December 23, 2002

Kos Pharmaceuticals, Inc.

1001 Brickell Bay Drive

25^th^ Floor

Miami, Florida 33131

Mark B. McClellan, M.D., Ph.D.

Commissioner of the Food and Drug Administration

5600 Fishers Lane

Rockville, Maryland 20857

Re: FDA's Proposed Amendments to 21 C.F.R. Part 314

Dear Dr. McClellan,

Please find attached Kos Pharmaceuticals, Inc.'s comments to the Food
and Drug Administration's proposed amendments to 21 C.F.R. Part 314. Kos
submits that the FDA's proposed interpretation of §505(j)(2)(B)(iii) of
the Hatch-Waxman Act to eliminate the possibility of multiple 30 month
stays on ANDA approval should not be maintained. First, the FDA does not
need to eliminate the possibility of multiple 30 month stays in order to
prevent the improper listing of patents in the Orange Book. Instead,
implementation of the proposed amendments that (1) clarify the types of
patents that may and may not be listed and (2) require a detailed
declaration from the NDA holder will prevent improper listings.

Second, Kos submits that the FDA's proposed new interpretation of
subsection (B)(iii) is improper. Subsection (B)(iii) must be read in
light of the other sections of the statute, which clearly dictate that
an ANDA filer must give the patent holder notice of any Paragraph IV
Certification. Also, every added Paragraph IV certification is an
amendment regardless of whether the ANDA already contains such a
certification. Each Paragraph IV Certification is a unique submission
specific to the patent certified to and addresses the ANDA filer's
non-infringement, invalidity, and/or unenforceability contentions with
respect to that patent.

Third, Kos submits that the elimination of the 30 month stay for
legitimately late-listed patents will deprive a patent holder of a
statutory remedy for infringement of its patent provided under the
Hatch-Waxman Act, will penalize the patentee for delays in patent
prosecution that it did not create, and will deprive the courts of their
statutory power to determine the necessity of 30 month stays in a given
situation. Further, there is little evidence that the elimination of
multiple 30 months stays in ANDA litigation will result in greater
public availability of generic pharmaceuticals. For the above reasons,
Kos submits that the FDA's proposal to eliminate the possibility of
multiple 30 months stays for legitimately late-listed patents not be
maintained.

Sincerely,

Adrian Adams

President and CEO

Kos Pharmaceuticals, Inc.

Comments Submitted to the

Food and Drug Administration

regarding its\
Proposed Amendments to

21 C.F.R. Part 314

[Submitted by]{.underline}

Kos Pharmaceuticals, Inc.

1001 Brickell Bay Drive, 25th Floor

Miami, Florida 33131

December 23, 2002

I.  INTRODUCTION

Kos Pharmaceuticals, Inc. ("Kos") submits the following comments in
response to the Food and Drug Administration's ("FDA's") proposal to
amend its patent listing requirements (as enumerated in 21 C.F.R. Part
314) for New Drug Applications ("NDAs"). The FDA has proposed these
amendments to deter patents from being improperly listed in the
*Approved Drug Products with Equivalence Evaluations* ("the Orange
Book"), and, as a result, to prevent delays in the introduction of
generic pharmaceuticals onto the market.

The FDA's proposal would (1) amend FDA regulation 21 C.F.R.\
§ 314.53(b) to limit the types of patents that may be listed in the
Orange Book, (2) amend FDA regulation 21 C.F.R. § 314.53(c)(2)(i) to
require NDA holders to submit a more detailed declaration when
submitting a patent to be listed in the Orange Book, and (3) amend FDA
regulations 21 C.F.R. §§ 314.52(a)(3) and 314.95(a)(3) to eliminate the
requirement that an Abbreviated New Drug Application ("ANDA") applicant
give notice to a patentee that the ANDA has been amended to include
additional Paragraph IV certifications. The FDA has proposed amendment
(3) to reflect its new interpretation of § 505(j)(2)(B)(iii) of the
Hatch-Waxman Act (codified as 21 U.S.C. § 355(j)(2)(B)(iii)), which it
is using to support its position that multiple 30 month stays on the
approval of ANDAs should be eliminated.

Kos submits that the FDA's interpretation of § 505(j)(2)(B)(iii) is
incorrect and unnecessary to accomplish the FDA's goals. Amendment of 21
C.F.R.\
§§ 314.53(b) and (c)(2)(i) would successfully prevent much of the abuse
that the FDA has identified, rendering unnecessary the FDA's strained
interpretation of\
§ 505(j)(2)(B)(iii). Furthermore, the FDA over-states the alleged abuse
of the\
patent-listing provisions by ethical companies. Finally, the FDA's
proposed interpretation of § 505(j)(2)(B)(iii) would deprive the
patentee of fundamental statutory rights and would place an undue burden
on the FDA to decide issues that are properly left to the courts.

II. the fda's proposed amendments to 21 C.F.R. §§ 314.53(b) AND
    (c)(2)(i) will prevent the abuses that the fda has identified

The FDA's proposal to eliminate successive 30 month stays on ANDA
approval is unnecessary. The FDA's amendments to 21 C.F.R. §§ 314.53(b)
and (c)(2)(i) will effectively prevent the fraudulent Orange Book patent
listings perceived by the FDA, thus removing the primary barrier in the
marketing of generic pharmaceuticals.

A.  The FDA Can Prevent the Improper Listing of Patents in\
    the Orange Book without Eliminating the Possibility of Successive\
    30 Month Stays on ANDA Approval

The FDA has proposed (1) amending 21 C.F.R. §315.53(b) to enumerate the
types of patents that may and may not be listed by the NDA holder in the
Orange Book, and (2) amending 21 C.F.R. §314.53(c)(2)(i) to require the
NDA holder to submit a more detailed declaration than is currently
required when submitting a patent for listing in the Orange Book. These
two rules, by themselves, will prevent the improper listing of patents
in the Orange Book and will ensure that the marketing of generic
pharmaceuticals to the public will not be unfairly delayed.

1.  Enumerating the Patents that May and May Not be Listed in the Orange
    Book by an NDA Holder will Prevent the Improper Listing of Patents
    in the Orange Book

Under the new rule proposed by the FDA, the patents that the patentee
may list in the Orange Book include: drug substance (ingredient)
patents, drug product (formulation and composition) patents, product by
process patents, and method of use patents. In addition, in order to be
listed, these patents must claim the formulation or method of use of the
drug that was described in the drug's NDA. The proposed regulation also
identifies the types of patents that the patentee may not list in the
Orange Book: process patents or patents claiming packaging, metabolites,
or intermediates of the approved drug product.

This amendment would have a significant impact on reducing the number of
improper patent listings, and thus accomplish the FDA's objectives. A
study by the Federal Trade Commission ("FTC") entitled *Generic Drug
Entry Prior to Patent Expiration* ("the Study") found only eight
instances where "late-listed patents" have resulted in multiple 30
months stays on ANDA approval.[^1] The FDA's proposed amendments would
have prevented the patents at issue in four of these eight instances
from ever being listed in the Orange Book, thus preventing the issue of
multiple 30 month stays from ever arising in such situations.

In three of these situations, the listed patents did not claim the
formulation or method of use of the drug that was described in the
drug's NDA, and thus could not have been listed under the FDA's proposed
amendment. The NDA holder for Tiazac^®^ late-listed a patent in the
Orange Book that allegedly claimed Tiazac's ^®^ drug substance. However,
the formulation disclosed in the patent did not claim the formulation
described in the approved NDA for Tiazac^®^.[^2] Similarly, the holder
of the NDAs for both the tablet and capsule forms of Neurontin^®^
late-listed a method patent as covering its drug product, even though
this patent did not claim the methods of use for Neurontin^®^ that were
set forth in its NDAs.

Under the FDA's proposed rules, none of these patents could have been
listed in the Orange Book. Both formulation and method of use patents
can be listed in the Orange Book only if they claim formulations or
methods approved in the NDA of the drug product.

In the fourth situation, the patent at issue could not have been listed
under the FDA's proposed amendments because it is one of the types of
patents that the FDA would exclude from ever being listed in the Orange
Book. In that example, the NDA holder for Buspar^®^ late-listed a patent
claiming a method of use of a metabolite produced by the administration
of Buspar^®^.[^3] Under the FDA's proposed rules, patents directed to
metabolites may not be listed in the Orange Book, so this patent would
not have been listed.

Finally, little empirical evidence exists to suggest that the
elimination of multiple 30 month stays in ANDA litigation will result in
greater public availability of generic pharmaceuticals. In fact, only
3.8% of all ANDAs (or 17 of the 442 active ANDAs) have been ever been
stayed, even once, [^4] making the FDA's proposal to eliminate
successive 30 month stays at best an ineffective way to address the
FDA's concerns. Furthermore, the stay imposed on ANDA approval resulting
from patent infringement litigation has not been shown to delay the time
that the generic drug is brought to market. The ANDA approval process
typically takes about 30 months, regardless of whether or not the ANDA
filer has been sued for infringement.[^5]

On average, pharmaceutical patents are challenged within five years of
their issuance, long before their expiration dates. In many cases,
generic drug manufacturers apply for ANDA approval as early as 48 months
after NDA approval of the branded drug product.[^6] Arguments that
branded drug manufactures are abusing the use of multiple 30 month stays
to gain extended patent protection for their products are exaggerated
and incorrect.

2.  Requiring an NDA Holder to Submit a More Detailed Declaration in
    Order to List its Patent in the Orange Book\
    Will Prevent the Improper Listing of Patents

Amending 21 C.F.R. § 314.53(c)(2)(i) to require the NDA applicant to
include a more detailed declaration when submitting patent information
for listing in the Orange Book will further reduce improper patent
listings. Currently, the declaration accompanying a listing provides
only that: "The undersigned declares that Patent No. \_\_\_ covers the
formulation, composition, and/or method of use of (name of drug
product). This product is (currently approved under section 505 of the
Federal Food, Drug, and Cosmetic Act) \[or\] (the subject of this
application for which approval is being sought)."

In contrast, the FDA's proposal for a more detailed declaration would
require the patentee to specify whether its patent covers a drug
substance, drug product, and/or method of use; to identify the
particular patent claims directed to the drug substance, drug product,
and/or method of use; and to state that the drug substance, drug
product, and/or method of use claimed in the patent is the subject of
the NDA. These more detailed requirements will clearly make it more
difficult to list a patent improperly.

III. THE FDA'S INTERPRETATION OF § 505(j)(2)(B)(iii) IS INCORRECT

The FDA's proposed new interpretation of § 505(j)(2)(B)(iii) is
incorrect. First, § 505(j)(2)(B)(iii) must be interpreted in light of
the other sections of the\
Hatch-Waxman Act.[^7] The Act clearly dictates that an ANDA applicant
must give the patent holder notice of any Paragraph IV certification,
not just the applicant's original certification. Second, every
additional Paragraph IV certification submitted by an ANDA filer after
submission of the ANDA should be considered an "amendment" to the ANDA.
Each Paragraph IV certification is a unique submission that addresses
the ANDA filer's non-infringement, invalidity, and/or unenforceability
contentions with respect to each patent listed in the Orange Book.

A.  The FDA's Interpretation of § 505(j)(2)(B)(iii) Ignores the\
    Plain Language of the Statute

Section 505(j)(2)(B)(iii) of the Hatch-Waxman Act provides:

> "If an \[ANDA\] application is amended to include a certification
> described in subparagraph (A)(vii)(IV), the notice required by clause
> (ii) shall be given when the amended application is submitted."

Both the courts and the FDA have interpreted § 505(j)(2)(B)(iii) in a
uniform manner since its enactment. In general, both have found that,
under § 505(j)(2)(B)(iii), an ANDA applicant must submit a certification
for each patent listed in the Orange Book. In addition, each time the
ANDA applicant submits a Paragraph IV certification, it is required to
provide notice of the Paragraph IV certification to the patentee and the
NDA holder. Upon receipt of the notice of the ANDA applicant's Paragraph
IV certification, the patentee has 45 days to filed a patent
infringement lawsuit against the ANDA applicant. If the patent holder
chooses to file suit, the FDA cannot approve the its ANDA until the
earlier of (1) 30 months or (2) a court decision that the patent is
invalid or not infringed.[^8]

The basis for this interpretation is clear when the provisions of the
statute are viewed together. In particular, § 505(j)(2)(A)(vii)(IV)
provides that an ANDA filer must submit a Paragraph IV certification for
each patent that claims the listed drug that is the subject of the NDA.
Sections 505(j)(2)(B)(i) and (iii) require that the ANDA applicant must
give notice of each Paragraph IV certification to the NDA holder and the
patentee when an amendment is submitted. Moreover, under § 505(b)(3)(A),
an ANDA applicant submitting a Paragraph IV certification must include a
specific statement in the ANDA application that it will give such
notice. This statutory framework is clear. The ANDA applicant is
required to give notice of each Paragraph IV certification to the patent
holder, regardless of whether the Paragraph IV certification is part of
the original ANDA application or an amended ANDA application.

The FDA's proposed interpretation of § 505(j)(2)(B)(iii) requires notice
of a Paragraph IV certification to be provided to a patentee only once
-- either (1) at the time the original ANDA is submitted, if it contains
a Paragraph IV certification, or (2) the first time an ANDA is amended
to include a Paragraph IV certification (but only if the original ANDA
does not contain a Paragraph IV certification). The FDA argues that the
presence of the term "amended" in the statute means that this section
was intended only to apply to an ANDA applicant that did not include a
Paragraph IV certification in its original ANDA.

This is interpretation is inconsistent with the plain meaning of the
statute. Indeed, the FDA admits that its new interpretation is
inconsistent with the way it has interpreted § 505(j)(2)(B)(iii) for
years. The FDA should continue to interpret\
§ 505(j)(2)(B)(iii) to require notice of a Paragraph IV certification
each time such certification is filed.

B.  Every Additional Paragraph IV Certification Submitted by an ANDA
    Filer after Submission of its ANDA Should be Considered an
    "Amendment" to the ANDA

Under 21 C.F.R. § 314.96, an ANDA applicant may amend its unapproved
ANDA by (1) revising existing information or (2) providing additional
information, including additional Paragraph IV certifications. In the
past, each additional Paragraph IV certification has been treated as a
separate amendment that has triggered a separate notice requirement.
However, the FDA's new interpretation of the statute treats only the
first Paragraph IV certification submitted by an ANDA holder (after the
filing of its ANDA) as an amendment.

This view undermines the purpose of a Paragraph IV certification. A
Paragraph IV certification is not a broad, generic document to be filed
once, as the FDA seems to suggest, but instead a unique document that
contains information specific to each patent that is listed in the
Orange Book. Each Paragraph IV certification is directed to one or more
specific patents. Each Paragraph IV certification discloses the reasons
that the ANDA applicant believes the specific patents addressed are
invalid, unenforceable, or will not be infringed by the ANDA product.
Thus, a Paragraph IV certification with respect to one patent cannot
address later-listed patents. For this reason alone, each Paragraph IV
certification should be treated as a separate amendment that gives rise
to a separate notice requirement and a separate 30 month stay on ANDA
approval.

IV. the fda's proposed interpretation of § 505(j)(2)(B)(iii)\
    will unfairly penalize patentees and discourage innovation

The elimination of 30 month stays for legitimately late-listed patents
will deprive a patent holder of a statutory remedy for infringement of
its patents provided under the Hatch-Waxman Act and will penalize the
patentee for delays in patent prosecution that it did not create. The
FDA's proposal would also deprive the courts of their statutory power to
determine the necessity of 30 month stays in a given situation, thereby
discouraging the development of new drugs in general.

A.  The FDA's Proposed Interpretation Deprives the Patentees of their
    Statutory Right to Sue for Infringement Resulting from the Filing of
    an ANDA

Under 35 U.S.C. § 271(e)(2)(A), it is an act of infringement to submit
an ANDA for a drug composition or a method of using a drug that is
claimed in a patent. As previously discussed, a patent holder may sue an
ANDA applicant for infringement of any patent listed in the Orange Book
(even late-listed patents) after receiving notice from the applicant
that its ANDA contains a Paragraph IV certification stating that the
listed patents is invalid, unenforceable, and/or not infringed by the
ANDA applicant's generic drug product. This statutory provision was part
of the balance Congress struck in enacting the Hatch-Waxman Act, which
was intended to allow new drugs to be marketed more cheaply and quickly
by substantially shortening the time and effort needed to obtain
marketing approval of generic drugs.[^9]

Under the present regulations, the patentee receives this notice from
the ANDA applicant (1) if its ANDA as originally filed contains a
Paragraph IV certification, and (2) any time the ANDA applicant
supplements or amends its ANDA to contain any additional Paragraph IV
certification.

Under the FDA's proposed interpretation, however, the patentee will
receive notice that an ANDA applicant has filed a Paragraph IV *only
once*. After this initial notice is received, the ANDA filer is under no
obligation to give notice to the patent holder that it has amended its
ANDA to include additional Paragraph IV certifications, even though the
filing of its amended ANDA is a statutory act of infringement. The
patentee would thus be deprived of its statutory right to sue for
infringement of its legitimately later-listed patent.

This proposed interpretation is in direct conflict with the statutory
rights afforded to patentees under § 271(e)(2)(A) and will undermine the
carefully considered balance struck by Congress in enacting the
Hatch-Waxman Act. In effect, the FDA's proposal to eliminate the notice
requirement (in order to eliminate multiple 30 month stays) would
undermine established patent law.

B.  The FDA's Amendments Will Unfairly Penalize Patentees for Delays
    that They Did Not Cause

Under the amendments, the ANDA applicant does not have to provide notice
to the patentee of a Paragraph IV certification of a patent that has
been late-listed in the Orange Book when a Paragraph IV certification
has previously been filed. However, ultimate control of the timing of
patent issuance, and therefore, the date on which a patent will
subsequently be listed in the Orange Book, lies with the United States
Patent and Trademark Office, not the patentee. Moreover, a patent may be
listed in the Orange Book only within a 30 day period following its date
of issue. Thus, the patentee's remedies for infringement of its patents
are at the mercy of the Patent and Trademark Office and uncertainties
regarding the duration of patent prosecution.

In addition, a patent applicant has little incentive to delay the
issuance of its patent intentionally. A patent terminates 20 years from
its earliest filing date, a policy that encourages the swift prosecution
of patents.

C.  The Decision of Whether to Permit Successive 30 Month Stays in ANDA
    Litigation is Properly Left to the Courts, Not the FDA

The courts, not the FDA, should determine whether to permit successive
30 month stays in ANDA litigation. The FDA is attempting to assert its
regulatory authority in an area traditionally reserved for the
judiciary.

Presently, the court in which a suit for infringement of listed patents
is pending has the discretion to decide whether a stay in an ANDA case
should be extended and whether multiple ANDA cases brought on the same
generic drug as a result of\
later-listed patents should be consolidated for a single trial. Through
its proposed interpretation, the FDA is attempting to create a bright
line rule that eliminates the possibility of multiple 30 month stays in
all ANDA cases, thus shifting power traditionally reserved for the
courts to the FDA.

Courts, however, are in a much better position to determine on a\
case-by-case basis whether a 30 month stay should be shortened or
extended. The court is familiar with the facts of each case, the patents
and technology at issue, and the parties' claims and defenses. Indeed,
in situations where a second suit is filed on later-listed patents,
courts have the power to (and often do) consolidate the suits for a
single trial and thus avoid multiple 30 month stays altogether.
Consequently, the court, not the FDA, is in the best position to
evaluate each of these factors in deciding whether the stay in a
particular ANDA case should be extended.

V.  CONCLUSION

The FDA should not eliminate the possibility of multiple 30 stays for
ANDA approval.

The FDA's strained interpretation of § 505(j)(2)(B)(iii) ignores
judicial precedent, its own prior statements, and the basic tenets of
statutory construction. Furthermore, its view of the statute undermines
the purpose of the Paragraph IV certification that gives rise to a 30
month stay.

The FDA does not need to eliminate the possibility of multiple 30 month
stays in order to prevent the improper listing of patents in the Orange
Book. Instead, it can rely on its proposed amendments to 21 C.F.R. §§
314.52(b) and (c)(2)(i) to accomplish that same objective.

The patent system is designed to encourage innovation by rewarding those
who disclose their invention to the public with exclusive rights to
their invention for a certain period of time. The FDA's proposal to
eliminate multiple 30 month stays will contribute to the overall erosion
of intellectual properly rights of pharmaceutical companies. If the
patent protection afforded to pharmaceutical companies becomes weak,
innovation regarding better drug delivery and new methods of use for
existing drugs will be chilled. Inventors will have no incentive to
further improve or characterize their drugs.

Thus, Kos submits that the FDA's proposed interpretation of\
§ 505(j)(2)(B)(iii) of the Hatch-Waxman Act to eliminate the possibility
of multiple 30 month stays on ANDA approval should not be maintained.

[^1]: A "late-listed patent" is a patent listed in the Orange Book after
    an ANDA (and any related Paragraph IV certifications) has been
    filed. The products involved in these late-listed patent situations
    were Tiazac^®^, Neurontin^®^ (tablets and capsules), Buspar^®^,
    Hytrin^®^, Platinol^®^, Paxil^®^, and Taxol^®^.

[^2]: *See Andrx Pharm., Inc., v. Biovail Corp.*, 276 F.3d 1368,
    1373-1376 (Fed. Cir. 2002).

[^3]: *See Mylan Pharm., Inc., v. Thompson*, 139 F. Supp 2d. 1, 9 (D.
    Col. 2002).

[^4]: *A Review of the FTC Report, 'Generic Drug Entry Prior to Patent
    Expiration': Before the Subcomm. on Health*, Oct. 9, 2002 (statement
    of the Honorable L. Crawford, Acting Commissioner, U.S. FDA).

[^5]: *A Review of the FTC Report, 'Generic Drug Entry Prior to Patent
    Expiration': Before the Subcomm. on Health*, Oct. 9, 2002 (statement
    of the Honorable T. Muris, chairman, FTC).

[^6]: *A Review of the FTC Report, 'Generic Drug Entry Prior to Patent
    Expiration': Before the Subcomm. on Health*, Oct. 9, 2002 (statement
    of Mr. G. Glover, attorney, Ropes & Gray).

[^7]: Title I of the Drug Price Competition and Patent Term Restoration
    Act, Pub. L. No. 98-417, 98 Stat. 1585 (1984).

[^8]: 21 U.S.C. §355(c)(3)(C)

[^9]: *See Eli Lilly & Co. v. Medtronic, Inc.*, 496 U.S. 661, 676
    (1990).