[Federal Register: October 24, 2002 (Volume 67, Number 206)]
[Proposed Rules]
[Page 65447-65465]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr24oc02-21]
[[Page 65447]]
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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 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; Proposed Rule
[[Page 65448]]
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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
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: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
its patent listing requirements for new drug applications (NDAs). The
proposal would clarify the types of patents that must and must not be
listed and revise the declaration that NDA applicants must provide
regarding their patents to help ensure that NDA applicants list only
appropriate patents. The proposal would also revise the regulations
regarding the effective date of approval for certain abbreviated new
drug applications (ANDAs) and certain applications submitted under
section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (the act)
(505(b)(2) applications). In certain situations, Federal law bars FDA
from making the approval of an ANDA or 505(b)(2) application effective
for 30 months if the applicant certified that the patent claiming a
drug is invalid or will not be infringed, and the patent owner or NDA
holder brings suit for patent infringement. The proposal also would
state that there will be only one opportunity for a 30-month stay in
the approval date of each ANDA or 505(b)(2) application. The proposal
is designed to make the patent listing process more efficient and to
enhance the ANDA and 505(b)(2) application approval processes.
DATES: Submit written or electronic comments by December 23, 2002.
Submit written comments on the information collection requirements by
November 25, 2002.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/
dockets/ecomments. Submit written comments on the information
collection provisions to the Office of Information and Regulatory
Affairs, Office of Management and Budget (OMB), New Executive Office
Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, Attn: Stuart
Shapiro, Desk Officer for FDA.
FOR FURTHER INFORMATION CONTACT: Jarilyn Dupont, Office of Policy,
Planning, and Legislation (HFW-14), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-3360.
SUPPLEMENTARY INFORMATION:
I. Background
A. What Is the Relationship Between Patent Listing, Patent
Certification, and the Date of Approval for Certain Applications?
Title I of the Drug Price Competition and Patent Term Restoration
Act (Public Law 98-417, 98 Stat. 1585 (1984) (``Hatch-Waxman
amendments'')) amended the act to authorize the approval of duplicate
or ``generic'' versions of approved drug products. Title I also amended
section 505(b)(1) of the act (21 U.S.C. 355(b)(1)) by requiring 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 imposes a similar patent listing obligation on
persons whose NDAs we have approved when the NDA holder could not have
filed the patent information with its application (either because the
application was filed before the act required NDA applicants to submit
patent information or because the patent issued after we had approved
the NDA).
We publish patent information in our approved drug products list
entitled ``Approved Drug Products With Therapeutic Equivalence
Evaluations.'' The list is known popularly as the ``Orange Book''
because of its orange-colored cover.
The Hatch-Waxman amendments also require persons submitting a
505(b)(2) application or ANDA to make certifications regarding the
listed patents pertaining to the drug which they intend to duplicate
(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). 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) application 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), the act requires the applicant to
notify the patent owner and NDA holder (see sections 505(b)(3) and
505(j)(2)(B) of the act.) In general, the notice states that an
abbreviated application has been submitted for the drug with respect to
which the paragraph IV certification is made and 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 an action for patent infringement is brought within 45 days after
the paragraph IV certification has been received, then we may not make
the approval of an abbreviated application effective for 30 months, or
such shorter or longer period as a court may order or the date of a
court decision (see sections 505(c)(3)(C) and 505(j)(4)(B)(iii) of the
act).
These statutory provisions reflect the Hatch-Waxman amendments'
attempt to balance two competing interests: Promoting competition
between ``brand-name'' and ``generic'' drugs and encouraging research
and innovation. The act promotes competition by creating a process to
expedite the filing and approval of ANDAs and 505(b)(2) applications
and for resolving challenges to patents before marketing begins. At the
same time, the act seeks to protect the patent owner's or NDA holder's
interests by giving it the opportunity to list patents, to receive
paragraph IV certifications, and to delay an ANDA's or 505(b)(2)
application's effective date of approval during patent infringement
litigation. (We will refer to the date the approval is made effective
as the ``approval date'' throughout the remainder of this preamble.)
We published regulations pertaining to patent listing and patent
certifications in the Federal Register on October 3, 1994 (59 FR
50338). The regulations regarding the submission of patent information
are at Sec. Sec. 314.50(h) and 314.53 (21 CFR 314.50(h) and 314.53),
while the patent certification requirements are at Sec. Sec. 314.50(i)
and 314.94(a)(12) for 505(b)(2) applications and ANDAs respectively.
[[Page 65449]]
B. What Events Led to This Proposal?
In recent years, we have seen NDA applicants list new patents
shortly before other listed patents for the same drug product are
scheduled to expire. Some listings, such as those for BuSpar (buspirone
hydrochloride), Paxil (paroxetine hydrochloride), Tiazac (diltiazem
hydrochloride), and Prilosec (omeprazole), have resulted in high
profile litigation. (We discuss some of these cases in section II.A of
this document.) A number of disputes over recently listed patents have
addressed whether the patent meets the regulatory requirements for
listing in the Orange Book and have sometimes resulted in decisions
that are not entirely consistent with our regulatory policy or our
interpretation of our regulations.
Additionally, on May 16, 2001, the Bureau of Competition and the
Policy Planning Staff of the Federal Trade Commission (FTC) submitted a
citizen petition (FDA docket number 01P-0248) (FTC Citizen Petition)
that requested our 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
FTC was conducting an extensive study of generic drug competition. FTC
issued the study in July 2002, 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
pertain to the brand-name drug product. The FTC Report noted that FTC
had submitted a citizen petition to us. FTC also recommended that the
law be changed 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, FTC asked that we issue a
regulation or guidance clarifying whether an NDA holder could list
various types of patents in the Orange Book. The types of patents for
which FTC sought clarification were patents that claimed metabolites,
polymorphs, or intermediates, product by process patents, and double
patents (see FTC Report at pages A-39-A-45).
II. Description of the Proposed Rule
Given these patent listing issues, the FTC citizen petition, and
the FTC Report, we decided to issue this proposed rule to help NDA
applicants and NDA holders determine whether specific patents must be
submitted to us for listing and to help 505(b)(2) application
applicants, ANDA applicants, and other interested parties determine
whether a patent listing is proper. This proposed rule will address:
[sbull] The types of patents that must and must not be listed;
[sbull] The patent certification statement that NDA applicants must
submit as part of an NDA, an amendment to an NDA, or a supplement to an
NDA; and
[sbull] The 30-month stay in effective dates of approval for a
505(b)(2) application or an ANDA.
A. Proposed Sec. 314.53(b)--What Patents Must Be Listed in the Orange
Book?
1. What Does the Current Regulation Say?
Our patent listing regulation, at Sec. 314.53, applies to persons
submitting an NDA, an amendment to an NDA, or a supplement to an NDA.
Section 314.53(b) describes the patents for which information must be
submitted and states, in part, that the applicant:
* * * shall submit information on each patent that claims the
drug that is the subject of the new drug application or amendment or
supplement to it and with respect to which a claim of patent
infringement could reasonably be asserted if a person not licensed
by the owner of the patent engaged in the manufacture, use, or sale
of the drug product. For purposes of this part, such patents consist
of drug substance (ingredient) patents, drug product (formulation
and composition) patents, and method of use patents. Process patents
are not covered by this section and information on process patents
may not be submitted to FDA.
Section 314.53 reflects the statutory provision that requires NDA
applicants to file the patent number and 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'' (see section 505(b)(1) of the
act). Thus, both the act and our regulations establish two distinct
criteria for a patent intended for listing in the Orange Book: (1) The
patent must claim the approved drug product or a method of using the
approved drug product; and (2) the patent must be one with respect to
which a claim of patent infringement could reasonably be asserted if a
person not licensed by the patent owner sought to engage in the drug's
manufacture, use, or sale.
2. How Have We Interpreted the Regulation?
As we mentioned earlier in section I.B of this preamble, the FTC
Citizen Petition sought our guidance on whether an NDA holder can list
a patent claiming an unapproved aspect of an approved drug. The
petition maintained that the act and our regulations do not allow
listing of a patent that claimed ``only an unapproved component, an
unapproved formulation, or an unapproved use of a drug product'' (see
FTC Citizen Petition at page 3).
Our longstanding interpretation is that the term ``drug'' in the
patent listing provisions means the approved drug product. We
successfully argued in Pfizer v. FDA, 753 F. Supp. 171 (D. Md. 1990),
that the term ``drug'' as used in sections 505(b)(1) and 505(c)(2) of
the act refers to the ``drug product'' for which the NDA was filed.
Pfizer had maintained that ``drug'' meant both the drug substance
(active ingredient) and the drug product, and thus any patent claiming
any drug product which contained the active ingredient that was the
subject of the approved NDA must be submitted, regardless of whether
the patent claims the approved drug product itself. This case began
with our refusal to list a patent in the Orange Book because Pfizer did
not certify that the drug and the formulation or composition of the
drug claimed by the patent were currently approved. The drug dosage
form covered by Pfizer's approved NDA was a capsule, but the patent
Pfizer had sought to list claimed a tablet.
The court upheld our position that: (1) An NDA approval covers a
specific drug product; (2) the approved drug product becomes the listed
drug; and (3) ANDA applicants must certify only to patents claiming
that listed drug. The court found that ``FDA's interpretation is not
only reasonable but also consistent with the language of the statute,
Congressional intent, prior judicial interpretations of [21 U.S.C.]
Sec. 355, and the agency's own regulations'' (see 753 F. Supp. at 171-
72). It also found that section 505(b)(1) of the act modifies the
statutory definition of ``drug'' at section 201(g)(1) of the Act (21
U.S.C. 321(g)(1)) to allow listing only of patents which claim the drug
``for which the applicant submitted the application.'' Further, the
court noted that sections 505(b)(1)(B) and (C) of the act require that
an NDA application contain ``a full list of the articles used as
components of such drug'' and ``a full statement of the
[[Page 65450]]
composition of such drug,'' and that these requirements made sense only
for a drug product and not for a drug substance that was independent of
the approved NDA. Because Pfizer's NDA covered a specific drug product
in capsule form (as opposed to covering the drug product's active
ingredient alone or covering other dosage forms that contain the active
ingredient), the court held that Pfizer could not list the patent
covering the tablets.
In 1994, after the Pfizer decision had issued, we published a final
rule that codified the patent listing requirement at 21 CFR 314.53 (see
59 FR 50338 (October 3, 1994)). Although the rule repeated the
statutory requirement that the patent must claim the drug that is the
subject of the NDA, the final rule replaced the proposed rule's
reference to patents consisting of ``drug (ingredient) patents'' with
patents consisting of ``drug substance (ingredient) patents'' (see 59
FR 50338 at 50343) (emphasis added). We also replaced ``patents that
claim a drug or drug product'' with ``patents that claim a drug
substance or drug product'' (id.) (emphasis added). Our intent was to
clarify that the rule's reference to ``drug'' in the phrase ``drug or
drug product'' was intended to mean ``drug substance'' rather than
``drug product.'' (The rule mentioned drug products separately.) We
made this change because some patents claim the approved drug product's
active ingredient rather than the entire drug product (i.e., the drug
product's active and inactive ingredients). In other words, if the
patent claims the drug substance that was approved in the NDA, it must
be listed.
However, some courts interpreted Sec. 314.53 differently than we
had intended. In Zenith Laboratories, Inc. v. Abbott Laboratories,
Inc., 1996 WL 33344963 (D. N.J. 1996), Abbott had listed patents for
the dihydrate form of terazosin hydrochloride (the drug substance in
the NDA-approved product whose trade name was Hytrin) and also for the
anhydrous form of terazosin hydrochloride that differed from Hytrin's
drug substance only in its crystalline forms. (An anhydrous form of a
chemical contains no water molecules, whereas a dihydrous form contains
two water molecules.) Zenith had filed an ANDA to market a drug product
containing a different form of terazosin hydrochloride, and claimed
that the active ingredient in its product had a different crystalline
structure from Hytrin, did not infringe the patent on Hytrin, and that
Abbott's patents on the anhydrous form of the active ingredient did not
cover the approved drug product. The court found that the patents at
issue did claim the approved drug product. The court interpreted Sec.
314.53(b) to mean that, if a patent claims the drug substance of an
approved drug product, then the patent is covered by the approved drug
product and may be listed in the Orange Book even if the patent claims
a form of the drug substance that is different than the form in the
approved drug product. Moreover, the court indicated that we may
approve an ANDA for a drug product that contains the patented form of
the active ingredient. The court also cited two statements from the
Orange Book to support its ruling that different forms of the same
active ingredient may be considered pharmaceutically equivalent if
their dissolution, solubility, and absorption are the same as the
listed drug. The court concluded that the patents were likely to be
construed as claiming the drug substance for the NDA-approved drug
regardless of the differences in hydration.
In Ben Venue Laboratories, Inc. v. Novartis Pharmaceutical Corp.,
10 F. Supp.2d 446 (D.N.J. 1998), Novartis had listed a patent which
claimed the crystalline pentahydrate form of Aredia (pamidronate
disodium). The ANDA applicant argued that the appropriateness of the
patent listing turned on whether Novartis' approved product contained a
crystalline hydrate of pamidronate (id. at page 453). The parties did
not dispute that the final drug product did not contain the
pentahydrate form of pamidronate. Novartis admitted that its dosage
form contained an anhydrous form of pamidronate, but argued that patent
was properly submitted because the patent covered the ``drug
substance'' and because Sec. 314.53 required the listing of such
patents (id.). The court found that it was proper to list a patent that
claims a component of the approved drug product even when that
component does not appear in the exact same form in the final drug
product (id. at pages 453-457). The court distinguished the Pfizer
opinion as depending largely on the applicant's attempt to list a
patent for a new, unapproved tablet (id. at page 455).
The court also noted that Pfizer predated our 1994 final rule and
stated that:
The statute governing listing of patents merely states that NDA
applicants shall file ``any patent which claims the drug.'' 21
U.S.C. Sec. 355(b)(1). The regulations clearly indicate that the
FDA interprets the ambiguous term ``drug'' in 21 U.S.C. Sec.
355(b)(1) to include certain drug substances or active ingredient
patents, and requires their listing in the Orange Book. The Court
concludes that the FDA's construction of the statute to require
listing of certain drug substance patents as well as drug product
patents is a permissible reading of the statute, and the parties do
not argue otherwise. See Chevron, U.S.A., Inc. v. Natural Resources
Defense Counsel [sic], 467 U.S. 837 (1984). Therefore Ben Venue's
assertion that ``the drug substance or active ingredient does not
determine proper listing'' and that ``the drug product--and it
alone--controls the proper listing,''* * * are inaccurate. See 10 F.
Supp.2d at page 455.
Although we were not a party to the litigation, we implicitly did
not accept the conclusion or reasoning of the Zenith Laboratories and
Ben Venue Laboratories decisions. On February 7, 2001, we wrote to
Biovail Laboratories to confirm the propriety of a corrected patent
listing under Sec. 314.53(f). Biovail had changed its manufacturing
process for Tiazac (diltiazem hydrochloride), but had not sought our
approval before making those changes. The approved product contained
diltiazem hydrochloride in time-release coated beads, whereas Biovail's
changed product contained both immediate release diltiazem
hydrochloride powder and time-release coated beads. Biovail asserted
that the changes were within the scope of its approved NDA, yet we
learned about the changes only through litigation between Biovail and
another company. In our letter to Biovail, we stated that, ``FDA does
not list patents for drug substances, compositions, formulations and
methods of use that are not approved for the listed drug'' (see Letter
from Ralph Lillie, Director, Office of Information Technology, Center
for Drug Evaluation and Research, to Biovail Laboratories, Inc., dated
March 23, 2001). We also took the position that Biovail had to submit a
supplement to its NDA to cover the immediate release diltiazem
component and stated that:
Patents for drug substances, composition, formulations, and
methods of use that are not approved for the listed drug are not
listed in the Orange Book. A patent submitted in an application or
supplement that is not yet approved will be listed in the Orange
Book only if, and when the drug product is approved.
(See id. at page 2.)
On November 21, 2000, we responded to a citizen petition (FDA
docket number 00P-0499) submitted by Lord, Bissell & Brook on behalf of
Apotex, Inc. The petition asserted, in part, that two patents claiming
anhydrous forms of paroxetine hydrochloride did not claim the
hemihydrate listed drug. (An anhydrous form of paroxetine hydrochloride
has no water molecules associated with it, whereas a hemihydrate form
has one water
[[Page 65451]]
molecule associated with every two paroxetine molecules.) Relying on
the NDA holder's representations that the patents claimed the approved
drug product, we concluded that the patents had been correctly
submitted for listing. We stated that, ``Patents must be listed if they
claim the drug substance, or active ingredient, of an approved drug
product, or if they claim a drug substance that is the component of
such a product'' (Response from Janet Woodcock, M.D., Director, Center
for Drug Evaluation and Research, to Hugh L. Moore et al., Lord,
Bissell & Brook, dated November 21, 2000, at page 6 (footnote
omitted)). In a footnote, we noted that our position was ``fully
consistent with Pfizer'' because the Pfizer case ``involved the
question of the listing of patents for a drug in a dosage form other
than the dosage form approved by FDA'' (id. at page 6, note 18),
whereas the paroxetine situation involved a patent which, according to
the NDA holder, claimed the approved drug product. We further stated
that we considered anhydrous and hemihydrous forms of drug substances
to be pharmaceutical equivalents and to contain the same active
ingredient (id. at page 6, note 16). We cited Zenith Laboratories and
Ben Venue Laboratories for the proposition that courts, rather than
FDA, would resolve whether the patent covered the approved drug. Our
letter did not take issue with the holdings of those courts (id. at
page 5, note 13).
Recently, in Andrx Pharmaceuticals, Inc. v. Biovail Corp., 276 F.3d
1368 (Fed. Cir. 2002), a case involving the patent listing
correspondence with Biovail Laboratories described in a preceding
paragraph, the court held that ``the critical question is the
relationship of the patent to the drug products and drug substances
covered by the NDA'' (id. at page 1376). The issue in the Andrx
Pharmaceuticals case was Biovail's listing of a patent that claimed an
extended release formulation of diltiazem that was different from the
one we had approved. In a footnote, the Court of Appeals for the
Federal Circuit cited our 1994 final rule and interpreted the final
rule as changing our patent listing procedures (id. at page 1377, note
5). The court stated that our supposed change in position was a ``more
liberal construction'' of the statute and led to more patents being
listed in the Orange Book (id.).
3. Which Patents Would the Proposal Require to Be Listed or Not
Listed?
Given these court decisions which are not entirely consistent with
our policies, the FTC Report, the FTC Citizen Petition, and other
documents questioning patent listing requirements, we decided to
clarify our regulations to describe the types of patents that must and
must not be listed. Consequently, proposed Sec. 314.53(b) would state,
in relevant part, that an applicant submitting an NDA, amending an NDA,
or submitting a supplement to an NDA:
* * * shall submit information on each patent that claims the
drug or a method of using the drug that is the subject of the new
drug application or amendment or supplement to it and with respect
to which a claim of patent infringement could reasonably be asserted
if a person not licensed by the owner of the patent engaged in the
manufacture, use, or sale of the drug product. For purposes of this
part, such patents consist of drug substance (ingredient) patents,
drug product (formulation and composition) patents, product by
process patents, and method of use patents. Process patents, patents
claiming packaging, patents claiming metabolites, and patents
claiming intermediates are not covered by this section, and
information on these patents may not be submitted to FDA. 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 application within the
meaning of section 505(j)(2)(A)(ii) of the Act. For patents that
claim a drug product, the applicant shall submit information only on
those patents that claim a drug product that is the subject of a
pending or approved application. 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 the
subject of a pending or approved application. For approved
applications, the applicant shall identify the indication or other
condition of use in the approved labeling that corresponds to the
listed patent and claim identified. * * *
We have italicized the new or revised regulatory language to make it
more readily identifiable for this preamble discussion. We explain the
proposed changes in more detail in the following paragraph.
a. What Patents Must Not Be Listed Under the Proposal?
Proposed Sec. 314.53(a) would expressly state that information on
patents claiming packaging, patents claiming metabolites, and patents
claiming intermediates must not be submitted. In general, we find that
these patents fail to meet the two prong criteria for listing because
they do not claim the approved drug product.
Patents claiming a drug product's packaging or container may not be
listed. We find that, although information regarding a drug's packaging
or container is part of an NDA (see 21 CFR 314.50(d)(1)(ii)(a)), we do
not approve that packaging or container per se. The packaging or
container is therefore distinct from the approved drug product, so a
patent that claims a type of packaging or container fails to satisfy
the first prong because the patent does not claim the drug. In
addition, in contrast to the active ingredient, inactive ingredients,
and conditions of use, the Hatch-Waxman amendments do not identify a
listed drug's packaging or container as an element for us to review or
consider in determining whether to approve an ANDA or 505(b)(2)
application.
The failure to claim the approved product is especially apparent
for patents claiming metabolites because those metabolites exist only
after a person has taken the drug and his or her body has broken the
drug down into the metabolite. While there have been no court decisions
regarding the listing of patents claiming a metabolite, one court has
examined whether a person can seek patent term restoration for a patent
claiming a metabolite rather than the approved drug itself. In Hoechst-
Roussel Pharmaceuticals, Inc. v. Lehman, 103 F.3d 756 (Fed. Cir. 1997),
a court had to decide whether the Patent and Trademark Office correctly
interpreted the patent term extension provisions at 35 U.S.C. 156. The
patent term extension provisions were part of the Hatch-Waxman
amendments (as Title II of the Hatch-Waxman amendments). The patent
term extension provisions require that the patent for which an extended
term is sought to ``claim'' the approved drug (see 35 U.S.C. 156(a) and
156(g)(1)(B) (discussing how a product must have been subject to a
regulatory review period before its commercial marketing or use and
defining the regulatory review period, in part, in terms of an NDA
approval)). However, the patent in question claimed a metabolite rather
than the approved drug itself. The court considered the meaning of the
term ``claim,'' and the term's relationship to the concept of
infringement, and concluded that a patent claiming a metabolite or the
use of a metabolite does not claim the approved drug product. The
court's reasoning and conclusion are equally applicable to patent
listings. Therefore, we conclude that a patent claiming a metabolite
does not claim an approved drug and does not meet the statutory
requirements for listing in the Orange Book.
The proposal would also instruct applicants not to submit patent
information if the patent claims an intermediate. Intermediates are
materials that are produced during the steps of the processing of
active pharmaceutical ingredient, but are not
[[Page 65452]]
present in the final drug product themselves (see Food and Drug
Administration, ``Guidance for Industry: Q7A--Good Manufacturing
Practice Guidance for Active Pharmaceutical Ingredients'' (August
2001)). Under existing FDA regulations, intermediates are ``in-process
materials'' rather than drug substances or even drug components (see 21
CFR 210.3(b)(9); 211.110). Thus, patents that claim intermediates do
not claim the approved drug product and, for that reason, fail the
first prong for listing.
We note that, as is currently the case, patents that claim methods
of use that are not approved for the listed drug or are not the subject
of a pending application may not be submitted.
b. What Additional Patents Would the Proposal Require to be Listed?
1. Product by Process Patents
The proposal would include ``product by process patents'' in the
class of patents that must be listed because product by process patents
are a type of product patent. In brief, a product by process patent
claims a product by using or listing process steps to wholly or
partially define the claimed product (see In re Luck, 476 F.2d 650
(C.C.P.A. 1973); In re Brown, 459 F.2d 531, 535 (C.C.P.A. 1972)). In a
product by process patent, the claims must particularly point out and
distinctly claim the product or genus of products for which patent
protection is sought (see In re Brown, 459 F.2d at page 535). These
patents, therefore, meet the two-prong criteria for patent listing
because they claim the approved drug product and are of a type with
respect to which a claim of patent infringement could reasonably be
made if a person not licensed by the patent owner engaged in the
manufacture, use, or sale of the drug; consequently, including product
by process patents in the class of patents that must be listed is
appropriate.
We must emphasize that product by process patents differ from
process patents because, in a product by process patent, the patented
invention is the product (as opposed to the process used to make the
product) (see In re Bridgeford, 357 F.2d 679, 682 (C.C.P.A. 1966)).
Section 505(b)(1) of the act does not require information on process
patents, and we do not list process patents in the Orange Book (see
Sec. Sec. 314.50(i)(2) and 314.53(b)).
We are concerned, however, that persons unfamiliar with patent law
might confuse product by process patents with process patents, and seek
to list process patents with us. Therefore, we invite comment on ways
to ensure that only appropriate product by process patents are listed,
while maintaining the act's restriction against listing process
patents.
2. Patents Claiming a Different Form of the Drug Substance
Section 314.53(b) currently states, ``For patents that claim a drug
substance or drug product, the applicant shall submit information only
on those patents that claim a drug product that is the subject of a
pending or approved application.'' The proposal would revise this
sentence to read as follows:
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
application within the meaning of section 505(j)(2)(A)(ii) of the
act. For patents that claim a drug product, the applicant shall
submit information only on those patents that claim a drug product
that is the subject of a pending or approved application.
This would mean that an applicant would be able to submit patent
information on a drug substance even when the patented drug substance
was a different form than the drug substance that is the subject of the
pending or approved NDA as long as the drug substances are the ``same''
active ingredient under section 505(j)(2)(A)(ii) of the act. Whether
two different drug substances are the ``same'' active ingredient is a
scientific determination based upon the specific characteristics of the
drug substances involved. We have, for example, determined that
anhydrous and hydrated entities, and different polymorphs (different
crystalline forms of the same substance), may be the ``same'' active
ingredient (see Food and Drug Administration, ``Approved Drug Products
With Therapeutic Equivalence Evaluations,'' 22nd Ed., section 1.7 at
page xv (2002)). Therefore, for example, if the approved drug substance
was an anhyrdrate, and the patent claimed a hemihydrate, proposed Sec.
314.53(b) would allow the applicant to submit patent information for
the hemihydrate if the anhydrate and hemihydrate are the ``same''
active ingredient.
In making a determination that two drug substances are the same
active ingredient, the NDA holder should consider whether the drug
substances can be expected to perform the same with respect to such
characteristics as dissolution, solubility, and bioavailability. We
invite comment on whether we should revise the codified language to
require the NDA holder to submit additional information regarding the
basis for the assertion that the drug substances are the same active
ingredient.
We recognize that allowing NDA applicants and NDA holders to submit
such patent information appears to conflict with our longstanding
position that the patent must claim the approved drug product or the
drug product that is the subject of the application. However, we
believe this change in our patent listing policy is both reasonable and
appropriate, and may even conserve agency and industry resources. Our
rationale for allowing such drug substance patents to be listed
depends, in large part, on our position concerning pharmaceutical and
therapeutic equivalence. We consider drug products to be
pharmaceutically equivalent if they have the same active ingredient(s),
the same dosage form, the same route of administration, and are
identical in strength or concentration. We consider drug products to be
therapeutically equivalent if they are pharmaceutically equivalent and
can be expected to have the same clinical effect and safety profile
when administered to patients under the conditions specified in the
labeling. A major premise in the ANDA approval system is that the ANDA
drug is therapeutically equivalent to the brand-name or ``reference
listed drug.'' In assessing whether the active ingredients in the
reference listed drug and the generic drug product are the ``same,''
and would support a determination of therapeutic equivalence, we have
concluded that, in certain instances, the generic drug's active
ingredient does not have to have the exact physical form as the
reference listed drug's active ingredient (see Letter from Dennis
Baker, Associate Commissioner for Regulatory Affairs, FDA, to Donald O.
Beers and David C. Korn, Arnold & Porter, and to William J. McNichol,
Jr., Marc J. Scheineson, and Tracy Zurzolo Frisch, Reed Smith LLP,
dated February 15, 2002, at pages 3-4, 7, 9-11). We have approved ANDAs
when the drug substance in the generic drug product was a different
polymorph than the drug substance in the listed drug. These products
are therapeutically equivalent.
If a generic drug product can be the ``same'' as the reference
listed drug, notwithstanding differences in the drug substances'
physical form, then it is consistent to interpret ``drug substance,''
for purposes of listing patent information, as including drug
substances having different physical forms. We note that the Hatch-
Waxman amendments contained the patent listing and ANDA provisions in
the same title, so it would be logical for us to interpret these two
provisions of the act in a consistent manner (see Ben
[[Page 65453]]
Venue Laboratories, 10 F.Supp.2d, at page 457).
Additionally, it is conceivable that an ANDA applicant may file an
ANDA for a drug product that contains a drug substance that does not
share the same chemical structure as the NDA-approved drug, but is
nevertheless covered by a patent. For example, assume that the NDA drug
is a hydrated form of the drug substance, and the ANDA drug substance
would be an anhydrate. If the patent for the NDA drug claims the
hydrated drug substance, the ANDA applicant would be able to certify,
correctly under current FDA regulations, that it was not infringing the
patent and file a paragraph IV certification. However, if the patent
owner also had a patent on the anhydrous form and the NDA holder were
not allowed to submit patent information on the anhydrate because the
patent does not claim the approved drug product, the ANDA applicant
consulting the Orange Book would have no notice of the patent claiming
the anhydrate. The missing patent information could mislead potential
ANDA applicants into submitting ANDAs containing the anhydrate and
unknowingly infringing the patent claiming the anhydrate. We, in turn,
could expend resources on reviewing an ANDA for a drug that is covered
by the unlisted patent, and the patent owner could expend resources in
defending the patent. This waste in agency and industry resources could
be avoided if we require NDA applicants and NDA holders to submit
information on patents that claim drug substances that are the same
active ingredient as that in the listed drug product.
Again, we recognize that requiring the submission of patent
information on drug substances that are the same active ingredient,
even when those drug substances are in a form that differs from the
drug substance in the approved drug product, appears to be a change
from our previous position. As discussed previously, we believe this
change is justified by our position on pharmaceutical and therapeutic
equivalence. We invite comment as to the potential impact of this
change on the submission of ANDAs and 505(b)(2) applications.
We also acknowledge that the interaction between the act's
requirements, our pre-existing regulations, and our positions in court
cases and elsewhere can make it difficult to interpret the act's patent
listing requirements and ANDA and 505(b)(2) application approval
requirements in a simple, harmonious manner. Although patents on
different forms of an active ingredient are properly listed, and a
pending ANDA containing a different form of the drug substance may be
considered to have the ``same'' active ingredient as the reference
listed drug, we must emphasize that this proposed rule does not alter
the requirement for NDA holders to submit a supplement before changes
are made to the synthesis of the drug substance (see 21 CFR
314.70(b)(1)(iv)). If an NDA holder wishes to use an active ingredient
whose form is different from the active ingredient described in the
approved NDA, the NDA holder must seek our approval before it uses the
different form of the active ingredient. Changes in the form of an
active ingredient warrant the filing of a supplemental NDA because of
the possible health consequences associated with the new form of the
drug substance.
B. Proposed Sec. 314.53(c)(2)(i)--What Does the Patent Declaration
Say?
Section 314.53(c)(2)(i) requires a person submitting an NDA, an
amendment to an NDA, or an NDA supplement, to submit a signed
declaration as part of its submission of patent information if the
patent covers the drug's formulation, composition, and/or method of
use. The declaration states:
The undersigned declares that Patent No. ---------- covers the
formulation, composition, and/or method of use of (name of drug
product). This product is (currently approved under section 505 of
the Federal Food, Drug, and Cosmetic Act) [or] (the subject of this
application for which approval is being sought).
(Emphases in original.) We designed this declaration to help ensure
that appropriate patents are listed and to preclude any need on our
part to decide patent issues because we lack the patent expertise,
resources, and statutory mandate to scrutinize patent listings (see 54
FR 28872 at 28909 (July 10, 1989)).
This declaration may be insufficient in practice to prevent NDA
applicants and NDA holders from attempting to list inappropriate
patents. The FTC Report suggested that ``many of the later-issued
patents do not appear to claim the approved drug product or an approved
use of the drug'' (see FTC Report at 37), but recognized that we lack
the expertise and resources to review or decide patents disputes (id.
at page 41; see also aai Pharma v. Thompson, 296 F.3d 227 (4th Cir.
2002) (``the FDA has no expertise in making patent law judgments'')).
The courts have also concurred in our view that we lack the authority
to review the ``listability'' of patents (see American Biosci. 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, Civ. No. U.S. Dist. LEXIS 2477, at 7-8 (D. Md. Jan. 17,
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)). The FTC Report
also noted that ANDA applicants must certify to a listed patent even if
they dispute the appropriateness of the listing (see FTC Report at 37;
see also 21 CFR 314.94(a)(12)(vii)). Although we continue to lack the
expertise, resources, and legal authority to examine patent issues, we
can ask NDA applicants and NDA holders to provide more patent
information to help ensure that only appropriate patents are listed.
The proposed rule, if finalized, will prompt NDA holders and NDA
applicants to make careful and well-considered representations in their
patent declarations and produce greater compliance with our patent
listing requirements.
The proposed rule would, therefore, revise Sec. 314.53(c)(1) and
(c)(2) by rewording the general patent declaration requirement in
paragraph (c)(1) and by replacing the existing, general declaration at
paragraph (c)(2)(i) with a more detailed declaration that would act as
a ``checklist'' that would focus on patent claims and would ensure that
applicants submit only appropriate patent information and stand behind
the accuracy of that information. Proposed Sec. 314.53(c)(1) and
(c)(2)(i) would read as follows:
(1) General requirements. An applicant described in paragraph (a)
of this section shall submit the declaration described in paragraph
(c)(2) of this section for each claim of the patent that meets the
requirements described in paragraph (b) of this section.
(2) Patent declaration. For each patent that claims a drug
substance (active ingredient), drug product (formulation and
composition), and/or method of use, the applicant shall submit the
following declaration:
This is a submission of patent information for an NDA submitted under
section 505 of the Federal Food, Drug, and Cosmetic Act (the Act).
Time sensitive patent information pursuant to 21 CFR 314.53 for NDA
[numsign] ----------
The following is provided in accordance with section 505(b) of the Act:
Trade Name: ------------
Active Ingredient(s): ------------
Strength(s): ------------
Dosage Form(s): ------------
[[Page 65454]]
Approval Date (if the submission is a supplement to an approved NDA):
------------
Please provide the following information for each patent submitted, and
identify the relevant claim(s) by number.
A. 1. United States patent number: ------------
2. Expiration date: ------------
3. Name of the Patent Owner: ------------
4. Agent (if patent owner or applicant does not reside or have a place
of business in the United States) ------------
B. For each patent identified in A, please provide the following
information:
1. The type of patent claims that apply to the drug substance or drug
product that is the subject of the application:
2. Drug Substance (Active Ingredient)
------ Yes ------ No
a. Claim number(s): ------------
3. Drug Product (Composition/Formulation):
------ Yes ------ No
a. Claim number(s): ------------
4. Method of Use:
------ Yes ------ No
a. Claim number(s): ------------
C. For each drug substance claim identified, please provide the
following information:
1. Is the claim one that claims the drug substance that is the active
ingredient in the approved or pending NDA, an amendment to the NDA, or
a supplement to the NDA?
------ Yes ------ No
If ``yes,'' please identify the claim(s) by number.
2. Is the claim one that claims a drug substance that is the ``same''
active ingredient as the active ingredient in the pending or approved
NDA, amendment to the NDA, or a supplement to the NDA?
------ Yes ------ No
If ``yes,'' please identify the claim(s) by number.
3. If the answer to question C.1 or C.2 is ``yes,'' do you acknowledge
that an ANDA or 505(b)(2) application containing the same active
ingredient that is claimed by the patent is the ``same'' for ANDA or
505(b)(2) approval purposes?
------ Yes ------ No
[If the answers to questions C.1, and C.2, or C.3 is ``no,'' stop here.
The patent may not be listed in the Orange Book as a patent that claims
the drug substance.]
D. For each drug product claim identified, please provide the following
information:
1. Is the claim one that claims the approved formulation or composition
and/or the formulation or composition for which approval is being
sought?
------ Yes ------ No
If ``yes,'' please identify the claim(s) by number.
[If the answer to question D.1 is ``no'' in every instance, stop here.
The patent may not be listed in the Orange Book as a patent that claims
the drug product.]
E. For each method of use claim identified, please provide the
following information:
1. Is the claim one that claims:
(a) an approved method of use of the approved drug product? If
``yes,'' please identify the use with reference to the approved
labeling for the drug product and identify the relevant patent claim
number(s);
------ Yes ------ No
(b) a method of use of the approved drug product for which use
approval is being sought; or
------ Yes ------ No
(c) a method of use of the drug product for which approval is being
sought?
------ Yes ------ No
If the answer to questions E.1(b) or (c) is ``yes'', please identify
the use with reference to the proposed labeling for the drug product
and identify relevant patent claim number(s).
[If the answers to questions E.1(a) through (c) are ``no,'' stop here.
The patent may not be listed in the Orange Book as a patent that claims
a method of use.]
Note that the proposed declaration would emphasize identification
of the relevant patent claims by number. The number would correspond to
the patent claim number in the patent itself. Precise identification of
the relevant patent claims will help all parties focus on the same
claim and may prevent arguments as to whether a particular claim
pertained to the approved drug product or was infringed by the product
described in an ANDA or 505(b)(2) application.
We are also proposing to require NDA holders and NDA applicants to
identify the specific pending or approved use claimed by a method of
use patent. This information will assist parties in assessing patent
infringement matters and should expedite our approval of ANDAs and
505(b)(2) applications that do not seek approval for the protected use.
The proposal would also amend Sec. 314.53(c)(2)(ii) to place more
emphasis on patent claims rather than on the patent generally. Section
314.53(c)(2)(ii) currently instructs an NDA holder to amend its patent
declaration within 30 days after approval of its application.
Current FDA regulations also address the content of the notice of
certification of invalidity or noninfringement of patent that ANDA and
505(b)(2) application applicants must submit if their applications
contain a paragraph IV certification (see Sec. Sec. 314.95(c) and
314.52(c) respectively (21 CFR 314.95(c) and 314.53(c))). Section
505(j)(2)(A) of the act, however, states that we may ``not require that
an abbreviated application contain information in addition to that
required by clauses (i) through (viii).'' (No comparable statutory
restriction exists for 505(b)(2) applications.) We invite comment on
whether our current regulations regarding notice to the NDA holder and
patent owner by ANDA applicants and 505(b)(2) application applicants
could or should be amended.
C. Proposed Sec. Sec. 314.94(a) and 314.52(a)--How Many Times Can
an Application's Approval Date Be Delayed for a 30-Month Period?
We have consistently maintained that the Hatch-Waxman amendments
create the opportunity for multiple 30-month stays to an ANDA's or
505(b)(2) application's approval date if those applicants submitted a
paragraph IV certification and an action is brought for patent
infringement within the statutory 45-day period. For example, assume
that an ANDA applicant submitted a paragraph IV certification, provided
the proper notice to the NDA holder and patent owner, and was sued for
patent infringement within 45 days after providing the notice. Under
section 505(j)(4)(B)(iii) of the act, we would be obliged to not
approve the ANDA for a 30-month period beginning on the date of the
receipt of the notice provided by the ANDA applicant to the NDA holder
and patent owner, although the 30-month period could be longer or
shorter depending on a court order or resolution of the litigation. If
the NDA holder submitted new patent information to us, and the new
patent information resulted in another paragraph IV certification and
another action for patent infringement, our position has been that
another 30-month stay in the effective date of ANDA approval could
result.
We recently stated our position in Andrx Pharmaceuticals, Inc. v.
Biovail Corp., No. 01-6194-civ-Dimitrouleas/Johnson (S.D. Fla.). We
argued that the 30-month stay provided by section 505(j)(5)(B)(iii) of
the act ``is not rendered inapplicable to a patent newly listed in the
Orange Book simply because the holder of the NDA has already received
the benefit of such a stay with respect to a previously listed patent
for the same drug'' (see Memorandum of Federal Defendants in
[[Page 65455]]
Opposition to Plaintiff's Motion for Summary Judgment Declaring
Additional 30-Month Stay Inapplicable or Eliminated, at page 5). Andrx
had argued that a 30-month stay in the approval date applies only where
an ANDA applicant provides notice in the context of an original ANDA
and not in an amended ANDA. We argued that section 505(j)(5)(B)(iii) of
the act provides for a stay of up to 30 months regardless of whether
the paragraph IV certification was part of an original ANDA or an
amended ANDA. We stated that the act's reference to section
505(j)(2)(B)(i) of the act, which itself refers to sections
505(j)(2)(B)(ii) and (B)(iii) of the act, required that section
505(j)(2)(B) be read as a whole and, as a result, requires us to make a
30-month stay available whenever a paragraph IV certification was filed
and timely patent litigation ensued, thereby permitting multiple 30-
month stays of a single ANDA approval.
We also maintained, in Andrx Pharmaceuticals, Inc., that if the 30-
month stay applied only when an original ANDA contained a paragraph IV
certification, an applicant could amend an ANDA to include a paragraph
IV certification, and there would be no notice to the NDA holder or
patent owner and no opportunity for even a single, 30-month stay. We
stated that such a result could not be reconciled with the Hatch-Waxman
amendments' intent to strike a balance between generic drug approval
and encouraging future innovation (id. at page 9, note 6).
We note, along with the FTC Report, that the number of 30-month
stays per product has been increasing. The FTC Report found that,
before 1998, patent infringement litigation ``generated, at most, one
30-month stay per drug product per ANDA,'' and most cases (eight out of
nine) involved alleged infringement of one or two patents (see FTC
Report at page 36). However, after 1998, FTC found that, for drug
products with substantial annual net sales, patent litigation was
increasing, with a growing number of NDA holders or patent owners (five
out of eight cases) alleging infringement of three or more patents
(id.). The FTC Report even noted one instance where the NDA holder had
listed 12 patents in the Orange Book (id. at page 45). The FTC Report
also found that NDA holders were beginning to list later-issued
patents, many of which ``do not appear to claim the approved drug
product or an approved use of the drug,'' after an ANDA had been filed,
and this resulted in a delay of FDA approval by 4 to 40 months (id. at
page 36). In some cases, a single ANDA has been subject to as many as
five stays (id. at page 46). The FTC Report addressed multiple stays in
the context of a limited number of ``blockbuster'' drugs. The total
number of stays in ANDA approvals is higher, and we agree with FTC that
the number of stays appears to be increasing over time.
Consequently, we examined the act to assess whether requiring
successive 30-month stays was the only reasonable interpretation of the
act. We determined that another reasonable interpretation existed.
Accordingly, through this proposed rule, we intend to adopt a different
interpretation of the act. Our revised interpretation would limit the
number of 30-month stays to the opportunity for only one stay per ANDA.
Our reasoning is as follows:
[sbull] Section 505(j)(2)(B)(iii) of the act states that if an ANDA
is amended to ``include'' a paragraph IV certification, then the notice
to the NDA holder and to the patent owner ``shall be given when the
amended application is submitted.''
[sbull] However, if the ANDA contained a paragraph IV
certification, then any ANDA amendment containing a paragraph IV
certification does not amend the ANDA to ``include'' a paragraph IV
certification because the ANDA already contained a paragraph IV
certification.
[sbull] In the circumstances described previously, the submission
of a second paragraph IV certification in an ANDA amendment or
supplement does not trigger the notice requirement in section
505(j)(2)(B)(ii) of the act because the ANDA is never amended or
supplemented to ``include'' (i.e., contain) a paragraph IV
certification.
[sbull] Consequently, under section 505(j)(5)(B)(iii) of the act,
only one 30-month stay in the ANDA's approval date is possible, because
the subsequent paragraph IV certifications will not have resulted in a
second notice to the patent owner and NDA holder, and the 45-day period
for filing a patent infringement suit, as described in section
505(j)(5)(B)(iii) of the act, will not have run. To put it another way,
if the ANDA applicant is not obliged to submit the notice to the patent
owner and NDA holder, then the pre-requisites to trigger the 30-month
stay in an ANDA's approval date are not met, so the 30-month stay would
not be available.
A similar argument for a single, 30-month stay per application can
be made for 505(b)(2) applications that contain a paragraph IV
certification.
Under this interpretation of the act, ANDA and 505(b)(2)
application applicants would still be required to make paragraph IV
certifications where applicable, but the addition of a second paragraph
IV certification to an ANDA or a 505(b)(2) application that had already
contained at least one paragraph IV certification would not trigger an
obligation to provide a second notice to the NDA holder or to the
patent owner and would not result in another opportunity for a 30-month
stay. Instead, as in the case of paragraph I (no patent information has
been filed) or paragraph II (patent has expired) certifications, the
subsequent paragraph IV certification would allow us to approve the
ANDA or 505(b)(2) application immediately if the Act would otherwise
permit us to do so.
The parties would, of course, be free to litigate issues regarding
patent infringement, but proposed multiple, 30-month stays per ANDA or
505(b)(2) application would no longer be possible. Our interpretation
would not adversely affect a patent owner's ability to protect its
patent rights. If an ANDA or 505(b)(2) application applicant makes one
paragraph IV certification, the patent owner and the NDA holder would
always receive notice and would always have the opportunity to protect
the patented invention. If the NDA holder files another patent later,
and the ANDA or 505(b)(2) application applicant believes that the
later-filed patent is invalid or will not be infringed, the patent
owner and NDA holder are still able to protect the later-filed patent
because: (1) The notice already alerted the patent owner and NDA holder
to the existence of the ANDA or 505(b)(2) application; and (2) any
defense of the later-filed patent will not depend on the existence of a
subsequent notice to the patent owner or NDA holder. In other words,
with respect to later-filed or subsequently filed patents, the patent
owner and NDA holder still have patent infringement and judicial
remedies available to them even without receiving another notice. The
patent owner, for example, can still seek an injunction to protect the
patent on such terms as a court deems reasonable under 35 U.S.C. 283.
If a court finds that the patent is infringed, the patent owner may be
entitled to damages under 35 U.S.C. 284.
We recognize that there are other arguments to support a single,
30-month stay in each ANDA or 505(b)(2) application's approval date.
For example, one argument could be that the act contemplates only one
30-month stay in an ANDA's approval date because section
505(j)(5)(B)(iii) of the act refers to ``the'' 30-month stay. This
argument presumes that the original ANDA contained a paragraph IV
certification and resulted in a 30-month stay. We do not concur with
this
[[Page 65456]]
interpretation of the act because, in certain situations, it could
result in no notice to the patent owner or NDA holder. For example, if
the original ANDA contained a paragraph III certification (stating that
the patent will expire on a specific date), and the ANDA applicant
later amends the ANDA to contain a paragraph IV certification, one
could argue that no notice to the patent owner or NDA holder would be
necessary, and there would not be an opportunity for even a single, 30-
month stay. In contrast, under our proposed interpretation of the act,
the opportunity for one 30-month stay in the abbreviated application's
effective date always exists, and the patent owner and NDA holder would
always receive one notice from the ANDA or 505(b)(2) application
applicant who challenges at least one of the listed patents. This would
preserve the balance between encouraging ANDA and 505(b)(2) application
approvals and encouraging innovation because: (1) The elimination of
multiple 30-month stays will lead to faster ANDA or 505(b)(2)
application approvals, and (2) the patent owner and NDA holder will
still receive notice and will be able to take steps to defend the
patented invention from alleged patent infringement. As courts have
observed, ``The Hatch-Waxman Act represented Congress's efforts to
strike a compromise between the competing interests of pioneer
pharmaceutical companies and generic manufacturers'' (see Mylan
Pharmaceuticals, Inc. v. Thompson, 139 F.Supp.2d 1, 4 (D.D.C. 2001);
see also Mylan Pharmaceuticals, Inc. v. Henney, 94 F.Supp.2d 36, 52-53
(D.D.C. 2000) (interpretation of Hatch-Waxman must take into account
the compromise nature of the statute); Fisons Corp. v. Shalala, 860
F.Supp. 859, 862 (D.D.C. 1994) (``A variety of federal courts have
recognized that this Act represents a compromise, and aids both sets of
drug manufacturers; see, e.g., Tri-Bio Laboratories v. United States,
836 F.2d 136, 139 (3rd Cir. 1987)).'' A maximum of one 30-month stay
per ANDA or 505(b)(2) application represents a reasonable compromise.
Additionally, we note that interpreting the act to allow only a
maximum of one 30-month stay per ANDA or 505(b)(2) application is
consistent with the specific legislative history that accompanied the
passage of the Hatch-Waxman amendments.\1\ When the 97th Congress
considered patent term extension legislation, many members were
concerned that the bill would not prevent brand-name companies from
obtaining multiple patent term extensions for patents that claimed a
drug and, by doing so, inhibit competition from generic drugs (see 128
Cong. Rec. H6916, H6919 (September 13, 1982) (remarks of Rep.
Kastenmeier)). Some charged that the bill would extend the effective
patent life of top-selling drugs for more than 17 years (the patent
term that existed at the time) through ``pyramiding'' or
``evergreening'' of patents (id. at page H6922) (remarks of Rep. Gore).
The House of Representatives, by a vote of 250 to 132, rejected passing
the bill by suspension of the rules, and so the bill failed to be
passed despite unanimous support in the Senate and strong support in
the House. When the Senate revisited the legislation in the next year,
the President of the Pharmaceutical Manufacturers Association (now
known as the Pharmaceutical Research and Manufacturers of America)
testified that, in 1982:
---------------------------------------------------------------------------
\1\ We further note that, although reliance on legislative
history may have its perils, its use is more justified where, as in
this case, the statute is ambiguous (see, e.g., PanAmSat Corp. v.
FCC, 198 F.3d 890, 895 (D.C. Cir. 1999) (stating that a court does
not resort to legislative history ``to cloud a statutory text that
is clear'') (citation omitted).
---------------------------------------------------------------------------
* * * critics of the bill sought to create the impression that
innovative firms were acquiring patents in constellation, pyramiding
one on top of another to extend effective protection. Among people
not knowledgeable about the intricacies of patent law, this
understandably occasioned alarm and suspicion.
(See Hearing on S. 1306, Senate Judiciary Cmte., 98th Cong., 1st Sess.
56-57 (testimony of Lewis A. Engman, President, Pharmaceutical
Manufacturers Association)).
The statutory language creating paragraph IV certifications,
provisions for giving notice of such certifications, and rules
governing amended applications is identical to language in S. 2748 as
introduced by Senator Hatch in 1984. The House Judiciary Committee
reported essentially identical language by voice vote, and the only
relevant report language states that notice is required under paragraph
505(j)(2)(B)(iii) when an ANDA ``is subsequently amended so as to bring
it within this notice requirement'' (see H. Rep. 98-857, Part 2, 98th
Cong., 2d Sess. 14 (1984) (emphases added)). This understanding by the
House Judiciary Committee suggests that if an ANDA applicant had
provided notice to the patent owner and NDA holder, and then amended
the ANDA to make a patent certification regarding a newly-filed patent,
then the ANDA applicant would not have to provide another notice
because, by virtue of its first notice to the patent owner and NDA
holder, the ANDA applicant was already within the notice requirement.
Our proposed interpretation is thus consistent with the legislative
history.
For all these reasons, we propose to amend Sec. Sec. 314.95(a)(3)
and 314.52(a)(3) to state that the requirement to provide a notice of
invalidity or noninfringement of patent:
* * * does not apply to a use patent that claims no uses for
which the applicant is seeking approval. This paragraph also does
not apply if the applicant amends its application to add a
certification under [Sec. 314.94(a)(12)(i)(A)(4) for an ANDA
applicants or Sec. 314.50(i)(1)(i)(A)(4) for 505(b)(2) application
applicants] when the application already contained a certification
under [Sec. 314.94(a)(12)(i)(A)(4) or Sec. 314.50(i)(1)(i)(A)(4)]
to another patent.
The proposed amendments to Sec. Sec. 314.95(a)(3) and
314.52(a)(3), if made final, will lead to a changed interpretation of
Sec. Sec. 314.95(d) and 314.52(d) respectively. Sections 314.95(d) and
314.52(d) state that if an application is amended to include a
paragraph IV certification, then the ANDA or 505(b)(2) application
applicant shall send the notice of certification of invalidity or
noninfringement of patent at the same time that it submits its
amendment to us. Under the proposed rule, an ANDA or 505(b)(2)
applicant who is amending its application to include a paragraph IV
certification must provide notice to the patent owner and NDA holder
only if the ANDA or 505(b)(2) application did not previously contain a
paragraph IV certification.
III. Implementation
A. How Would the Rule Affect Notices?
Under the framework proposed in this rule, the possibility exists
that if two ANDA applicants file paragraph IV certifications to a
later-filed patent, and one ANDA applicant has already submitted a
paragraph IV certification to a previously-filed patent, one ANDA
applicant could be subject to a 30-month stay with respect to the
later-filed patent while the other would not. To illustrate this
problem:
1. Assume that ANDA applicant [numsign]1 files a paragraph IV
certification to a patent, while ANDA applicant [numsign]2 files a
paragraph III certification to the same patent. The patent owner brings
a suit for patent infringement against ANDA applicant [numsign]1 and
obtains a 30-month stay in the ANDA's approval date.
2. Assume that the NDA holder files another patent.
3. If ANDA applicants [numsign][numsign] 1 and 2 both file
paragraph IV certifications for the second patent, the proposed rule,
if finalized, would not require ANDA applicant [numsign]1 to provide
notice to the
[[Page 65457]]
patent owner and NDA holder, because the ANDA previously contained a
paragraph IV certification. However, ANDA applicant [numsign]2 is
subject to a potential 30-month stay in the ANDA approval date because
it would be required to provide notice to the patent owner and NDA
holder.
While this hypothetical situation appears to treat the two ANDA
applicants differently, we believe that our interpretation does treat
the ANDA applicants alike, because both ANDA applicants would be
subject to the possibility of only one 30-month stay in the ANDA
approval date.
Our proposed interpretation of the 30-month stay does not affect an
ANDA applicant's eligibility for 180-day exclusivity. In brief, section
505(j)(5)(B)(iv) of the act gives the ANDA applicant who files the
first paragraph IV certification for a listed patent 180 days of
exclusivity (against other ANDA applicants). We interpret the 180-day
exclusivity provision as providing 180-day exclusivity to the first
ANDA applicant whose ANDA contains a paragraph IV certification to a
patent, even if the paragraph IV certification is one that would not
result in an obligation to notify the patent owner and NDA holder and
would not subject the applicant to the risk of patent litigation and a
30-month stay. The FTC Report suggested that if only a single, 30-month
stay per ANDA were allowed, the number of patents listed after NDA
approval might decrease (see FTC Report at page v).
B. How Would the Rule Affect Pending Applications?
Assuming that we issue a final rule, we intend to apply the rule to
pending applications 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 to 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 regulation, 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.
This proposed rule provides sufficient notice to all interested
parties, whether they are NDA holders, NDA applicants, ANDA applicants,
or 505(b)(2) application applicants, to adjust their submissions and
actions by the time we issue a final rule. (This assumes, of course,
that we issue a final rule.) NDA holders who wish to receive the
benefits of the pre-existing regulation will have enough time to decide
whether to pursue additional patents and to list them. ANDA and
505(b)(2) application applicants will be able to plan their submissions
more efficiently as they will know whether their applications will be
subject to the possibility of one or more 30-month stays of approval if
they make a paragraph IV certification. 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. However, we invite comments on how a final rule should be
implemented.
IV. Legal Authority
Our principal legal authority for the proposed rule exists at
sections 505 and 701 (21 U.S.C. 371) of the act. Section 505(b) of the
act describes the contents of an NDA and 505(b)(2) applications,
including the patent listing and patent certification requirements.
Section 505(j) of the act describes the contents of an ANDA, including
patent certification requirements. Both sections 505(b) and 505(j) of
the act also describe the 30-month stay of approval dates of a
505(b)(2) application or ANDA if the 505(b)(2) applicant or ANDA
applicant made a paragraph IV certification and a timely action for
patent infringement ensues.
The proposed rule would clarify the types of patents which NDA
applicants and NDA sponsors must and must not submit to FDA for listing
in the Orange Book. It would also require a more detailed patent
declaration from NDA applicants and NDA holders.
For 505(b)(2) applicants and ANDA applicants, the proposal would
have the effect of reducing the number of notifications sent to patent
owners and NDA holders. Sections 505(b)(2)(A) and 505(j)(2)(A)(vii) of
the act, respectively, require patent certifications, while sections
505(b)(3)(A) and 505(j)(2)(B) of the act require those applicants who
have made a paragraph IV certification to provide a notice to the
patent owner and NDA holder. Because the proposal would not require
ANDA applicants and 505(b)(2) applicants to provide notice if: (a) the
original ANDA or 505(b)(2) application contained a paragraph IV
certification; and (b) the applicants amend their applications to
include another paragraph IV certification in response to another
patent listing, fewer notifications of invalidity or noninfringement of
a patent would result.
Thus, section 505 of the act, in conjunction with our general
rulemaking authority in section 701(a) of the act, serves as our
principal legal authority for this proposal.
V. Environmental Impact
The agency has 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.
[[Page 65458]]
VI. Executive Order 13132: Federalism
The agency has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. We have determined that
the rule does not contain policies that have substantial direct effects
on the States, on the relationship between 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
rule does not contain policies that have federalism implications as
defined in the Executive order and, consequently, a federalism summary
impact statement is not required.
VII. Paperwork Reduction Act of 1995
This proposed rule contains information collection requirements
that are subject to public comment and review by the Office of
Management and Budget (OMB) under the Paperwork Reduction Act of 1995
(44 U.S.C. 3501-3520). We describe these provisions below in this
section of the document with an estimate of the annual reporting
burden. Our estimate includes the time for reviewing instructions,
searching existing data sources, gathering and maintaining the data
needed, and completing and reviewing each collection of information.
We invite comments on: (1) Whether the collection of information is
necessary for the proper performance of FDA's functions, including
whether the information will have practical utility; (2) the accuracy
of FDA's estimate of the burden of the collection of information,
including the validity of the methodology and assumptions used; (3)
ways to enhance the quality, utility, and clarity of the information to
be collected; and (4) ways to minimize the burden of the collection of
information on respondents, including through the use of automated
collection techniques, when appropriate, and other forms of information
technology.
Title: Applications for FDA Approval to Market a New Drug: Patent
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 proposed rule would clarify the types of patent
information that must and must not be submitted to FDA as part of an
NDA or as an amendment or supplement to an NDA. The proposal would also
require persons submitting an NDA or amendment or supplement to such an
application to make a detailed patent declaration as part of the
application. The proposal would also permit the possibility of only one
30-month stay of each ANDA's or 505(b)(2) application's approval date
in the event of patent infringement litigation because the proposal
would not require ANDA applicants or 505(b)(2) applicants to provide a
notice of certification of invalidity or noninfringement of patent if
their applications already contain such a certification.
Description of Respondents: Persons submitting, amending, or
submitting a supplement to an NDA, and persons submitting an ANDA or
505(b)(2) application containing a patent certification of invalidity
or noninfringement of 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), 80 1.55 124 1,690 209,560
(h), and (k)
314.52(a)(3) and 37 1 37 16 592
314.95(a)(3)
----------------------------------------------------------------------------------------------------------------
Total .................. ............ .............. ............ 210,152
----------------------------------------------------------------------------------------------------------------
\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.
[sbull] According to our earlier information collection estimates
for Sec. Sec. 314.52 and 314.95, there are an estimated 37 respondents
who provide a notice of certification of invalidity or noninfringement
of patent each year, and each respondent submits an estimated 2
responses, with an estimated 16 burden hours per response. Because the
proposed rule would allow only one 30-month stay in the effective date
of approval for each 505(b)(2) application or ANDA, this would mean
that these 505(b)(2) or ANDA applicants would (if the rule is
finalized) file only one notice per year (unless they are filing
multiple applications for different drugs and making paragraph IV
certifications in more than one case). So, assuming that these
applicants submit only one 505(b)(2) application or ANDA per year that
contains a paragraph IV certification, the applicants would submit only
one notice of certification of invalidity or noninfringement of patent
each year. Thus, the information collection burden for Sec. Sec.
314.52 and 314.95 would decrease to 592 hours (37 respondents x 1
response per respondent x 16 hours per response = 592 hours).
[sbull] To estimate the number of enhanced patent declarations that
will be submitted annually, we referred to historical data on
submissions of NDAs. In 2001 and 2002, we received 94 and 66 NDAs
respectively. We therefore estimate that there will be 80 ((94
applications + 66 applications)/2 years = 80 applications/year) annual
instances where an NDA applicant or NDA holder would be affected by the
proposed patent listing and patent declaration requirements. According
to our earlier information collection estimates for Sec. 314.50(h)
(the provision under which we covered patent listing and patent
declaration matters as described in Sec. 314.53), there are an
estimated 1.55 annual responses per respondent. So, using the same 1.55
ratio, this would mean that 80 NDA applicants and NDA holders would
submit 124 annual responses (80 respondents x 1.55 responses per
respondent = 124 responses). However, proposed Sec. 314.53(b) and (c)
would have different impacts on the hours per response. On the one
hand, proposed Sec. 314.53(b) might decrease the reporting burden
because it would specify certain patents that must not be filed in the
Orange Book and thus discourage NDA applicants and NDA holders from
submitting information on those patents. On the other hand, proposed
Sec. 314.53(b) would also require NDA applicants and NDA holders to
submit patent information on different forms of the drug substance, and
this could result in more patent information being submitted. We cannot
determine whether the potential net effect will increase, decrease, or
not change the overall burden associated with submitting patent
information, so we
[[Page 65459]]
have not assigned any change in the total reporting burden for the
proposed change in patent information alone. In contrast, proposed
Sec. 314.53(c) would make the patent declaration more detailed. The
change in the declaration would increase the burden hours per response
in Sec. 314.50(h) (the provision under which we covered patent
declarations described in Sec. 314.53(c)) because respondents would 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 estimated that the revised patent declaration will
result in an additional information collection burden of 24 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). We are unable to determine how many of the 1,666 hours
were devoted to patent declarations, so, in this table, we simply add
24 hours to the 1,666 hour estimate for Sec. 314.50(a) through (f),
(h), and (k), resulting in a burden hour estimate of 1,690 hours (1,666
hours + 24 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) would
increase to 209,560 hours (124 annual responses x 1,690 hours per
response = 209,560 hours). We invite comment as to whether we need to
adjust our estimate of 24 burden hours per response.
We have submitted the information collection requirements of this
rule to OMB for review. Interested persons are requested to send
comments regarding information collection to the Office of Information
and Regulatory Affairs, OMB (see ADDRESSES).
VIII. Analysis of Impacts
FDA has examined the impacts of the proposed 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 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 an expenditure 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 proposed rule, and have determined that the
proposed rule is consistent with the principles set forth in the
Executive order and in these statutes.
The proposed rule is an economically significant regulatory action
as defined by the Executive order. With respect to the Regulatory
Flexibility Act, the agency certifies that this proposed rule is not
expected to have a significant impact on a substantial number of small
entities. The proposed rule is also a major rule under the
Congressional Review Act. The discussion of costs and benefits is
consistent with the requirements of the Unfunded Mandates Reform Act.
A. Objectives of the Proposed Regulation
The proposed rule has multiple objectives. We are clarifying the
types of patents that must and must not be listed and revising the
declaration that NDA applicants must provide regarding their patents.
In addition, through this proposal, we are adopting a different
interpretation of the act that will limit the number of 30-month stays
to one per ANDA or 505(b)(2) application. This clarification, revision,
and reinterpretation will help ensure that NDA applicants list
appropriate patents in the Orange Book while preventing the NDA holders
from thwarting generic entry through the use of multiple 30-month
stays. Through these actions, we are preserving the balance struck in
the Hatch-Waxman Amendments between encouraging innovation and
encouraging the availability of generic drugs. The estimated 10-year
total costs of this proposed rule are approximately $51.5 billion and
the annualized cost is $4.9 billion. The estimated 10-year total
benefits of this proposed rule are approximately $53.9 billion and the
annualized benefit is $5.1 billion. These 10-year total benefits
include consumer savings of approximately $34.8 billion from earlier
access to less expensive prescription pharmaceuticals. The 10-year
benefits exceed the costs by approximately $2.4 billion and the
annualized benefits exceed the annualized costs by approximately $230
million.
1. The 30-Month Stay
The Hatch-Waxman Amendments benefit consumers by bringing lower
priced generic versions of previously approved drugs to market, while
simultaneously promoting new drug innovation through the restoration of
patent life lost during regulatory proceedings. A firm wishing to
market a generic version of a previously approved innovator drug can
submit an ANDA. An ANDA refers to a previously approved NDA (the
``listed drug'') and relies upon our finding of safety and
effectiveness for the listed drug.
Persons submitting an ANDA or a 505(b)(2) application must make
certifications regarding the listed patents claiming the drug they wish
to duplicate. The applicant must certify one of the following for each
patent: (1) That no patent information on the drug product that is the
subject of the ANDA has been submitted to us; (2) that such patent has
expired; (3) the date on which such patent expires; or (4) that such
patent is invalid or will not be infringed by the manufacture, use, or
sale of the drug product for which the ANDA is submitted. These
certifications are known as ``paragraph I,'' ``paragraph II,''
``paragraph III,'' and ``paragraph IV'' certifications, respectively.
A paragraph IV certification begins a process in which the question
of whether the listed patent is valid or will be infringed by the
proposed generic product may be answered by the courts prior to the
expiration of the patent. The ANDA or 505(b)(2) application applicant
who files a paragraph IV certification to a listed patent must notify
the patent owner and the NDA holder for the listed drug that it has
filed an application containing a paragraph IV certification. The
notice must include a detailed statement of the factual and legal basis
for the applicant's opinion that the patent is not valid or will not be
infringed. If the NDA holder or patent owner files a patent
infringement suit against the ANDA or 505(b)(2) application applicant
within 45 days of the receipt of notice, we may not give final approval
to the ANDA or 505(b)(2) application for at least 30 months from the
date of the notice. This 30-month stay per ANDA or 505(b)(2)
application will apply unless the court reaches a decision earlier in
the patent infringement case or otherwise orders a longer or shorter
period for the stay.
We recognize that, in recent years, NDA holders have been able to
use multiple 30-month stays to delay
[[Page 65460]]
generic competition. Under current regulations, the patent
certification process allows for one or more 30-month stays of an ANDA
or 505(b)(2) application's approval. NDA holders can prevent FDA
approval of ANDAs or 505(b)(2) applications beyond the initial 30-month
stay by listing an additional patent in the Orange Book after the
applicant has filed its ANDA or 505(b)(2) application. These applicants
would be required to re-certify to the newly-listed patent. The NDA
holder would then be given 45 days to file suit for patent
infringement, and our approval of the initial ANDA or 505(b)(2)
application would be delayed for an additional 30-month period from the
notice date or until a court decision in the newly instituted patent
litigation.
According to the FTC Report, from 1992 to 2000, NDA holders have
listed patents in the Orange Book after an ANDA has been filed for a
drug product on eight occasions. Six of these eight occasions have
occurred since 1998. In all eight of these instances, the subsequent
patent resulted in a delay to generic access to markets beyond the
initial 30-month stay. We are not aware of any case in which a court
has decided that the ANDA infringed upon the subsequent listed patent.
According to the FTC Report, in the four instances of multiple stays in
which a court has decided on the validity or infringement of a later-
listed patent, the patent has been found either invalid or not
infringed by the ANDA.\2\
---------------------------------------------------------------------------
\2\ FTC Report, p. iv.
---------------------------------------------------------------------------
2. The Economic Impact of Generic Competition
The generic drug industry plays an important role in the economics
of the healthcare industry. According to Caves, Whinston, and Hurwitz
(1991), generic drug prices can be as little as 20 percent of the
brand-name price for the same product.\3\ Laws encouraging doctors to
prescribe generic drugs when available are a part of the current effort
to hold down the cost of healthcare.\4\ A report from the Congressional
Budget Office (CBO) report estimated that in 1994 (when the generic
drug market was smaller than its current size) consumers saved between
$8 and $10 billion by substituting generic for brand-name drugs in
pharmacy sales.\5\ While the first 30-month stay enhances the incentive
to innovate, subsequent stays generated by later-listed patents do not
seem to give rise to the same incentives in most cases. By using
multiple 30-month stays, NDA holders are able to delay competition from
generic drugs. Delaying generic competition harms consumers by slowing
the introduction of lower priced products to the market and thwarts the
intent of the Hatch-Waxman Amendments.
---------------------------------------------------------------------------
\3\ Caves, Richard, M. D. Whinston, and M. A. Hurwitz, 1991.
``Patent Expiration, Entry, and Competition in the U.S.
Pharmaceutical Industry,'' Brookings Papers in Economic Activity:
Microeconomics, p. 36.
\4\ Hellerstein, Judith K. 1994. ``The Importance of the
Physician in the Generic Versus Trade-Name Prescription Decision,''
RAND Journal of Economics: 29:1:108-136.
\5\ Congressional Budget Office, How Increased Competition From
Generic Drugs Has Affected Prices and Returns in the Pharmaceutical
Industry (July 1998). Note that the sale of drugs through pharmacies
is a subset of all drug sales so total savings to consumers would be
expected to be higher than the given figure.
---------------------------------------------------------------------------
The agency considered potential impacts on innovation and believes
any negative effect to be minimal. 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. The
patents that form the basis for these subsequent stays do not appear to
warrant automatic protection from generic competition.
According to the FTC report, every court ruling involving a
subsequent 30-month stay has found the underlying patent to be either
invalid or not infringed. Also according to the FTC report, extending
patents through multiple stays is a strategy that has become popular in
the last few years and is not a longstanding universally-recognized
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.\6\
---------------------------------------------------------------------------
\6\ A more detailed discussion of the replacement effect and of
the relationship between research and social welfare can be found in
Jean Tirole, The Theory of Industrial Organization (Cambridge: MIT
Press, 1988), pp. 392, 399-400.
---------------------------------------------------------------------------
B. Costs of the Regulation
This section develops estimates of the cost to NDA holders from the
proposed rule. As previously stated, this proposed rule clarifies those
types of patents that must or must not be listed and eliminates the use
of multiple 30-month stays per ANDA to delay generic competition. The
innovator drug industry, as NDA holders, would be expected to bear the
costs of the proposed rule. Generic drug companies and consumers would
be expected to benefit. The impact on these entities that benefit is
addressed in section III.C of this preamble. We do not estimate a
specific impact involving those submitting 505(b)(2) applications. We
recognize these applicants, like those submitting ANDAs, must make
certifications and would be affected by this proposed rule. We believe
any benefits would be difficult to quantify with any precision and
would be quite small, relative to the benefits to generic drug
companies.
This proposed rule will be costly to NDA holders because earlier
generic competition will erode innovator market share. This loss of
market share to generics will result in reduced revenues to the
innovator. These reduced revenues would be mitigated somewhat by a
reduction in the administrative, marketing, and sales expenses.
To estimate the impact of earlier generic competition, we estimate
the revenues to NDA holders and generics under a base case scenario
under which multiple 30-month stays per ANDA are not allowed and a
scenario in which generic entry may be delayed subject to an additional
stay. The impact of the proposed rule would be the difference between
the two scenarios.
1. Delaying Generic Competition
To estimate the impact of delays to generic competition, we use a
modified version of the economic model from our report to Congress on
the pediatric exclusivity provision to the Food and Drug Administration
Modernization Act.\7\ Generic entry erodes the listed drug's market
share, typically over a period of several years. At the same time, the
price of the typical generic drug is also falling. By tracking the
decline of listed drug's market share and the fall in the price of the
generic competition, the model calculates changes in sales over time
for innovator and generic sectors.
---------------------------------------------------------------------------
\7\ U.S. Food and Drug Administration, The Pediatric Exclusivity
Provision: Status Report to Congress, January 2001, p. 43
---------------------------------------------------------------------------
In the model, we assume the reference listed drug's market share
falls from 100 percent to 60 percent in the first year of generic
marketing, and then to 45 and 30 percent in years two and three. The
price of the average generic drug falls with time, and this is also
captured by the model. The model assumes for each 6-month interval over
the first 3 years of competition, the generic price as a fraction of
innovator price falls from 100 percent at introduction, to 80 percent
after 6 months, and finally 33.5 percent after 3 years.\8\ Several
studies have
[[Page 65461]]
shown generic competition to have only very small effect on innovators'
prices.\9\ Innovator prices do frequently rise after generic entry, but
we lack the data to confidently incorporate an estimate of this into
this model. If innovator price increases were incorporated into this
model, the magnitudes of the estimated impacts would be expected to be
larger. We request comment providing data on price behavior after
generic entry into the market.
---------------------------------------------------------------------------
\8\ The decline over 3 years at 6-month intervals is as follows:
100 percent at introduction (0 months); 80 percent (6 months); 60
percent (12 months); 52.5 percent (18 months); 45 percent (24
months); 37.5 percent (30 months); 33.5 percent (36 months). The
ultimate price ratio of 33.5 percent is consistent with a market
with 10 generic entrants, per Caves, Whinston, and Hurwitz (1991),
p. 36, table 9.
\9\ See Box 4 in Congressional Budget Office (1998), p. 30.
---------------------------------------------------------------------------
The model calculates the impact on innovator and generic sectors
each month for a 10-year period. Using immediate generic entry as a
base case, the model calculates the relative impact of delaying entry
for a certain number of months. These monthly impacts on each sector
are converted to present value using a 7 percent discount rate.
According to appendix H of the FTC report, there have been 8
multiple 30-month stays, but the frequency of these stays has been
increasing. Four drugs experienced multiple stays during 2000 and 2001.
Based on this information, we assume that, absent this proposed rule,
there would be 2 (4 drugs/2 years) situations with multiple 30-month
stays each year. Thus, in calculating the annual impact of this
proposed rule, we multiply the peak annual sales of the average
affected drug by 2 to account for the frequency of the event. While we
believe this to be a reasonable estimate, we recognize, as mentioned in
the FTC Report, that a substantial sales volume of brand-name drug
products will be coming off patent in the next few years. If there are
more drugs affected by this rule than we estimate, this would increase
both the benefits and costs of this rule.
To develop a profile of the typical drug for which there were
multiple 30-month delays, we started with the instances in Appendix H
and table 4-3 of the FTC Report. As two instances from the FTC report
concern different dosage forms of the same drug, gabapentin, we count
it only once in our analysis. Generic competition for one of the drugs,
Cisplatin, was delayed because of a single 30-month stay and an alleged
double patent. As we do not believe this situation is addressed by this
proposed rule, we eliminated it from the analysis. The information on
the six remaining drugs is contained in table 2.
Table 2.--Drugs Used in Analysis
----------------------------------------------------------------------------------------------------------------
Estimated Additional Stay Period Estimated Peak
Active Ingredient FTC Stay Period (Months) (Months) Sales (000)
----------------------------------------------------------------------------------------------------------------
Buspirone 30\1\ 4 $700
----------------------------------------------------------------------------------------------------------------
Terazosin 70\2\ 46 $580
----------------------------------------------------------------------------------------------------------------
Gabapentin 37 24 $1,710
----------------------------------------------------------------------------------------------------------------
Paroxetine 65 34 $3,780
----------------------------------------------------------------------------------------------------------------
Paclitaxel 60\1\ 3 $1,020
----------------------------------------------------------------------------------------------------------------
Diltiazem 60\1\ 28 $380
----------------------------------------------------------------------------------------------------------------
Average 50 (+20) +23 $1,360
----------------------------------------------------------------------------------------------------------------
\1\ Potentially, but actually shorter because of a court decision.
\2\ Periods not overlapping.
Sales Data Sources: Buspirone 2000 data, BMS Web site; Terazosin 1999 data, Pharmacy Times Web site; Gabapentin
2001 data, Drug Topics Web site; Paroxetine 2001 data, Scrip 2737, p. 15; Paclitaxel 2000 data, BMS Web site;
Ditiazem 2001 data, Forest Form 10K. For data prior to 2001, sales were escalated to the 2001 level using CPI-
U. For drugs that have not yet reached peak sales, the peak was estimated with a linear projection.
Table 2 includes the inflation adjusted peak sales and subsequent
delay for each of the six drugs. As a reference, we include delay
information from the FTC report. Based on the delay and sales
information for the six drugs, we find the typical delayed drug to have
peak annual sales of $1,360 million and subject to a 23-month delay. As
we do not possess current sales figures for all the drugs involved, we
invite comment on the accuracy of these estimates.
2. Impact of Delay on the Innovator Sector
The model results obtained from comparing the no delay and delay
scenarios are provided in table 3. To account for the frequency of
occurrence, we multiply the peak sales estimate by 2. To the extent
that this proposed rule would eliminate multiple 30-month stays per
ANDA after the first, the estimated impact on innovators would be an
annual revenue decrease of $3,159.50 million (approximately $3.2
billion).
Table 3.--Results of Delay Analyses
------------------------------------------------------------------------
Impact (In Millions)
Scenario Sales Delay (Months) --------------------------------
(000) Innovator Generic Consumer
------------------------------------------------------------------------
Base Case $2,720\ 23 ($3,160) $1,120 $2,040
1\
------------------------------------------------------------------------
\1\ Includes 2.0 frequency factor.
[[Page 65462]]
The cost impact on innovators is driven by the fact that a delay in
generic entry extends the time the innovator collects peak sales and
shortens the time the innovator collects 30 percent of peak sales.
Absent discounting, the impact on innovators would be the length of the
delay times 70 percent of the peak innovator drug revenues.
This impact on innovators may be mitigated to a small degree by
potential decreases in the administrative, marketing, and sales costs
associated with the product. A recent study of top pharmaceutical
companies found that marketing, administrative, and advertising
expenses averaged 27 percent of revenues.\10\ Part of this figure
includes certain fixed costs that would not change with a decline in
revenues. Moreover, to the extent that some of these support costs are
discretionary, they would most likely be focused on periods of intense
marketing, such as product roll-outs. Nevertheless, with the erosion of
market share, the rewards to marketing would decline and the need for
administrative support would be expected to decrease.
---------------------------------------------------------------------------
\10\ Families USA, Profiting From Pain: Where Prescription
Dollars Go, July 2002, p. 3.
---------------------------------------------------------------------------
Assuming half the 27 percent figure to be discretionary support
costs, and the discretionary support costs for the product in question
to be one-third of the average, then discretionary support costs would
be 4.5 percent of revenues (27 percent/6). The relevant annual cost
reduction would be $142.2 million ($3.160 billion x 4.5 percent). As we
lack precise data on the relationship between revenues and support
costs, we invite comment on the accuracy of this estimate.
3. Other Issues Related to Burdens to Innovators
The proposed rule would require NDA holders to submit a more
detailed patent declaration. To estimate the number of enhanced patent
declarations that will be submitted annually, we referred to historical
data on submission of NDAs, excluding those for orphan drugs. In 2000
and 2002, there were 94 and 66 NDAs respectively. We therefore estimate
that there will be 80 ((94 + 66) / 2) annual instances where an NDA
holder or NDA applicant will face this additional declaration burden.
Based on earlier information collection estimates, we assume there to
be an estimated 1.55 annual responses per respondent. Using this same
1.55 ratio, this would mean that the 80 NDA applicants and NDA holders
would submit 124 annual responses (80 respondents x 1.55 responses per
respondent).
We believe that, while the NDA holder or NDA applicant possesses
the additional patent information, there will be a burden in completing
the more detailed declaration. Based on other rules that require
respondents to compile and submit information in their possession, we
estimate the burden to be 24 hours per event. A regulatory affairs
specialist could perform the tasks associated with this process. Based
on the total average hourly compensation (including a 40 percent load
factor for benefits) of $55.72, the cost would be $1,337 ($55.72 per
hour x 24 hours) per event.\11\ The burden on individual firms would
depend on the number of declarations they submit. The estimated annual
burden to all declarants is $165,778 ($1,337 per event x 124 annual
events).
---------------------------------------------------------------------------
\11\ Hourly rate for ``lawyer'' from the Bureau of Labor
Statistics 2000 National Compensation Survey is $38.70, adjusted for
inflation at 2.85 percent (unadjusted CPI-U) and 40 percent for
benefits.
---------------------------------------------------------------------------
We also considered a potential impact due to the numbers of patents
listed. The proposed rule would require the submission of patent
information for patents that claim different forms of the drug
substance, and this would appear to increase the number of patent
filings. At the same time, the proposed rule would clarify the types of
patents that must not be submitted, and this would appear to reduce the
number of patent filings. These two countervailing effects are of
uncertain magnitude. We cannot quantify an impact, if any, from a
change in the number of patents listed, but we invite comment.
4. Enforcement Costs
The proposed rule, if finalized, can be enforced using existing
resources.
5. Total Costs of the Regulation
The annual cost of the proposed rule includes the lost revenues to
innovator firms from the erosion of market share, mitigated by the
decrease in support costs, and the additional cost of completing the
more detailed patent declaration. The estimated 1-year loss in revenues
from erosion of market share is $3,159.50 million, the reduction in
support costs would reduce this loss by $142.20 million, and the
estimated annual additional cost of completing the revised declarations
is approximately $166,000. Thus, the estimated 1-year cost to innovator
firms is $3,017.47 million (approximately $3.0 billion).
According to projections produced by the Office of the Actuary at
the Centers for Medicare and Medicaid Services, expenditures on
prescription pharmaceuticals are expected to increase dramatically in
the near future. This $3.0 billion 1-year estimate does not take these
increases into consideration and must be adjusted to account for them.
Prescription drug expenditures for 2003, for example, are expected to
be 12.8 percent greater than for 2002.\12\ After using the average
annual percent changes in prescription drug expenditures to adjust the
annual cost, the total reduction in revenues to the innovator sector
over the 10-year period 2002 through 2011 is estimated to be $51,507.55
million, or approximately $51.5 billion. Annualizing this impact over
that 10-year period at a 7 percent discount rate yields an annualized
cost of $4,863.76 million, or approximately $4.8 billion.
---------------------------------------------------------------------------
\12\ The annual percent increases in prescription drug
expenditures for each year, 2003 through 2011, are assumed to be
12.8 (2003), 12.3 (2004), 11.7 (2005), 11.0 (2006), 10.7 (2007),
10.5 (2008), 10.3 (2009), 10.2 (2010), and 10.1 (2011). See National
Health Care Expenditures Projections: 2001-2011, Centers for
Medicare & Medicaid Services, Office of the Actuary, table 11.
---------------------------------------------------------------------------
C. Benefits of the Regulation
This section develops estimates of the benefits from the proposed
rule. Eliminating multiple 30-month stays per ANDA will prevent delays
in generic drug competition. The 70 percent of the market lost by
innovators is a gain to both generic drug companies and consumers.
Generic drug companies gain through additional sales, and, to the
extent that generic prices are lower than innovator prices, consumers
benefit from the ``price gap.''
1. Gains to the Generic Drug Industry
We estimated the increase in sales to generic drug companies using
the same model used to estimate losses in sales to innovators. Assuming
typical drug peak sales to be $2.72 billion (including 2.0 frequency
factor) and a typical delay of 23 months, the estimated increase in 1-
year revenues to generic firms is $1,119 million (approximately $1.1
billion). After accounting for the baseline increases in pharmaceutical
expenditures, the total increase in generic industry revenues for the
period 2002 to 2011 is estimated to be $19,117.47 million or
approximately $19.1 billion. The annualized cost, using a 7 percent
discount rate is $1,805.23 million or approximately $1.81 billion.
While we recognize that the generic drug industry is doing more
marketing than it used to do, the effort is still substantially smaller
than what is done by innovator firms, and we do not make adjustments
for reductions associated support costs.
[[Page 65463]]
2. Gains to Consumers
The model assumes that after generic entry, the market will
eventually stabilize where the price of a generic drug will be 33.5
percent of the equivalent innovator drug. The gain to consumers would
be the difference between the generic and innovator price. This price
gap is equal to 66.5 percent of the innovator price. Under our
assumptions, the estimated consumer impact of the proposed rule is a 1-
year gain of $2,040 million (approximately $2 billion). This gain would
be from the elimination of multiple 30-month stays per ANDA that delay
the availability of less expensive drugs.
After increasing this 1-year estimate to account for the annual
expected increases in baseline pharmaceutical expenditures, the total
expected benefit to consumers for the period 2002 to 2011 is $34,822.35
or approximately $34.8 billion. The annualized benefit to consumers,
using a 7 percent discount rate, would be $3,288.21 or approximately
$3.3 billion.
It is difficult to determine which subgroups of consumers will
benefit most from access to generic drugs. The previously cited report
on Pediatric Exclusivity noted that about 21 percent of pharmaceutical
spending came from public sources (Federal, State & Local, Medicare and
Medicaid) and that this figure was expected to rise. The report also
noted that cheaper drugs would disproportionately benefit lower income
consumers in that these consumers would be less likely to have
insurance.
3. Other Issues Related to Benefits
In the past, some studies have allocated a portion of the gains to
generic drugs to the distribution sector (e.g., retail drug stores).
These studies typically based this approach on the belief that generic
drugs carried a substantially larger retail markup, in absolute dollar
terms, than did innovator drugs.
This belief appears to be based on literature using limited data
from the mid-1980s, a period when the generic drug industry was
substantially different from its current state. For this analysis, we
referred to more recent information, such as that found in the CBO
report, and found no evidence of substantially larger absolute retail
markup for generic drugs. While we believe recent data supports our
belief that the absolute markups are approximately the same, we invite
comment on this issue.
4. Total Benefits of the Regulation
The 1-year benefits of the regulation will include the increase in
revenues to generic firms and the savings to consumers from the earlier
availability of less expensive pharmaceuticals. The estimated total 1-
year benefit is $3,159 million (approximately $3.2 billion). Adjusting
this benefit to account for the expected increase in baseline
pharmaceutical expenditures, the total benefit for the years 2002
through 2011 is expected to be $53,931.97 million or approximately
$53.9 billion. Annualizing this stream of benefits over that 10-year
period at a 7 percent discount rate yields an annualized cost of $5,093
million or approximately $5.1 billion.
Table 4.--Benefits of the Proposed Rule to Generics and Consumers
----------------------------------------------------------------------------------------------------------------
Issue One-Year Impact (Millions)
----------------------------------------------------------------------------------------------------------------
Generic Earlier Access to Market $1,119.96
----------------------------------------------------------------------------------------------------------------
Consumer Drug Savings $2,039.54
----------------------------------------------------------------------------------------------------------------
Total Benefits $3,159.50
----------------------------------------------------------------------------------------------------------------
D. Comparison of Costs and Benefits
The estimated 10-year total costs of this proposed rule are $51,508
million. These costs would be borne by innovator firms in the form of
reduced revenues, mitigated by a reduction in support costs, and an
increased cost of completing the revised patent declaration. The
estimated annualized cost is $4,864 million.
The estimated 10-year benefits of this proposed rule are $53,932
million. These benefits would accrue to the generic drug firms and
consumers in the form of increased revenues and increased income from
access to cheaper drugs, respectively. The estimated annualized benefit
is $5,093 million. Absent the additional cost of completing the
declaration and the reduction in support costs, the costs equal the
benefits because the economic impact of this proposed rule is a
transfer, as consumers shift consumption from the products of the
innovator drug firms to those of generic drug firms. The total 10-year
quantified benefits exceed the costs by $2,424 million and the
annualized benefits exceed the annualized costs by $229 million. While
the quantified benefits do exceed the quantified costs, this proposed
rule has the additional important benefit of preserving the balance
struck in the Hatch-Waxman amendments.
E. Regulatory Alternatives
In creating this proposed rule, we considered several regulatory
alternatives, including not regulating. We rejected the alternative of
not regulating because under the current situation, NDA holders are
able to use multiple 30-month stays to delay generic entry and thwart
the intent of the Hatch-Waxman amendments. We also considered using the
current system of patent declarations. This alternative was also
rejected because the current declaration may be insufficient to prevent
NDA holders and NDA applicants from listing patents that should not be
listed under the law. This is particularly important in light of the
fact that we lack the resources, expertise, and authority to evaluate
patents to determine whether they should be listed in the Orange Book.
F. Impact on Small Entities
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. According to standards established
by the Small Business Administration, a small pharmaceutical
manufacturer employs fewer than 750 employees. We do not know the
precise number of innovator companies expected to use multiple 30-month
stays to delay generic entry. Nevertheless, we do not believe any of
these innovator companies to be small. Moreover, none of the innovator
companies identified in the FTC report as having used multiple 30-month
stays would qualify as a small entity. Therefore, the agency certifies
that this proposed rule is not expected
[[Page 65464]]
to have a significant impact on a substantial number of small entities.
Interested persons may submit to the Dockets Management Branch (see
ADDRESSES) written or electronic comments regarding this proposal. Two
copies of any comments are to be submitted, except that individuals may
submit one copy. Comments are to be identified with the docket number
found in brackets in the heading of this document. Received comments
may be seen in the Dockets Management Branch between 9 a.m. and 4 p.m.,
Monday through Friday.
List of Subjects in 21 CFR Part 314
Administrative practice and procedure, Confidential business
information, Drugs, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR part 314 be amended as follows:
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG
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.
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 to a use patent that claims no
uses for which the applicant is seeking approval. This paragraph also
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
another patent.
* * * * *
3. Section 314.53 is amended by revising paragraphs (b) and (c)(1)
through (c)(2) to read as follows:
Sec. 314.53 Submission of patent information.
* * * * *
(b) Patents for which information must be submitted. An applicant
described in paragraph (a) of this section shall submit information on
each patent that claims the drug or a method of using the drug that is
the subject of the new drug application or amendment or supplement to
it and with respect to which a claim of patent infringement could
reasonably be asserted if a person not licensed by the owner of the
patent engaged in the manufacture, use, or sale of the drug product.
For purposes of this part, such patents consist of patents that claim
the drug substance (ingredient), patents that claim the drug product
(formulation and composition), product by process patents, and patents
that claim a method of use. Process patents, patents claiming
packaging, patents claiming metabolites, and patents claiming
intermediates are not covered by this section, and information on these
patents may not be submitted to FDA. For patents that claim the drug
substance, the 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 within the meaning of section
505(j)(2)(A)(ii) of the act. For patents that claim a drug product, the
applicant shall submit information only on those patents that claim a
drug product that is the subject of a pending or approved application.
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 the subject of a pending or approved
application. For approved applications, the applicant shall identify
the indication or other condition of use in the approved labeling that
corresponds to the listed patent and claim identified.
(c) * * * (1) General requirements. An applicant described in
paragraph (a) of this section shall submit the declaration described in
paragraph (c)(2) of this section for each claim of the patent that
meets the requirements described in paragraph (b) of this section.
(2) Patent declaration. (i) For each patent that claims a drug
substance (active ingredient), drug product (formulation and
composition), and/or method of use, the applicant shall submit the
following declaration:
This is a submission of patent information for an NDA submitted
under section 505 of the Federal Food, Drug, and Cosmetic Act (the
Act).
Time sensitive patent information pursuant to 21 CFR 314.53 for NDA
[numsign]------------
The following is provided in accordance with section 505(b) of the
Act:
Trade Name: ------------
Active Ingredient(s): ------------
Strength(s): ------------
Dosage Form(s): ------------
Approval Date (if the submission is a supplement to an approved
NDA): ------------
Please provide the following information for each patent submitted,
and identify the relevant claim(s) by number.
A. 1. United States patent number: ------------
2. Expiration date: ------------
3. Name of the Patent Owner: ------------
4. Agent (if patent owner or applicant does not reside or have a
place of business in the United States) ------------
B. For each patent identified in A, please provide the following
information:
1. The type of patent claims that apply to the drug substance or
drug product that is the subject of the application:
2. Drug Substance (Active Ingredient)
------ Yes ------ No
a. Claim number(s): ------------
3. Drug Product (Composition/Formulation):
------ Yes ------ No
a. Claim number(s): ------------
4. Method of Use:
------ Yes ------ No
a. Claim number(s): ------------
C. For each drug substance claim identified, please provide the
following information:
1. Is the claim one that claims the drug substance that is the
active ingredient in the approved or pending NDA, an amendment to
the NDA, or a supplement to the NDA?
------ Yes ------ No
If ``yes,'' please identify the claim(s) by number.
2. Is the claim one that claims a drug substance that is the
``same'' active ingredient as the active ingredient in the pending
or approved NDA, amendment to the NDA, or a supplement to the NDA?
------ Yes ------ No
If ``yes,'' please identify the claim(s) by number.
3. If the answer to question C.1 or C.2 is ``yes,'' do you
acknowledge that an ANDA or 505(b)(2) application containing the
same active ingredient that is claimed by the patent is the ``same''
for ANDA or 505(b)(2) approval purposes?
------ Yes ------ No
[If the answers to questions C.1, and C.2, or C.3 is ``no,'' stop
here. The patent may not be listed in the Orange Book as a patent
that claims the drug substance.]
D. For each drug product claim identified, please provide the
following information:
1. Is the claim one that claims the approved formulation or
composition and/or the formulation or composition for which approval
is being sought?
------ Yes ------ No
If ``yes,'' please identify the claim(s) by number.
[If the answer to question D.1 is ``no'' in every instance, stop
here. The patent may not be listed in the Orange Book as a patent
that claims the drug product.]
E. For each method of use claim identified, please provide the
following information:
1. Is the claim one that claims:
(a) an approved method of use of the approved drug product? If
``yes,'' please identify the use with reference to the approved
labeling for the drug product and identify the relevant patent claim
number(s);
------ Yes ------ No
(b) a method of use of the approved drug product for which use
approval is being sought; or
[[Page 65465]]
------ Yes ------ No
(c) a method of use of the drug product for which approval is
being sought?
------ Yes ------ No
If the answer to questions E.1(b) or (c) is ``yes,'' please
identify the use with reference to the proposed labeling for the
drug product and identify relevant patent claim number(s).
[If the answers to questions E.1(a) through (c) are ``no,'' stop
here. The patent may not be listed in the Orange Book as a patent
that claims a method of use.]
(ii) Amendment of patent information upon approval. Within 30 days
after the date of approval of its application, if the application
contained a declaration required under paragraph (c)(2)(i) of this
section, the applicant shall, by letter, amend the declaration to
identify the patent claims that claim the drug substance, drug product,
or method of use that has been approved.
* * * * *
4. Section 314.95 is amended by revising 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 to a use patent that claims no
uses for which the applicant is seeking approval. This paragraph also
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
another patent.
* * * * *
Dated: September 19, 2002.
Lester M. Crawford,
Deputy Commissioner.
Tommy G. Thompson,
Secretary of Health and Human Services.
[FR Doc. 02-27082 Filed 10-14-02; 11:57 am]
BILLING CODE 4160-01-S