## ANDA 75-356 

July 30, 2003

Apotex Corporation

Attention: Marcy Macdonald

U.S. Agent for Torpharm

616 Heathrow Drive

Lincolnshire, Illinois 60069

Sent by Facsimile and U.S. Mail

Dear Ms. Macdonald:

This is in reference to your abbreviated new drug application (ANDA)
dated March 31, 1998, submitted pursuant to section 505(j) of the
Federal Food, Drug, and Cosmetic Act (the Act) for Paroxetine
Hydrochloride Tablets 10 mg, 20 mg, 30 mg, and 40 mg. Specifically, this
letter addresses the matter of 180-day exclusivity under section
505(j)(5)(B)(iv) of the Act for ANDAs referencing Paxil, manufactured by
GlaxoSmithKline (GSK).

As noted in the agency's publication entitled [Approved Drug Products
with Therapeutic Equivalence Evaluations]{.underline} [(]{.underline}the
Orange Book), multiple patents are listed for this drug product. The
patent numbers and expiration dates of the patents listed in the Orange
Book are as follows:

U.S. Patent No. 4,721,723 expiration (with pediatric exclusivity) June
29, 2007

U.S. Patent No. 5,789,449 \" July 6, 2009

U.S. Patent No. 5,872,132 \" November 19, 2015

U.S. Patent No. 5,900,423 \" November 19, 2015

U.S. Patent No. 6,063,927 \" October 23, 2019

U.S. Patent No. 6,080,759 \" November 19, 2015

U.S. Patent No. 6,113,944 \" June 14, 2015

U.S. Patent No. 6,121,291 \" September 17, 2017

U.S. Patent No. 6,133,289 \" November 19, 2015

U.S. Patent No. 6,172,233 \" July 15, 2018

(Note: Patents will be referred to in this letter by the last three
digits of the patent number.)

We have reviewed the submissions, including original applications and
amendments, for the ANDAs referencing Paxil, and have determined that
different applicants have been the first to submit paragraph IV
certifications for these patents. Torpharm was the first to submit
paragraph IV certifications for all four strengths as to the \'723
patent, the \'759 patent, the \'289 patent, and the \'233 patent, and as
to the \'291 patent for the 10 mg, 20 mg, and 30 mg strengths. Different
ANDA applicants were the first to submit paragraph IV certifications as
to the other listed patents and for other strengths.

As you may be aware, in a limited number of cases, FDA has addressed the
situation in which different ANDA applicants were first to submit patent
challenges as to different listed patents. FDA has adopted the \"shared
exclusivity\" approach to address eligibility for 180-day exclusivity in
these circumstances.

The facts related to the Paroxetine Hydrochloride ANDAs present many of
the same issues as were addressed by FDA in its application of the
shared exclusivity approach to approval of ANDAs for omeprazole
delayed-release capsules in November 2001. As explained below, the same
general principles apply to the Paroxetine ANDAs.

# 

# Background 

The statutory provision governing 180-day exclusivity reads:

> If the application contains a certification described in subclause IV
> of paragraph (j)(2)(A)(vii) and is for a drug for which a previous
> application has been submitted under this subsection \[containing\]
> such a certification, the application shall be made effective not
> earlier than one hundred and eighty days after -

(I) the date the Secretary receives notice from the applicant under the
    previous application of first commercial marketing of the drug under
    the previous application, or

(II) the date of a decision of a court in action described in
     clause (ii) holding the patent which is the subject of the
     certification to be invalid or not infringed,

whichever is earlier.

Section 505(j)(5)(B)(iv).[^1]

FDA\'s regulations at 21 CFR § 314.107(c)(1) & (2) address the beginning
of 180-day exclusivity as follows:

> If an abbreviated new drug application contains a certification that a
> relevant patent is invalid, unenforceable, or will not be infringed
> and the application is for a generic copy of the same listed drug for
> which one or more substantially complete abbreviated new drug
> applications were previously submitted containing a certification that
> the same patent was invalid, unenforceable, or would not be infringed,
> approval of the subsequent abbreviated new drug application will be
> made effective no sooner than 180 days from whichever of the following
> dates is earlier:

(i) The date the applicant submitting the first application first
    commences commercial marketing of its drug product; or

(ii) The date of a decision of the court holding the relevant patent
     invalid, unenforceable, or not infringed.

The \"applicant submitting the first application\" is the applicant that
submits an application that is both substantially complete and contains
a certification that the patent was invalid, unenforceable, or not
infringed prior to the submission of any other application for the same
listed drug that is both substantially complete and contains the same
certification.

In an August 2, 1999, response to petitions from two generic drug firms
addressing this issue with respect to approval of ANDAs for cisplatin,
FDA stated that these regulations must be interpreted, at least in the
situation with cisplatin, to make eligibility for 180-day exclusivity
based on who submitted the first paragraph IV certification for each
listed patent. (Docket No. 99P-1271/PSA1 and PSA2). Therefore, in cases
where multiple patents are listed, multiple applicants may be eligible
for periods of exclusivity for a single drug product. Based upon the
statements in the petition response, and FDA\'s actions in approving
ANDAs for cisplatin, the agency\'s approach had been to use a
patent-based analysis in determining eligibility for exclusivity. In
other words, the first applicant with a paragraph IV certification for
each listed patent was separately eligible for 180-day exclusivity based
on that patent. Note that, in the case of cisplatin, one of the patents
upon which eligibility for exclusivity was based had expired by the time
any of the ANDAs eligible for exclusivity could be approved, so the
agency\'s interpretation did not result in a delay in approvals of
ANDAs.

# Exclusivity Stand-Off

The agency has recognized, however, that if eligibility for exclusivity
is patent-based, without regard to the facts and circumstances of
specific applications, the agency could be prevented from approving
ANDAs referencing a particular drug product by multiple conflicting
exclusivities, which is inconsistent with the purpose and operation of
the statute. This issue is discussed in some detail in the preamble to
the proposed rule addressing changes to the ANDA approval regulations.
64 Fed. Reg. 42873, 42875-6 (August 6, 1999); *withdrawn* 67 Fed. Reg.
66593 (Nov. 1, 2002).

The situation with omeprazole ANDAs referencing Prilosec illustrated how
untenable the patent-based multiple exclusivity approach could be in
certain situations, when there are multiple patents listed for the
listed drug and different first applicants for these patents. Under the
patent-by-patent approach described in the cisplatin petition response,
different ANDA applicants would have been eligible for exclusivity with
respect to different patents listed for the reference listed drug.
Absent a regulatory solution, these different exclusivity periods would
have blocked approval of omeprazole ANDAs indefinitely.

An exclusivity stand-off whereby each ANDA applicant\'s approval is
delayed indefinitely would be so at odds with both the narrow purpose of
the 180-day exclusivity provision and the broader purposes of 1984 Drug
Price Competition and Patent Term Restoration Act (the Hatch-Waxman
Amendments) as to be absurd. Court decisions, including [Mova
Pharmaceutical Corp., v. Shalala]{.underline}, 140 F.3d 1060, 1074
(D.C.Cir. 1998), observe that the 180-day exclusivity period is intended
as a reward to the ANDA applicant who challenges a listed patent. Such a
challenge may make it possible for generic drugs to be approved before
the expiration date of the challenged patent. The exclusivity stand-off
would prevent the ANDA applicants who are eligible for the exclusivity
from benefiting in any meaningful way from the exclusivity, and could
substantially and indefinitely delay the availability of lower cost
drugs for consumers. In that case, the eligible first ANDA applicants
would be hamstrung by the very provision intended to provide them a
benefit, and competition would be stifled by the very provision intended
to encourage it. The only beneficiary of this interpretation would be
the innovator who -- despite the expiration of 30-month stays on ANDA
approval -- would see an indefinite extension of its monopoly market in
a manner inconsistent with the intent of the Hatch-Waxman Amendments.

[Regulatory Solution]{.underline}

To avoid results that cannot be reconciled with the purposes of the
180-day exclusivity provision in particular and the Hatch-Waxman
Amendments in general, the agency has sought an approach to 180-day
exclusivity that both hews as closely as possible to statutory language
and is consistent with the goals of the legislation. It seems clear that
Congress did not anticipate, and therefore did not address, this factual
situation in drafting the 180-day exclusivity provisions of the Act, and
FDA certainly did not contemplate it in promulgating the regulations now
in effect. As noted in the cisplatin petition response, these
regulations were adopted when the agency interpreted the statute to
require that an ANDA applicant be sued and win its patent litigation to
qualify for exclusivity. The chances of two applicants, each of whom was
first for a different patent, winning their patent litigation was
extremely low.[^2]

The text of the Act does not address the situation in which two ANDA
applicants\' eligibility for exclusivity will create a stand-off in
approvals, and the legislative history is similarly unilluminating.
Accordingly, the agency has the discretion to construe the statute
reasonably to further the purposes of the statute. Alternatively, even
if the statutory language could be interpreted to result in an
exclusivity stand-off, such an interpretation would be inconsistent with
the purpose of the statute, inconsistent with agency policy, and the
agency should reject it for producing an absurd result.

Once the interpretation resulting in the exclusivity stand-off is
rejected, the choice appears to be between rewarding all applicants who
submitted a first paragraph IV ANDA by giving them all the shared chance
to market during the exclusivity period, or rewarding the very first
applicant to challenge any listed patent by giving that applicant the
entire exclusivity period to itself.

Under the usual application of the 180-day exclusivity provision, the
agency would approve the ANDA eligible for exclusivity whenever it was
ready for approval, and the exclusivity would begin to run, independent
of the approval, with the commercial marketing of that drug product or
with a court decision on the patent, whichever was first. However, when
two or more applicants have exclusivity as to different patents that
effectively blocks one another, the approval of the eligible ANDAs (and
thus the possibility of the commercial marketing trigger coming into
play) cannot occur without some resolution of the stand-off. The agency
reviewed two approaches to resolving the question of which ANDA(s) may
be approved - and when -- in cases where different applicants are first
to submit paragraph IV certifications to different patents.

FDA determined that when approval of an ANDA eligible for exclusivity is
blocked by another applicant\'s eligibility for exclusivity, the
applicants that are eligible for the 180-day period of generic drug
exclusivity may share the same exclusivity period. An approach that
shares the exclusivity among all of the first ANDA applicants (\"shared
exclusivity\") would reward the first applicants to submit a paragraph
IV certification with respect to any listed patent, and is therefore
consistent with the most natural reading of the statutory text, which
refers to the paragraph IV certification [for the patent]{.underline}.
The general approach to shared exclusivity is as follows:

When different applicants have submitted first paragraph IV ANDAs for
different listed patents, FDA will approve the ANDAs that are first for
any listed patent as soon as they are otherwise eligible for approval.
That is, if it is only another applicant\'s eligibility for 180-day
exclusivity as to a different patent that would block approval for an
applicant that is itself eligible for 180 days of exclusivity, FDA will
approve the ANDA. Exclusivity for all the ANDAs eligible for exclusivity
at that time will be shared, and it will be triggered by the earlier of
either first commercial marketing of any first applicant or a court
decision on any one of the patents that qualified any applicant for
exclusivity.[^3] During that \"shared\" exclusivity period, FDA may
approve any ANDA eligible for exclusivity, but no other ANDAs.

Obviously, this approach may deprive any one applicant of the chance to
be the sole competitor to the NDA holder. But the exclusivity is already
structured in such a way that eligibility for exclusivity does not
guarantee 180 days as the sole marketed generic drug (i.e., the court
decision trigger could start exclusivity before an ANDA is approved, or
uncertainty over the patent could result in no marketing of an approved
product until an affirmance in the Federal Circuit of a district court
win). A shared exclusivity approach will limit the number of ANDAs
approved during the exclusivity period to the number of \"first\"
applicants. Moreover, it may give each first applicant some part of the
benefit from removing the multiple patents as barriers to approval, when
any one of those patents could have delayed approval of ANDAs. There is
also a clear benefit to consumers if FDA were to approve more then one
ANDA: with multiple ANDAs approved and eligible for exclusivity, it is
more likely that the exclusivity period will be triggered more quickly
and at least one of the generic drugs will reach the market during the
exclusivity period. Past experience has shown that first generics who
are the sole applicants eligible for exclusivity often find it in their
interest not to begin the exclusivity period.

FDA rejected a \"one first applicant\" approach, which would give all
the exclusivity to the very first ANDA applicant to submit a patent
challenge to any patent listed for the innovator drug. FDA would approve
only the ANDA of the applicant who submitted the first paragraph IV
certification for any patent, regardless of the patent for which it was
submitted. That applicant\'s exclusivity would then begin to run with
first marketing or a court decision on the patent that is the subject of
the first certification. During the exclusivity period the agency would
approve no other ANDA for the listed drug. When the exclusivity expired,
all subsequent applicants would be eligible for approval if they
otherwise met the approval requirements.

The one first applicant approach would reward the first applicant to
begin to clear the path to ANDA approvals by challenging a listed
patent. However, the agency believes that this approach would be less
consistent with the statutory language than the shared exclusivity
option, because this approach would be based upon a challenge to only
one listed patent (the one for which the earliest paragraph IV
certification was submitted). As noted above, the statute appears to
apply exclusivity specifically with respect to an ANDA containing a
paragraph IV certification for a patent for which a previous paragraph
IV certification has been received [for the same patent]{.underline}.
Also, although promptness in challenging patents listed early in the
Orange Book is important, it is certainly not adequate to remove the
barriers to approval posed by later listed patents. Finally, by vesting
the power to begin the exclusivity and the marketing of the drug in the
hands of only one applicant, this approach would hold the potential for
delays in the approval of generic drugs because there may be no court
decision on this particular patent and the sole first applicant might
not begin commercial marketing of its drug product. As a result, the
180-day exclusivity period would not begin to run, and the availability
of multiple generic drugs could be substantially delayed.

Thus, the agency has adopted the shared exclusivity approach as more
consistent with the statutory language, and with the intent of both the
180-day exclusivity provision and the Hatch-Waxman Amendments. FDA has
now applied this approach on several occasions.

[Shared 180-Day Exclusivity and Paroxetine Hydrochloride
Tablets]{.underline}

Shared exclusivity applies to Paroxetine Hydrochloride ANDAs because
different applicants are eligible for 180-day exclusivity as to
different listed patents.

The agency has determined that TorPharm\'s ANDA was the first
substantially complete ANDA containing a paragraph IV certification for
all four strengths as to the \'723 patent, the \'759 patent, the \'289
patent, and the \'233 patent, and as to the \'291 patent for the 10 mg,
20 mg, and 30 mg strengths. Different ANDA applicants were first to
submit paragraph IV certifications as to the other listed patents and
strengths.

Therefore, FDA has determined that it will approve your ANDA, and the
ANDAs of other applicants also eligible for 180-day exclusivity, as soon
as they are otherwise eligible for approval (i.e., all patents with a
paragraph III certification have expired, no 30-month stay, ANDA meets
other 505(j) approval requirements, etc.). Approval of an ANDA will not
trigger the beginning of exclusivity. Exclusivity will begin to run
with 1) the first commercial marketing of the drug product by any
sponsor eligible for 180-day exclusivity, or 2) a court decision on any
of the patents as to which any applicant qualified for the 180-day
exclusivity, whichever comes first. During the 180-day exclusivity
period, only those applicants eligible for exclusivity may be approved.
Once the 180 days of exclusivity expire, FDA may approve any other ANDAs
for Paroxetine Hydrochloride that are otherwise eligible for approval.

[Status of the TorPharm ANDA]{.underline}

FDA has determined that there is one remaining 30-month stay, relating
to the \'233 patent, applicable to TorPharm\'s ANDA. As you know, by
letter of July 1, 2003, GSK requested that FDA remove the \'927, \'759,
and \'233 patents from the Orange Book. Thus, GSK has effectively
abandoned its claim to that 30-month stay. There are no other barriers
to approval of TorPharm\'s ANDA and that ANDA is being approved today by
separate approval letter.

Pursuant to 21 C.F.R. § 314.94(a)(12)(viii)(B), FDA will not remove a
patent from the Orange Book that has been the subject of relevant patent
litigation until the agency has determined that no ANDA applicant is
eligible for 180-day exclusivity as to that patent. TorPharm is eligible
for 180-day exclusivity as to the \'759 and \'233 patents. Therefore,
FDA will not remove those patents from the Orange Book until the 180-day
exclusivity period has expired.[^4] There has been no relevant
litigation as to the \'927 patent, and therefore the \'927 patent is
being withdrawn from the Orange Book, and will not serve as a basis for
exclusivity. If TorPharm were to relinquish its eligibility for 180-day
exclusivity as to the \'759 and \'233 patents, those patents would be
removed from the Orange Book immediately.

Please note that a letter containing substantially the same information
is being sent to the other ANDA applicants eligible to share the 180-day
exclusivity for Paroxetine Hydrochloride. If you have any questions
regarding this letter, please contact Ms. Cecelia Parise, Regulatory
Policy Advisor to the Director, Office of Generic Drugs, at
301-827-5845.

> Sincerely,

/s/\"GB\"

Gary Buehler

Director

Office of Generic Drugs

Center for Drug Evaluation and Research

[^1]: The referenced provision governing paragraph IV certifications at
    section 505(j)(2)(a)(vii)(IV) states that an ANDA must contain

    > a certification, in the opinion of the applicant and to the best
    > of his knowledge, with respect to each patent which claims the
    > listed drug referred to in clause (i) or which claims a use for
    > such listed drug for which the applicant is seeking approval under
    > this subsection and for which information is required to be filed
    > under subsection (b) or (c)... .
    >
    > \(IV\) that such patent is invalid or will not be infringed by the
    > manufacture, use, or sale of the new drug for which the
    > application is submitted.

[^2]: In the years from 1984 to 1998, only three ANDA applicants
    qualified for 180-day exclusivity. Since the [Mova]{.underline}
    decision in 1999, over 70 ANDAs have received 180 days of
    exclusivity.

[^3]: FDA has been asked to clarify which court decisions on which
    patents may begin the running of \"shared\" exclusivity. FDA intends
    that exclusivity could be triggered by a court decision on any of
    the patents that qualify an ANDA applicant for exclusivity as of the
    time of the application of the shared exclusivity: that is, at the
    time an applicant eligible for 180-day exclusivity is ready for
    final approval except for another applicant\'s eligibility for
    180-day exclusivity as to another patent.

[^4]: Although FDA reached a different outcome recently in deciding to
    immediately delist a method of use patent (the \'479 patent) for
    gabapentin, that situation involved different circumstances. In the
    gabapentin case, the patent holder essentially admitted to FDA that
    it had violated FDA regulations in submitting the patent for listing
    that did not claim an approved use. Further, the court in [Purepac
    Pharm. Co. v. Thompson]{.underline}, 238 F. Supp. 2d 191(D.D.C.
    2002) found that the \'479 patent had been improperly submitted and
    enjoined FDA from refusing to approve any ANDA solely on the ground
    that it contained a section viii statement to the \'479 patent. For
    reasons explained in the gabapentin administrative decisions and
    litigation, those circumstances led FDA to immediately delist the
    patent. However, those circumstances are not present in this case.