Denver v. First Interstate Bank of Denver, 511
U.S. 164, 187 (1994).)
(Citations and internal quotation marks omitted.)
Although it would be both inappropriate and premature for us to
take a position on any legislative concept without seeing the details
of any specific proposed or draft legislation, we are always willing to
work with Congress. Until then, we will not take a position on
legislation to allow only one 30-month stay for patents filed within 30
days after NDA approval.
2. Will the Different Interpretation Affect Existing Exclusivities?
We stated in the preamble to the proposed rule that the
implementation of the final rule would not affect an ANDA's eligibility
for 180-day exclusivity under 505(j)(5)(B)(iv) of the act (see 67 FR
65448 at 65457).
(Comment 22) Several comments addressed different aspects of the
180-day and 3 year exclusivity provisions of the Hatch-Waxman
Amendments. The comments offered suggestions on changing the
exclusivity trigger, requiring the forfeit of the exclusivity if
parties agree to delay marketing and expressed concerns about the
potential increase in the availability of 180-day exclusivity if we
allow additional patents to be filed.
(Response) We appreciate the complexities of the various
exclusivities provided by the act. As we noted in the proposed rule,
eligibility for 180-day exclusivity will follow the same general
principles as before implementation of this final rule. The first ANDA
applicant to file a substantially complete ANDA, or supplement,
containing a paragraph IV certification to a listed patent will be
eligible for exclusivity as to that patent under section
505(j)(5)(B)(iv) of the act. For a paragraph IV certification to be
effective for exclusivity purposes, when notice is required, notice
must be given as described in the response to comment 13 of section
II.A of this document. However, when notice is not required, a
paragraph IV certification will be effective for exclusivity purposes
without notice. We understand that each patent listed in the Orange
Book may form the basis for a claim to 180-day exclusivity. Thus an
increase or decrease in listed patents as a result of this final rule
could affect the number of exclusivity periods. Other suggestions made
in the comments are beyond the scope of the final rule. We are not
altering our interpretation of exclusivity in the final rule.
3. Should the Provisions of the Final Rule Be Severable?
The proposed rule did not address whether each provision should be
considered independent of other provisions and, thus, severable if any
provision were determined to be invalid.
(Comment 23) Although there were no comments that directly
addressed severability, one comment suggested that the limitation on
multiple 30-months stays was unnecessary because the revised patent
listing provisions would prevent improper patents from being submitted
for listing in the Orange Book.
(Response) Although we agree that the changes to the patent
submission and listing provisions and the information required on the
declaration forms will help ensure that improper patents are not
submitted for listing, we also believe that eliminating multiple 30-
month stays will help maintain the balance intended by the Hatch-Waxman
Amendments and is equally important to the final rule. Each of the
final rule provisions reinforces interrelated goals. Clarifying that
certain patents may not be submitted for listing should lead to the
submission of fewer improper patents. Requiring additional patent
declaration information from NDA applicants or holders or patent owners
also should help ensure that only eligible patents are submitted.
Eliminating the opportunity for multiple 30-month stays also should
reduce incentives to submit improper patents.
Based on our past experience we acknowledge that the provisions of
this final rule will neither completely resolve all issues governing
patent submission, nor will they eliminate attempts to manipulate the
final rule for market advantage. We also believe that each provision
will reduce the opportunities for manipulation and, thus, is
independently justified and worthwhile. However, we believe each
provision stands on its own as a legal and practical matter.
From the comments we have received to the proposed rule, we believe
there is a possibility that we will be challenged on various portions
of the final rule. We expect we will prevail in any such challenge, as
the final rule and each of its provisions is legally sound. If,
however, a court should conclude that any one or more provisions of the
final
[[Page 36696]]
rule is invalid, we wish to emphasize our intent that the remaining
provisions of the final rule be permitted to take effect.
4. Implementation and Effective Date
The preamble to the proposed rule described how a final rule would
be applied to pending applications (see 67 FR 65448 at 65457) as
follows:
[sbull] For patents filed for an NDA that has not been approved by
the effective date of a final rule, the rule would apply on the
effective date. For example, if the final rule were to become effective
60 days after the date of publication in the Federal Register, and an
NDA was pending on the 60th day after the final rule's publication
date, the NDA applicant would have to comply with the final rule's
patent listing and patent declaration requirements. ANDA and 505(b)(2)
application applicants would be subject to the revised notice
requirement. Each ANDA or 505(b)(2) application referencing that NDA
would be subject to the possibility of only one 30-month stay per ANDA
or 505(b)(2) application.
[sbull] If we have approved the NDA as of the final rule's
effective date, and no ANDA has been filed before that date, then any
patent listed before that date would be subject to the pre-existing
regulation. For example, if the final rule were to become effective 60
days after the date of publication in the Federal Register, and we
approved the NDA on the 59th day after the date of publication, the NDA
applicant would not have to amend its patent listing and patent
declaration to comply with the final rule. ANDA and 505(b)(2)
applications submitted after the effective date would be subject to the
revised notice requirement. Each ANDA or 505(b)(2) application
referencing that NDA would be subject to the possibility of only one
30-month stay per ANDA or 505(b)(2) application.
[sbull] If we have approved the NDA as of the final rule's
effective date, and an ANDA or 505(b)(2) application has been filed
before that date, then any patent listed before that date would be
subject to the pre-existing regulations, as described in the example
immediately above. The ANDA or 505(b)(2) application applicant would
have to provide notice to the patent owner and NDA holder if the ANDA
or 505(b)(2) application contained a paragraph IV certification.
Multiple 30-month stays in the approval date would be possible.
[sbull] If the NDA holder or NDA applicant files patent information
after the final rule's effective date, then the NDA holder or applicant
is subject to the final rule's patent listing and patent declaration
requirements, and ANDA or 505(b)(2) application applicants would not
have to provide notice if their applications previously contained a
paragraph IV certification. Only one 30-month stay per each ANDA's or
505(b)(2) application's approval date would be possible.
We invited comment on how a final rule should be implemented.
(Comment 24) Several comments suggested alternative effective dates
including the following:
[sbull] Apply the final rule to all ANDAs filed before the
effective date of the final rule and cancel any existing multiple 30-
month stays;
[sbull] Apply the final rule retroactively to all current NDA
holders by requiring all NDA holders to be subject to only one 30-month
stay and apply the declaration provisions to require all current NDA
holders or patent owners to file a new declaration and certification
for already listed patents using the declaration statement in the
proposal;
[sbull] Apply the new declaration requirements retroactively to
require the new information on patents currently listed in the Orange
Book; if the propriety of a patent listed in Orange Book for a current
NDA holder or patent owner is questioned, the NDA holder or patent
owner must file a new declaration or FDA should delist the patent.
In contrast, other comments supported the implementation plan as
proposed.
(Response) We will implement the final rule on a prospective basis,
as we stated in the proposed rule. The fact that we made our intent
public in a proposed rule and the time lag between when the rule was
proposed and when this final rule is effective provides sufficient time
for most parties to adjust their practices and expectations, or to take
other steps to suit their business practices.
We do delay the implementation date for submission of information
concerning a patent claiming a polymorph that is the active ingredient
of the drug product described in the approved NDA. We provide a longer
period of implementation to accommodate the tests required to establish
that the drug product containing the polymorph will perform the same as
the drug product described in the NDA. This test data must exist when a
polymorph patent is submitted to us. We recognize that the testing
necessary to obtain the data for submission of polymorph patents
claiming the active ingredient of the product described in the NDA may
take at least 6 months to complete. There will be NDA applicants and
holders and patent owners who have not already conducted testing. The 6
months will provide time for NDA applicants and holders and patent
owners with patents pending at the PTO to conduct the tests needed to
produce the data required for the declaration statement in time to
submit any newly issued patent within 30 days of issuance.
We also decline to apply the final rule retroactively. If we
canceled all multiple 30-month stays currently applicable to ANDAs and
505(b)(2) applications or applied the declaration requirements to
already submitted patents for existing NDAs, we would be applying the
provisions retroactively. As we noted in the proposal (67 FR 65448 at
65457): ``If we were to adopt an alternative implementation plan, we
would risk upsetting legitimate expectations held by those who had
relied on our earlier interpretation of the act.'' As a general matter,
a statutory grant of legislative rulemaking does not encompass the
power to implement such regulations on a retroactive basis in the
absence of express language granting such power (see Bowen v.
Georgetown University Hospital, 488 U.S. 204, 208-09 (1988)). There is
no question that this rule ``changes the legal landscape'' (see
National Mining Ass'n v. Department of Labor, 292 F.3d 849, 858 (D.C.
Cir. 2002)). Applying this rule retroactively would subject us to
potential legal challenge. Thus, adopting these suggestions would lead
to even greater uncertainty as to the applicability of the provisions.
After further consideration, however, we believe that the proposed
rule's implementation plan will not fully effect our intent to
implement the provisions only prospectively. Accordingly, as described
in section IV of this document, we have clarified our implementation
plan to ensure prospective application of the final rule. Nevertheless,
patent owners may voluntarily complete, and NDA holders may voluntarily
complete and submit, new patent declarations, using FDA Forms 3542 and
3542a, for patents not subject to the final rule and currently listed
in the Orange Book. This course is particularly advisable for method-
of-use patents, in light of the Purepac decision and concerns about
implementation of section 505(j)(2)(A)(viii) of the act. Such voluntary
submission of new patent declarations will not bring patents within the
scope of the final rule with respect to notice and 30-month stays.
[[Page 36697]]
III. Description of the Final Rule
A. Section 314.53(b)--What Patents Must Be Submitted?
1. Which Patents Would the Final Rule Require To Be Submitted?
Section 314.53(b) describes the patents for which information must
be submitted. The final rule states, in relevant part, that information
must be submitted on the required declaration forms for each patent
that claims the drug or a method of using the drug that is the subject
of the NDA and with respect to which a claim of patent infringement
could reasonably be asserted if a person not licensed by the owner of
the patent engaged in the manufacture, use, or sale of the drug
product. The patents include patents that claim:
[sbull] The drug substance (active ingredient),
[sbull] The drug product (formulation and composition), and
[sbull] A method of use.
Those patents that claim a different polymorphic form of the drug
substance that is the active ingredient described in the NDA must be
submitted if the applicant has test data demonstrating that a drug
product containing the polymorph will perform the same as the drug
product described in the NDA. The drug product (formulation and
composition) patents submitted must claim the specific drug product
described in the pending or approved NDA. For patents that claim a
method of use, the NDA applicant or holder must submit only those
patents that claim indications or other conditions of use that are the
subject of a pending or approved application. Each pending or approved
method of use and related patent claim must be described.
2. What Patents Must Not Be Submitted?
Section 314.53(b), as finalized, states that information on patents
claiming packaging, patents claiming metabolites, and patents claiming
intermediates must not be submitted. Process patents also must not be
submitted. The final rule clarifies that the prohibition on submission
of packaging patents does not apply to patents that claim the drug
product as defined in Sec. 314.3. If a patent claims the finished
dosage form of the drug product, it must be submitted for listing.
B. Section 314.53(c)--What Does the Patent Declaration Say?
Section 314.53(c)(1) describes the general requirements for
submission of patent information and the conditions for acceptance of
the patent information. Section 314.53(c)(2)(i) requires a person
submitting an NDA, an amendment, or a supplement, to submit an original
signed declaration form as part of its submission of patent
information. The appropriate declaration form must be used for
submitting patent information. The information required to be submitted
is described. Each form seeks specific patent information and requires
a signed attestation from the NDA applicant or holder or patent owner
that the information is accurate and complies with the requirements of
the regulations.
Section 314.53(c)(2)(ii) requires that the NDA holder submit a
declaration form with information relating to the approved NDA and
additional information on use codes within 30 days of NDA approval. The
information required to be submitted is described. Each form includes
specific patent information and requires a signed attestation from the
NDA holder or patent owner that the information is accurate and
complies with the requirements of the regulations. This section also
requires submission of information on patents submitted for listing
after NDA approval. This declaration form is the only declaration form
that we will rely on to determine whether a patent is eligible for
listing based on the patent information submitted.
C. Section 314.53(c)(3)--What Is Required to Be Filed If There Are No
Relevant Patents?
The final rule modifies the statement used to describe the fact
that the NDA applicant or holder believes there are no relevant patents
to be submitted. The language is changed to conform to the descriptions
used for drug substance (active ingredient), drug product (formulation
and composition) and method of use to those used in the other
regulatory provisions.
D. Sections 314.95(a) and 314.52(a)--When Are Notice and Certification
Required?
The final rule modifies Sec. Sec. 314.95(a) and 314.52(a) to state
that, if an ANDA or 505(b)(2) application is amended to include a
paragraph IV certification, notice must be provided to the NDA holder
and patent owner only if the application did not already contain a
paragraph IV certification or there was not a full opportunity for a
30-month stay. If an ANDA or 505(b)(2) applicant changes its paragraph
IV certification before the 45-day period after notice to the NDA
holder and patent owner has expired, and the NDA holder or patent owner
has not initiated patent litigation, such paragraph IV certification
and related notice are not considered to have satisfied the requirement
of providing one notice of a paragraph IV certification and a full
opportunity for a 30-month stay.
IV. Implementation
The final rule will be effective on August 18, 2003.
[sbull] Patent information submitted to us (FDA) before the
effective date will be subject to our pre-existing regulations
governing patent submission, declarations, certifications, notice and
availability of 30-month stays;
[sbull] Patent information submitted to us on or after the
effective date will be subject to the final rule's provisions governing
patent submission, accompanying declarations, certifications, notice
and availability of 30-month stays;
[sbull] Patent information submitted to us on a newly applicable
claim, even if the patent was previously submitted to us, will be
subject to the final rule's provisions.
The final rule will have a compliance date of December 18, 2003,
for patent information submitted to us on patents claiming a polymorph
of the same active ingredient of the product described in the NDA.
As a result, within a single same approved or pending NDA, some
patents may be subject to our pre-existing regulations while other
patents may be subject to the final rule. The date on which the patent
information was submitted to us will determine which set of regulations
applies.
We believe that the effective dates will provide adequate time for
the NDA applicants, NDA holders, and patent owners to adjust their
business practices. The patent information required for submission is
information readily available to the NDA applicants and holders and
patent owners.
We have delayed the implementation date for patent information to
be submitted to us on patents claiming a polymorph that is the active
ingredient of the drug product described in the approved NDA. NDA
applicants and holders and patent owners with patents pending at the
PTO will have additional time (i.e., until 6 months after the date of
publication in the Federal Register) to conduct the tests needed to
produce the data required for the declaration statement in time to
submit any newly issued patent within 30 days of issuance.
V. Legal Authority
Our principal legal authority for the final rule is section 505 of
the act, in
[[Page 36698]]
conjunction with our general rulemaking authority in section 701(a) (21
U.S.C. 371) of the act. Section 505(b) and (c) of the act describes the
contents of an NDA and 505(b)(2) application, including the patent
submission and patent certification requirements. Section 505(j) of the
act describes the contents of an ANDA, including patent certification
requirements. Sections 505(b)(2)(A) and 505(j)(2)(A)(vii) of the act,
respectively, require patent certifications, while sections 505(b)(3)
and 505(j)(2)(B) of the act require those applicants who have made a
paragraph IV certification to provide notice to the NDA holder and
patent owner.
The final rule clarifies the types of patents which NDA applicants
and NDA holders must and must not submit to FDA for listing in the
Orange Book. It also requires a more detailed patent declaration from
NDA applicants and NDA holders or patent owners using declaration
forms. The specific legal authority for each provision is set forth in
the preamble discussion accompanying it.
For ANDA and 505(b)(2) applicants, the final rule reduces the
number of notifications sent to patent owners and NDA holders. The
specific legal authority for this action is set forth in the preamble
discussion of our changed interpretation.
VI. Environmental Impact
We have determined under 21 CFR 25.30(h) and 25.31(a) that this
action is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.
VII. Executive Order 13132: Federalism
We have analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. We have determined that this final
rule does not contain policies that have substantial direct effects on
the States, on the relationship between the National Government and the
States, or on the distribution of power and responsibilities among the
various levels of government. Accordingly, we have concluded that the
final rule does not contain policies that have federalism implications
as defined in the order and, consequently, a federalism summary impact
statement is not required.
VIII. Paperwork Reduction Act of 1995
This final rule contains information collection requirements that
are subject to public comment and review by the Office of Management
and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C.
3501-3520). We describe these provisions below in this section of the
document with an estimate of the annual reporting burden. Our estimate
includes the time for reviewing instructions, searching existing data
sources, gathering and maintaining the data needed, and completing and
reviewing each collection of information.
Title: Applications for FDA Approval to Market a New Drug: Patent
Submission and Listing Requirements and Application of 30-month Stays
on Approval of Abbreviated New Drug Applications Certifying That a
Patent Claiming a Drug Is Invalid or Will Not Be Infringed
Description: The final rule clarifies the types of patent
information that must and must not be submitted to FDA as part of an
NDA, an amendment or supplement. The final rule also requires persons
submitting an NDA, amendment or supplement, or submitting information
on a patent after NDA approval, to make a detailed patent declaration
using required FDA declaration forms. The final rule permits the
possibility of only one 30-month stay per each ANDA or 505(b)(2)
application's approval date in the event of patent infringement
litigation because the final rule does not require ANDA or 505(b)(2)
applicants to provide a notice of certification of invalidity or
noninfringement of a patent if the application already contains such a
certification or if a full opportunity for a 30-month stay resulted
after such notice.
Description of Respondents: Persons submitting an NDA, amendment or
supplement, or submitting information on a patent after NDA approval,
and persons submitting an ANDA or 505(b)(2) application containing a
patent certification of invalidity or noninfringement of a patent.
We estimate the burden of this collection of information as
follows:
Table 1.--Estimated Annual Reporting Burden\1\
----------------------------------------------------------------------------------------------------------------
Frequency of Total Annual Hours per
21 CFR Section No. of Respondents Responses Responses Response Total Hours
----------------------------------------------------------------------------------------------------------------
314.50(a) through (f), (h), 107 2.8 296 1,684 498,464
and (k) (citing 21 CFR
314.53) FDA Forms 3542 and
3542a
314.50(i)(1)(i) and 74 1.5 111 4 444
314.94(a)(12)
314.52(a)(3) and 74 1.01 74 12 897
314.95(a)(3)
----------------------------------------------------------------------------------------------------------------
Total 499,805
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
Our estimates are based on the following assumptions. For the years
1998 to 2002, the annual number of original applications we have
received containing a paragraph IV certification has been 61, 58, 79,
90, and 82, respectively. The annual average is 74 ((61 certifications
+ 58 certifications +79 certifications + 90 certifications + 82
certifications) / 5 years = 74 certifications / year). Because the
final rule requires notice of a paragraph IV certification filed in the
original ANDA or 505(b)(2) application or when the application is
amended to include a paragraph IV certification or when such notice did
not provide a full opportunity for a 30-month stay, this would mean
that these applicants would provide one notice to NDA holders and
patent owners, and, in rare instances, a second notice. We increase the
frequency of response to account for these rare second notices. There
may still be multiple certifications made by ANDA or 505(b)(2)
applicants which will not require notice. In previous estimates, we
have combined the information collection burden for both the notice and
certification. For purposes of the final rule, we assume that the
certification information collection burden is 4 hours and the
information collection burden for the notice is 12 hours. We also
account for the multiple number of certifications that may have to be
provided by an ANDA or 505(b)(2) applicant. Under pre-existing
regulations, we have had
[[Page 36699]]
NDA holders submit two or more patents for a single NDA. While this may
continue to occur, we believe that this final rule may reduce the
number of patents submitted for listing because we have clarified the
type of patents that must be submitted. The number of patents submitted
could increase because we allow polymorph patents to be submitted or it
could decrease if no test data exist to demonstrate that a drug product
containing the polymorph will perform the same as the drug product
described in the NDA. We, thus, estimate the number of annual
certifications at 1.5 x 74 (the number of original certifications).
Thus, the information collection burden for Sec. Sec. 314.50(i)(1)(i)
and 314.94(a)(12) (certifications) would be 444 hours (74 respondents x
1.5 response per respondent x 4 hours per response = 444 hours). The
information burden for Sec. Sec. 314.52(a)(3) and 314.95(a)(3)
(notices) would be 897 hours (74 respondents x 1.01 response per
respondent x 12 hours per response).
To estimate the number of enhanced patent declarations that will be
submitted annually, we referred to historical data on patent
submissions. For the years 1998 to 2002, the numbers of patents
submitted to us were 159, 205, 321, 280, and 268 respectively, for an
annual average of 246.6 ((159 patents +205 patents +321 patents+280
patents+268 patents) / 5 years = 247 patents / year). Because many of
these individual patents are included in multiple NDA submissions,
there could be multiple declarations for a single patent. From our
review of submissions, we believe the number of duplicate patent
listings to be 20 percent of the number of unique patents. Therefore,
we estimate 49.2 (246.6 patents x 20 percent) patent declarations will
be multiple listings, and there will be 296 (247 declarations + 49
declarations = 296 declarations) total annual patent declarations. As
we received 115 and 99 NDAs in 2000 and 2001, respectively, we assume
there will be 107 ((115 applications + 99 applications) / 2 years = 80
applications / year) instances where an NDA holder would be affected by
the patent declaration requirements and that each of these holders
would, on average, submit 2.8 (296 declarations / 107 instances = 2.8
declarations per instance) on FDA Forms 3542 or 3542a.
However, Sec. 314.53(b) and (c) have different impacts on the
hours per response. On the one hand, Sec. 314.53(b) might decrease the
reporting burden because it would specify certain patents that must not
be submitted, and thus NDA applicants and holders and patent owners
will not submit information on those patents. On the other hand, Sec.
314.53(b) will require NDA applicants and holders or patent owners to
submit patent information on different forms of the active ingredient
described in the NDA, and this could result in more patent information
being submitted or less patent information if test data do not exist to
demonstrate that a drug product containing the polymorph will perform
the same as the drug product described in the NDA. We cannot determine
whether the potential net effect will increase, decrease, or not change
the overall burden associated with submitting patent information, so we
have not assigned any change in the total reporting burden for the
change in patent information alone.
In contrast, Sec. 314.53(c) makes the patent declaration more
detailed. The change in the declaration will increase the burden hours
per response under Sec. 314.50(h) (the provision under which we
covered patent declarations described in Sec. 314.53(c)) because
respondents will be required to be more precise in their declarations.
Based on other rules that require respondents to compile and submit
information in their possession, we estimate that the information
required to be submitted on the patent declaration forms, FDA Forms
3542 or 3542a, will result in an additional information collection
burden of 18 hours. However, the previous burden hour estimate of 1,666
hours for Sec. 314.50 covered paragraphs (a) through (f), in addition
to paragraphs (h) and (k) (see 66 FR 29143 at 29146, May 29, 2001). We
are unable to determine how many of the 1,666 hours were devoted to
patent declarations, so, in this table, we simply add 18 hours to the
1,666 hour estimate for Sec. 314.50(a) through (f), (h), and (k),
resulting in a burden hour estimate of 1,684 hours (1,666 hours + 18
hours) to account for a respondent's need for more time to make and
verify the patent declaration. Thus, the information collection burden
for Sec. 314.50(a) through (f), (h), and (k)(citing Sec. 314.53) will
increase from the estimate we made in the proposed rule of 209,560
hours to 498,464 hours (296 annual responses x 1,684 hours per response
= 498,464 hours).
The information collection provisions of this final rule have been
submitted to OMB for review. Prior to the effective date of this final
rule, FDA will publish a notice in the Federal Register announcing
OMB's decision to approve, modify, or disapprove the information
collection provisions in this final rule. An agency may not conduct or
sponsor, and a person is not required to respond to, a collection of
information unless it displays a currently valid OMB control number.
IX. Analysis of Economic Effects
We have examined the impacts of the rule under Executive Order
12866, and the Regulatory Flexibility Act (5 U.S.C. 601-612), and under
the Unfunded Mandates Reform Act (UMRA) (2 U.S.C. 1501 et seq.).
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). Unless the agency
certifies that the rule is not expected to have a significant economic
impact on a substantial number of small entities, the Regulatory
Flexibility Act, as amended by the Small Business Regulatory
Flexibility Act (SBREFA), requires agencies to analyze regulatory
options that would minimize any significant economic impact of a rule
on small entities. Section 202 of UMRA requires that agencies prepare a
written statement of anticipated costs and benefits before proposing
any rule that may result in expenditures by State, local, and tribal
governments in the aggregate, or by the private sector, of $100 million
in any one year (adjusted annually for inflation). We have conducted
analyses of the rule, and have determined that the rule is consistent
with the principles set forth in the Executive Order and in these
statutes.
The final rule is a significant regulatory action as defined by the
Executive Order. With respect to the Regulatory Flexibility Act, we
certify that this final rule is not expected to have a significant
impact on a substantial number of small entities. This regulatory
action is also a major rule under the Congressional Review Act. The
discussion of costs and benefits is consistent with the requirements of
the UMRA.
A. Summary
The economic impacts arise from a variety of effects of this rule.
The primary effect is the elimination of multiple 30-month stays, which
(as explained earlier) will result in earlier market entry by generic
drug manufacturers without appreciable effects on pharmaceutical
innovation. Earlier generic competition will result in gains for two
groups. It will reduce pharmaceutical prices to consumers and increase
net revenues of generic drug manufacturers. Earlier competition also
[[Page 36700]]
will result in a revenue loss for innovator drug companies, which will
be offset slightly by a reduction in associated costs. We believe that
the rule will also reduce legal fees associated with disputed patents,
although we are unable to provide quantitative estimates of this
effect. In addition, innovator drug companies will face a burden of
completing revised patent declaration forms. Finally, those NDA holders
wishing to submit patents claiming different polymorphs of the active
ingredient described in the NDA will need to have test data
demonstrating ``sameness.'' Table 2 below provides a summary of our
estimates of these effects and overall net benefits. The benefits and
costs are annualized at a 7-percent discount rate over 10 years. We
have chosen this time period because the Centers for Medicare and
Medicaid Services (CMS), the source of the most reliable pharmaceutical
expenditure estimates, projects these expenditures only for the next 10
years. We expect that this rule will generate substantial net benefits
beyond this time period.
Table 2.--Economic Effects of the Rule\1\
------------------------------------------------------------------------
Amount per year
Effects (millions of dollars)
------------------------------------------------------------------------
Gains .....................
[sbull]Savings to consumers 3,290
[sbull] Net revenues to generic manufactures 1,810
[sbull]Reduced legal costs Not quantified
------------------------------------------------------------------------
Losses .....................
[sbull] Revenue loss to innovator firms (net of 4,870
associated costs) <10
[sbull] Costs of patent declarations and data to
support polymorph patent submissions
------------------------------------------------------------------------
Net Benefits 220
------------------------------------------------------------------------
\1\ Gains and Losses include impacts of an economic transfer in addition
to changes in resource costs.
These estimates are derived using methods and data similar to those
described at more length in the preamble to the proposed rule published
in the Federal Register on October 24, 2002 (see 67 FR 65448 at 65459
to 65464). In that analysis, we found that the increase in revenues to
generic drug manufacturers would be $19.117 billion over 10 years, or
$1.8 billion per year if annualized assuming a 7-percent discount rate.
The benefit to consumers would be $34.822 billion over 10 years or an
annualized $3.3 billion. We found that the reduction in revenues to
innovator firms would be mitigated somewhat by the reduction in
marketing expenses and that the cost would be $51.508 billion over ten
years, or an annualized $4.9 billion. The 10-year net benefit is $2.356
billion, and the annualized net benefit is approximately $220 million.
With respect to the changes in market shares, the gains to
consumers and generics equal the losses to innovators. An uncertainty
estimate on the cost side would equal the uncertainty on the benefit
side of such a transfer and would not affect our projection of net
benefits. Our projection of net benefits is driven by our estimate of
support costs. The primary economic impact of this action is a transfer
from innovator drug firms to consumers and generic drug firms. But as
innovator drug firms face a decline in revenues, they will save
substantial resources used to support their products. These support
costs, which include marketing, advertising, and administration,
outweigh the costs associated with polymorph testing and completing the
revised declaration, so the rule is a net benefit. These support costs
are based on a point estimate provided by literature that does not
customarily provide confidence intervals. We cannot, therefore, provide
confidence intervals about our net benefit estimate, but believe the
uncertainty to be small, relative to the projected net benefit.
We received no comment on the analysis published with the proposal.
We continue to believe these estimates to be reasonable and include
them in the final rule. This final rule, however, contains provisions
that differ from what was in the proposed rule. To account for these
provisions, we have changed our analysis of the burden of providing the
information required for completing the patent declaration and we
assess the impact of the requirement that NDA applicants or holders or
patent owners submitting patents claiming different polymorphs of the
active ingredient described in the NDA. In all other major respects,
however, our analysis is unchanged from the proposal, so we do not
repeat here some parts of our analysis that were described in detail in
the proposal (see 67 FR 65448 at 65459 to 65464).
B. Benefits of the Regulation
We have identified two principal effects from the elimination of
30-month stays. These effects are impacts associated with parties
gaining in economic transfer. Generic drug manufacturers gain the
market share lost by innovators. Generic revenues, therefore, would be
expected to increase. Also, to the extent that these generic drugs are
less expensive than innovator drugs, consumers will benefit from saving
money as a result of earlier access. Our model, as described in the
proposed rule (see 67 FR 65448 at 65460 to 65462), estimates costs and
benefits to consumers and innovators and generic drug firms for the
first year the rule would be in effect. The projected changes in market
shares and prices in the model are based on studies published in the
economic literature and by FDA. We then escalate the 1-year estimates
by the CMS--projected annual percentage increases in prescription drug
expenditures to obtain estimates for 10 years. This 10-year stream is
then annualized at a 7-percent discount rate to obtain the annualized
estimate.
1. Gains to Consumers
Generic drugs are cheaper than their innovator counterparts. As a
generic drug gains market share and its price falls, consumers save
more money. The elimination of multiple 30-month stays per ANDA and
505(b)(2) applications and earlier market entry by generic drugs will
reduce consumer expenditures on pharmaceuticals. We estimate that the
1-year savings to consumers are projected to be $2.040 billion. We use
the CMS pharmaceutical expenditure projections to escalate the base
year figure results in a 10-year consumer savings estimate of $34.822
billion for the final rule. Our annualized benefit using a 7-percent
discount rate is $3.288 billion, the same as the proposed rule.
[[Page 36701]]
2. Gains to the Generic Drug Industry
Innovator market share erosion is accompanied by a gain in generic
market share. We estimate the 1-year increase in revenues to be $1.120
billion. Escalating this impact by the annual increases in
pharmaceutical expenditures yields a 10-year revenue gain of $19.117
billion. Our annualized impact using a 7-percent discount rate is
$1.805 billion. These estimates are the same as in the proposed rule.
3. Benefits Not Quantified
Many important benefits associated with this final rule are
difficult to quantify. The benefits to consumers from lower prices also
involve favorable secondary benefits from improved access to less
expensive drugs. While the economic literature indicates generic
competition does not lead to significant overall increases in the
quantity of drugs demanded, we nevertheless recognize this rule has
favorable distributional effects for consumers who otherwise may not
have been able to afford some medications. Such a benefit is consistent
with the objective of improving access to affordable quality
healthcare. Consumers with better access to affordable safe and
effective therapies are healthier and enjoy a higher quality of life.
By addressing multiple 30-month stays, this final rule is removing
a barrier to entry for generic drug firms. In principle, the removal of
a barrier to entry would imply an increase in economic efficiency. The
existing economic literature, however, indicates no significant
increase in the quantity of drugs demanded with generic entry, implying
no gain in efficiency from the removal of the barrier to entry. Thus,
we do not quantify any efficiency gains in our analysis. Nevertheless,
this rule encourages more and earlier market entry by generic drug
firms and may impact consumption in a way not captured by the economic
literature. To that extent, we believe this rule has the potential to
increase economic efficiency.
The costs of allocating legal resources to defend patent
protections are substantial. We do not know the extent to which this
final rule will reduce such costs, but by eliminating multiple 30-month
stays per ANDA and 505(b)(2) application, we are reducing the number of
instances where innovator and generic drug firms would engage in such
litigation. Moreover, we believe that this rule will reduce litigation
because it clarifies which patents must and must not be submitted and
reduces incentives for submitting patents that may ultimately be found
invalid. It logically follows that the reduction in resources devoted
to litigation would result in savings to both innovator and generic
drug firms.
This final rule reduces the level of uncertainty associated with
drug marketing decisions. For example, the final rule diminishes
incentives associated with submitting later-issued patents late in the
patent life or exclusivity period of the product described in the NDA.
Increasing the predictability of the generic drug entry process reduces
product introduction costs faced by generic drug firms. In the final
rule, we are also addressing a source of confusion over the submission
of polymorph patents for listing in the Orange Book. We believe that a
more predictable business environment benefits both innovator and
generic drug firms.
Another important benefit of the final rule involves the balance
between rewarding innovation and the availability of less expensive
drugs. In striking this balance, we do not believe that the Hatch-
Waxman Amendments intended to create the potential for NDA holders to
obtain multiple 30-month stays to unduly delay generic competitors. We
believe this balance to be important, yet find the value difficult to
quantify. Nevertheless, in addressing the issue of multiple 30-month
stays, we believe this action has the very valuable benefit of
preserving the balance struck in the Hatch-Waxman Amendments.
4. Total Benefits of the Regulation
The total quantified benefits of this final rule include the gains
in generic drug manufacturer revenues and consumer savings from earlier
access to less expensive pharmaceuticals. These quantified gains to
consumers and generic drug companies are the result of an economic
transfer. The 1-year benefits to generic drug manufacturers and
consumers are $1.119 billion and $2.040 billion, respectively.
Escalating these base year costs over 10 years yields generic drug
manufacturer revenue gains of $19.117 billion and consumer savings of
$34.822 billion, for a total of $53.940 billion. The 10-year annualized
benefits, using a 7-percent discount rate, are $1.805 billion for
generic drug manufacturers and $3.288 billion for consumers, for a
total of $5.093 billion.
C. Costs of the Regulation
In the proposed rule, we identified two sources of costs.
Innovators lose revenues from earlier generic competition and
innovators must complete patent declarations. The loss in revenues to
innovator drug companies is part of an economic transfer, but is
included in this analysis with the resource costs associated with this
action. We summarize the revenue loss and we assess the costs
associated with the declaration requirement. In addition, we estimate
the burden to industry from the requirement that, for submission of
patents claiming different polymorphs of the active ingredient
described in the NDA, there must be test data demonstrating that a drug
product containing the polymorph will perform the same as the drug
product described in the NDA.
In the proposed rule, we addressed potential concerns about the
effect this action may have on innovation. After considering potential
impacts, we concluded that any negative effect would be minimal. As
discussed in the proposed rule, while the initial 30-month stay is part
of the balance struck in the Hatch-Waxman Amendments to reward
innovation, the subsequent stays are not part of this balance.
According to the FTC report, most of the court rulings examined by the
FTC, which involved a subsequent 30-month stay, found the underlying
patent to be either invalid or not infringed. Extending market
exclusivity through multiple stays is a strategy that has become
popular in the last few years and is not a longstanding source of
research funding. Subsequent stays could actually hinder innovation
through the replacement effect, in that they provide a disincentive for
an NDA holder to improve upon its own product. Moreover, to the extent
that subsequent 30-month stays might be associated with increases in
spending on research, these increases do not necessarily improve social
welfare (see 67 FR 65460). We received no comment on our assessment of
the impact on innovation and continue to believe it to be reasonable.
1. Innovator Revenue Loss
As discussed in the analysis of impacts in the proposed rule, the
elimination of multiple 30-month stays per ANDA or 505(b)(2)
application allows generic drugs to enter the market earlier. Upon
entry, generic versions of an innovator drug gradually lower their
prices and take market share from the innovator. With the loss of
market share, innovator revenues are lower than they would be had the
innovator been allowed to use multiple 30-month stays to delay generic
entry. In the analysis in the proposed rule, we used data from
instances where generics had been blocked with multiple 30-month stays
and calculated the impact of a typical
[[Page 36702]]
drug being blocked for a typical period of time. We estimated the 1-
year loss in innovator revenues to be $3.160 billion. As discussed in
the proposed rule, we believe that the negative impact on innovators
from earlier generic competition will be mitigated somewhat by a
reduction in required innovators' costs. With earlier generic
competition, innovators will reduce marketing expenses. In the proposed
rule, we estimated the 1-year reduction in support costs to be
approximately $142 million. For the final rule, we estimate that the 1-
year loss in revenues, after adjusting for the reduction in support
costs, is $3.017 billion, the same as in the proposed rule.
2. Declaration Costs
In the proposed rule, we used earlier information collection data
to estimate there will be 124 annual patent declarations by innovator
firms. We now believe that the number of patents submitted to us each
year would better estimate the annual number of patent declarations.
For the years 1998 to 2002, the numbers of patents submitted to us were
159, 205, 321, 280, and 268 respectively, for an annual average of 246.
We understand that many of these individual patents are included in
multiple NDA submissions, so there could be multiple declarations for a
single patent and this method could underestimate the number of
declarations. From our review of submissions, we believe the number of
duplicate patent listings to be 20 percent of the number of unique
patents. Therefore, we estimate 49.2 (246.6 x 20 percent) patent
declarations will be multiple listings, and there will be 295.8 (246.6
+ 49.2) annual patent declarations. We have created patent declaration
forms to make the submission of patent information less burdensome. The
two forms, for filing with an NDA submission and upon or after NDA
approval, will contain more information, but we have simplified the
format to make these easier to complete. In simplifying the forms, we
believe our initial estimate of 24 additional hours per declaration to
complete these forms likely overstates the actual burden. To account
for the simplification of the declaration process, we have lowered the
expected time required to complete a patent declaration to 18 hours.
A regulatory affairs specialist could perform the tasks associated
with this process. Based on the total average hourly compensation of
$55.14\2\ the estimated cost would be $992 ($55.14 per hour x 18 hours)
per event. The burden on individual firms would depend on the number of
declarations they submit. We estimate that the 1-year burden for
submitting patent declaration forms is $293,000 ($992 per event x 295.8
events).
---------------------------------------------------------------------------
\2\ The figure of $55.14 represents the hourly rate for
``lawyer'' from the Bureau of Labor Statistics 2003 National
Compensation Survey of $38.77, and then adjusted for inflation at
1.58 percent (unadjusted CPI-U) and increased 40 percent to account
for benefits.
---------------------------------------------------------------------------
3. Cost of Submitting Polymorph Patents
We are requiring the submission of patent information for patents
that claim different polymorphs of the active ingredient described in
the NDA. NDA holders will now be able to submit these polymorph patents
for listing in the Orange Book, as long as they have test data
demonstrating that a drug product containing the polymorph will perform
the same as the drug product described in the NDA.
We cannot make a precise estimate of the impact of these
requirements, as costs can vary substantially depending on the
substance being tested, the number of subjects required, the cost of
raw materials, and other factors. As part of an unrelated study in
1998, we commissioned a contractor, Eastern Research Group (ERG) to
estimate the cost of bioequivalence testing. We believe the burden of
demonstrating that a drug product containing the polymorph will perform
the same as the drug product described in the NDA to be similar to that
of demonstrating bioequivalence. Our estimates include both the cost of
manufacturing the batch and the cost of conducting the bioequivalence
testing. ERG found the cost of performing such testing to be between
$70,000 and $750,000.\3\ We believe the cost of showing ``sameness'' to
be at the higher end of this range, and estimate the burden to be
between $500,000 and $750,000. The midpoint of this estimate is
$625,000. (We did not adjust the ERG estimates for inflation.)
---------------------------------------------------------------------------
\3\ Pharmaceutical Industry Cost Savings Through Use of the
Scale-up and Post-Approval Change Guidance for Immediate Release
Solid Oral Dosage Forms ( SUPAC-IR), prepared for FDA, 1998, p. 63.
---------------------------------------------------------------------------
We believe a firm's decision to submit a polymorph patent for
listing will depend on whether the expected benefits to the firm from
listing exceed the costs of showing ``sameness.'' We recognize that
potential benefits from listing polymorph patents may be reduced by the
elimination in the final rule of multiple 30-month stays in approval of
ANDA or 505(b)(2) applications. Thus, the cost of demonstrating
``sameness'' would deter submitting patents for listing with expected
values less than approximately $625,000. We believe the typical value
of a deterred polymorph patent to be substantially less than the cost
of submission of the patent for listing, as many of the patents have
little value without the ability to delay generic entry through
multiple 30-month stays. For this analysis, we assume such low value
patents to be worth approximately 20 percent of the cost of showing
``sameness,'' or $125,000.
We believe the annual number of polymorph patents that will be
submitted for listing to be small, but we do not know with certainty.
We reviewed a publicly available listing of NDAs in which an outside
party had identified patents it judged to be polymorph patents. Of the
105 NDAs in the sample, there were 13 polymorph patents. Applying that
same ratio to the 107 expected NDAs per year, we estimate 13.2 (107 x
13 / 105) potential polymorph patents to be submitted for listing per
year. We assume that a polymorph patent will have a high potential
value (greater than $625,000--the midpoint of the testing cost
estimates) and be submitted, or will have a low potential value
($125,000) and not be submitted. With the elimination of multiple 30-
month stays per ANDA or 505(b)(2) application, we believe the number of
high-value polymorph patents to be a subset of the number of total
polymorph patents, and assume three-fourths of the potential patents
will not be submitted for listing. Thus, we assume 3.3 (13.2 potential
patents x 0.25 likelihood of being high value) patents will be
submitted for listing at a 1-year cost of $2.06 million (3.3 patents x
$625,000 cost per patent). Likewise, we assume 9.9 (13.2 potential
patents x 0.75 likelihood of being low value) patents will not be
submitted each year. We estimate the 1-year cost from the inability to
submit these patents for listing to be $1.24 million (9.9 patents x
$125,000 value of low-value patent) and the 1-year burden associated
with the test data demonstrating ``sameness'' for polymorph patents to
be submitted for listing is estimated to be $3.3 million ($2.06 million
+ $1.24 million).
4. Total Costs of the Regulation
The total costs of the final rule include the lost revenues to
innovator firms from the erosion of market share, mitigated by the
decrease in support costs, the cost of completing a more detailed
patent declaration, and the costs associated with the requirement that
test data exist demonstrating ``sameness'' in order to submit a
polymorph patent for listing. The estimated 1-year loss in revenues
from
[[Page 36703]]
erosion of market share is $3.160 billion and the reduction in support
costs would reduce this loss by $142 million. We estimate the 1-year
cost of providing the patent declaration information by completing the
patent declaration forms is $293,000 and the cost associated with
polymorph patents is $3.3 million. Thus, we estimate the 1-year cost to
innovator firms is $3.022 billion.
We recognize that in projecting the future impact of this final
rule, we must account for changes in the market for pharmaceuticals.
The Office of the Actuary at CMS, projects that expenditures on
prescription pharmaceuticals will increase dramatically in the near
future. As in the proposed rule, we account for the projected growth in
pharmaceutical expenditures by escalating our 1-year estimate by the
annual CMS projected growth in prescription drug expenditures. We
estimate the 10-year costs for the final rule are $51.584 billion. We
annualized over the 10-year period at a 7 percent discount rate yields
to obtain a cost of $4.871 billion.
D. Summary of Costs and Benefits
We estimate the 10-year cost of this final rule to be $51.584
billion and the annualized cost to be $4.871 billion. The 10-year
benefit of this final rule is estimated to be $53.940 billion and the
annualized benefit is $5.093 billion. These benefit and cost figures
include the estimated impacts of an economic transfer. Thus, the 10-
year net benefit is $2.356 billion and the annualized net benefit is
$222 million. The quantified benefits exceed the quantified costs.
Moreover, there are benefits that are difficult to quantify. These
benefits include reduced costs of litigation and more predictability in
the business environment. The benefits to consumers also involve
favorable secondary benefits, such as improved access to less expensive
drugs. It also preserves the balance struck in the Hatch-Waxman
Amendments.
E. Regulatory Alternatives
In creating this final rule, we considered several regulatory
alternatives, including not enacting this rule. We rejected the
alternative of not enacting this final rule because under the current
situation, NDA holders and patent owners are able to use multiple 30-
month stays to delay generic entry and frustrate the intent of the
Hatch-Waxman Amendments. We considered allowing the submission of
polymorph patents for listing in the Orange Book without the required
test data demonstrating ``sameness.'' We rejected this alternative as
we decided that a patent claiming different polymorphs of the active
ingredient described in the NDA needed to have test data demonstrating
that a drug product containing the polymorph will perform the same as
the drug product described in the NDA. This requirement is similar to
the requirement of establishing bioequivalence.
We also considered using the current system of patent declarations.
This alternative was also rejected because the pre-existing declaration
information may be insufficient to prevent NDA applicants and holders
and patent owners from submitting patents to us that should not be
submitted and listed under the act. The choices to require tests
demonstrating ``sameness'' for polymorph patents and the required
patent information provided in the patent declarations are particularly
important in light of the fact that we lack the authority, expertise
and resources to evaluate patents submitted to determine whether they
should be listed in the Orange Book.
F. Small Business Impact
Unless the agency certifies that the rule is not expected to have a
significant impact on a substantial number of small entities, the
Regulatory Flexibility Act, as amended by SBREFA, requires agencies to
analyze regulatory options that would minimize any significant economic
impact of a rule on small entities. In the proposed rule, we certified
that we believed the rule is not expected to have a significant impact
on a substantial number of small entities, as we did not know of any
small innovator companies that use or would use multiple 30-month stays
to block entry from generic competitors. We did not receive comment on
this certification and we continue to believe that this final rule will
not have a significant impact on a substantial number of small
entities.
List of Subjects in 21 CFR Part 314
Administrative practice and procedure, Confidential business
information, Drugs, Reporting and recordkeeping requirements.
0
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
0
1. The authority citation for 21 CFR part 314 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 356,
356a, 356b, 356c, 371, 374, 379e.
0
2. Section 314.52 is amended by redesignating paragraph (a)(3) as
paragraph (a)(4) and by adding new paragraph (a)(3) to read as follows:
Sec. 314.52 Notice of certification of invalidity or noninfringement
of a patent.
(a) * * *
(3) This paragraph does not apply if the applicant amends its
application to add a certification under Sec. 314.50(i)(1)(i)(A)(4)
when the application already contained a certification under Sec.
314.50(i)(1)(i)(A)(4) to a patent unless:
(i) The notice of the previous certification under Sec.
314.50(i)(1)(i)(A)(4) was withdrawn or changed to a certification other
than a certification under Sec. 314.50(i)(1)(i)(A)(4); and
(ii) The 45-day period under section 505(c)(3) of the act had not
expired; and
(iii) No person receiving notice under paragraphs (a)(1) and (a)(2)
of this section had brought an action against the applicant for
infringement of the patent that was the subject of the withdrawn or
changed certification under Sec. 314.50(i)(1)(i)(A)(4).
* * * * *
0
3. Section 314.53 is amended by revising paragraph (b) and paragraphs
(c)(1) through (c)(3) to read as follows:
Sec. 314.53 Submission of patent information.
* * * * *
(b) Patents for which information must be submitted and patents for
which information must not be submitted--(1) General requirements. An
applicant described in paragraph (a) of this section shall submit the
required information on the declaration form set forth in paragraph (c)
of this section for each patent that claims the drug or a method of
using the drug that is the subject of the 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 (active ingredient) patents, drug product
(formulation and composition) patents, and method-of-use patents. For
patents that claim the drug substance, the applicant shall submit
information only on those patents that claim the drug substance that is
the subject of the pending or approved application or that claim a drug
substance that is the same as the active ingredient that is the subject
of the approved or pending
[[Page 36704]]
application. For patents that claim a polymorph that is the same as the
active ingredient described in the approved or pending application, the
applicant shall certify in the declaration forms that the applicant has
test data, as set forth in paragraph (b)(2) of this section,
demonstrating that a drug product containing the polymorph will perform
the same as the drug product described in the new drug application. For
patents that claim a drug product, the applicant shall submit
information only on those patents that claim a drug product, as is
defined in Sec. 314.3, that is described in the pending or approved
application. For patents that claim a method of use, the applicant
shall submit information only on those patents that claim indications
or other conditions of use that are described in the pending or
approved application. The applicant shall separately identify each
pending or approved method of use and related patent claim. For
approved applications, the applicant submitting the method-of-use
patent shall identify with specificity the section of the approved
labeling that corresponds to the method of use claimed by the patent
submitted. Process patents, patents claiming packaging, patents
claiming metabolites, and patents claiming intermediates are not
covered by this section, and information on these patents must not be
submitted to FDA.
(2) Test Data for Submission of Patent Information for Patents That
Claim a Polymorph. The test data, referenced in paragraph (b)(1) of
this section, must include the following:
(i) A full description of the polymorphic form of the drug
substance, including its physical and chemical characteristics and
stability; the method of synthesis (or isolation) and purification of
the drug substance; the process controls used during manufacture and
packaging; and such specifications and analytical methods as are
necessary to assure the identity, strength, quality, and purity of the
polymorphic form of the drug substance;
(ii) The executed batch record for a drug product containing the
polymorphic form of the drug substance and documentation that the batch
was manufactured under current good manufacturing practice
requirements;
(iii) Demonstration of bioequivalence between the executed batch of
the drug product that contains the polymorphic form of the drug
substance and the drug product as described in the NDA;
(iv) A list of all components used in the manufacture of the drug
product containing the polymorphic form and a statement of the
composition of the drug product; a statement of the specifications and
analytical methods for each component; a description of the
manufacturing and packaging procedures and in-process controls for the
drug product; such specifications and analytical methods as are
necessary to assure the identity, strength, quality, purity, and
bioavailability of the drug product, including release and stability
data complying with the approved product specifications to demonstrate
pharmaceutical equivalence and comparable product stability; and
(v) Comparative in vitro dissolution testing on 12 dosage units
each of the executed test batch and the new drug application product.
(c) Reporting requirements--(1) General requirements. An applicant
described in paragraph (a) of this section shall submit the required
patent information described in paragraph (c)(2) of this section for
each patent that meets the requirements described in paragraph (b) of
this section. We will not accept the patent information unless it is
complete and submitted on the appropriate forms, FDA Forms 3542 or
3542a. These forms may be obtained on the Internet at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov
by searching for ``forms''.
(2) Drug substance (active ingredient), drug product (formulation
or composition), and method-of-use patents--(i) Original Declaration.
For each patent that claims a drug substance (active ingredient), drug
product (formulation and composition), or method of use, the applicant
shall submit FDA Form 3542a. The following information and verification
is required:
(A) New drug application number;
(B) Name of new drug application sponsor;
(C) Trade name (or proposed trade name) of new drug;
(D) Active ingredient(s) of new drug;
(E) Strength(s) of new drug;
(F) Dosage form of new drug;
(G) United States patent number, issue date, and expiration date of
patent submitted;
(H) The patent owner's name, full address, phone number and, if
available, fax number and e-mail address;
(I) The name, full address, phone number and, if available, fax
number and e-mail address of an agent or representative who resides or
maintains a place of business within the United States authorized to
receive notice of patent certification under sections 505(b)(3) and
505(j)(2)(B) of the act and Sec. Sec. 314.52 and 314.95 (if patent
owner or new drug application applicant or holder does not reside or
have a place of business within the United States);
(J) Information on whether the patent has been submitted previously
for the new drug application;
(K) Information on whether the expiration date is a new expiration
date if the patent had been submitted previously for listing;
(L) Information on whether the patent is a product-by-process
patent in which the product claimed is novel;
(M) Information on the drug substance (active ingredient) patent
including the following:
(1) Whether the patent claims the drug substance that is the active
ingredient in the drug product described in the new drug application or
supplement;
(2) Whether the patent claims a polymorph that is the same active
ingredient that is described in the pending application or supplement;
(3) Whether the applicant has test data, described in paragraph
(b)(2) of this section, demonstrating that a drug product containing
the polymorph will perform the same as the drug product described in
the new drug application or supplement, and a description of the
polymorphic form(s) claimed by the patent for which such test data
exist;
(4) Whether the patent claims only a metabolite of the active
ingredient; and
(5) Whether the patent claims only an intermediate;
(N) Information on the drug product (composition/formulation)
patent including the following:
(1) Whether the patent claims the drug product for which approval
is being sought, as defined in Sec. 314.3; and
(2) Whether the patent claims only an intermediate;
(O) Information on each method-of-use patent including the
following:
(1) Whether the patent claims one or more methods of using the drug
product for which use approval is being sought and a description of
each pending method of use or related indication and related patent
claim of the patent being submitted; and
(2) Identification of the specific section of the proposed labeling
for the drug product that corresponds to the method of use claimed by
the patent submitted;
(P) Whether there are no relevant patents that claim the drug
substance (active ingredient), drug product (formulation or
composition) or method(s) of use, for which the applicant is seeking
approval and with respect to which a claim of patent infringement could
reasonably be asserted if a person not licensed by the owner of the
patent engaged in the manufacture, use, or sale of the drug product;
[[Page 36705]]
(Q) A signed verification which states:
``The undersigned declares that this is an accurate and complete
submission of patent information for the NDA, amendment or
supplement pending under section 505 of the Federal Food, Drug, and
Cosmetic Act. This time-sensitive patent information is submitted
pursuant to 21 CFR 314.53. I attest that I am familiar with 21 CFR
314.53 and this submission complies with the requirements of the
regulation. I verify under penalty of perjury that the foregoing is
true and correct.''; and
(R) Information on whether the applicant, patent owner or attorney,
agent, representative or other authorized official signed the form; the
name of the person; and the full address, phone number and, if
available, the fax number and e-mail address.
(ii) Submission of patent information upon and after approval.
Within 30 days after the date of approval of its application or
supplement, the applicant shall submit FDA Form 3542 for each patent
that claims the drug substance (active ingredient), drug product
(formulation and composition), or approved method of use. FDA will rely
only on the information submitted on this form and will not list or
publish patent information if the patent declaration is incomplete or
indicates the patent is not eligible for listing. Patent information
must also be submitted for patents issued after the date of approval of
the new drug application as required in paragraph (c)(2)(ii) of this
section. As described in paragraph (d)(4) of this section, patent
information must be submitted to FDA within 30 days of the date of
issuance of the patent. If the applicant submits the required patent
information within the 30 days, but we notify an applicant that a
declaration form is incomplete or shows that the patent is not eligible
for listing, the applicant must submit an acceptable declaration form
within 15 days of FDA notification to be considered timely filed. The
following information and verification statement is required:
(A) New drug application number;
(B) Name of new drug application sponsor;
(C) Trade name of new drug;
(D) Active ingredient(s) of new drug;
(E) Strength(s) of new drug;
(F) Dosage form of new drug;
(G) Approval date of new drug application or supplement;
(H) United States patent number, issue date, and expiration date of
patent submitted;
(I) The patent owner's name, full address, phone number and, if
available, fax number and e-mail address;
(J) The name, full address, phone number and, if available, fax
number and e-mail address of an agent or representative who resides or
maintains a place of business within the United States authorized to
receive notice of patent certification under sections 505(b)(3) and
505(j)(2)(B) of the act and Sec. Sec. 314.52 and 314.95 (if patent
owner or new drug application applicant or holder does not reside or
have a place of business within the United States);
(K) Information on whether the patent has been submitted previously
for the new drug application;
(L) Information on whether the expiration date is a new expiration
date if the patent had been submitted previously for listing;
(M) Information on whether the patent is a product-by-process
patent in which the product claimed is novel;
(N) Information on the drug substance (active ingredient) patent
including the following:
(1) Whether the patent claims the drug substance that is the active
ingredient in the drug product described in the approved application;
(2) Whether the patent claims a polymorph that is the same as the
active ingredient that is described in the approved application;
(3) Whether the applicant has test data, described at paragraph
(b)(2) of this section, demonstrating that a drug product containing
the polymorph will perform the same as the drug product described in
the approved application and a description of the polymorphic form(s)
claimed by the patent for which such test data exist;
(4) Whether the patent claims only a metabolite of the active
ingredient; and
(5) Whether the patent claims only an intermediate;
(O) Information on the drug product (composition/formulation)
patent including the following:
(1) Whether the patent claims the approved drug product as defined
in Sec. 314.3; and
(2) Whether the patent claims only an intermediate;
(P) Information on each method-of-use patent including the
following:
(1) Whether the patent claims one or more approved methods of using
the approved drug product and a description of each approved method of
use or indication and related patent claim of the patent being
submitted;
(2) Identification of the specific section of the approved labeling
for the drug product that corresponds to the method of use claimed by
the patent submitted; and
(3) The description of the patented method of use as required for
publication;
(Q) Whether there are no relevant patents that claim the approved
drug substance (active ingredient), the approved drug product
(formulation or composition) or approved method(s) of use and with
respect to which a claim of patent infringement could reasonably be
asserted if a person not licensed by the owner of the patent engaged in
the manufacture, use, or sale of the drug product;
(R) A signed verification which states: ``The undersigned declares
that this is an accurate and complete submission of patent information
for the NDA, amendment or supplement approved under section 505 of the
Federal Food, Drug, and Cosmetic Act. This time-sensitive patent
information is submitted pursuant to 21 CFR 314.53. I attest that I am
familiar with 21 CFR 314.53 and this submission complies with the
requirements of the regulation. I verify under penalty of perjury that
the foregoing is true and correct.''; and
(S) Information on whether the applicant, patent owner or attorney,
agent, representative or other authorized official signed the form; the
name of the person; and the full address, phone number and, if
available, the fax number and e-mail address.
(3) No relevant patents. If the applicant believes that there are
no relevant patents that claim the drug substance (active ingredient),
drug product (formulation or composition), or the method(s) of use for
which the applicant has received approval, and with respect to which a
claim of patent infringement could reasonably be asserted if a person
not licensed by the owner of the patent engaged in the manufacture,
use, or sale of the drug product, the applicant will verify this
information in the appropriate forms, FDA Forms 3542 or 3542a.
* * * * *
0
4. Section 314.95 is amended by redesignating paragraph (a)(3) as
paragraph (a)(4) and by adding new paragraph (a)(3) to read as follows:
Sec. 314.95 Notice of certification of invalidity or noninfringement
of a patent.
(a) * * *
(3) This paragraph does not apply if the applicant amends its
application to add a certification under Sec. 314.94(a)(12)(i)(A)(4)
when the application already contained a certification under Sec.
314.94(a)(12)(i)(A)(4) to a patent unless:
(i) The notice of the previous certification under Sec.
314.94(a)(12)(i)(A)(4) was withdrawn or changed to a certification
other than a certification under Sec. 314.94(a)(12)(i)(A)(4);
[[Page 36706]]
(ii) The 45-day period under section 505(j)(5)(B)(iii) of the act
had not expired; and
(iii) No person receiving notice under paragraphs (a)(1) and (a)(2)
of this section had brought an action against the applicant for
infringement of the patent that was the subject of the withdrawn or
changed certification under Sec. 314.94(a)(12)(i)(A)(4).
* * * * *
Dated: May 23, 2003.
Mark B. McClellan,
Commissioner of Food and Drugs.
Dated: June 9, 2003.
Tommy G. Thompson,
Secretary of Health and Human Services.
[This appendix will not appear in the Code of Federal Regulations.]
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[FR Doc. 03-15065 Filed 6-12-03; 1:00 pm]
BILLING CODE 4160-01-S