314.50(i) or 314.94(a)(12)(i)(A)(4),        letter:
 respectively, the applicant must send the   If an applicant
 notice required by Sec.  Sec.   314.52(a)   submits an amendment or
 or 314.95(a), respectively, at the same     supplement to its 505(b)(2)
 time the amendment is submitted to FDA      application or ANDA that
                                             includes a paragraph IV
                                             certification, the
                                             applicant must send notice
                                             required by Sec.
                                             314.52(a) or Sec.
                                             314.95(a), respectively, at
                                             the same time the amendment
                                             is submitted to FDA.
                                                Notice of
                                                paragraph IV
                                                certification is
                                                required regardless of
                                                whether notice already
                                                has been provided for
                                                another paragraph IV
                                                certification contained
                                                in the application or in
                                                an amendment or
                                                supplement to the
                                                application.
                                            Amendment to a 505(b)(2)
                                             application or an ANDA
                                             (Sec.  Sec.   314.52(d)(2)
                                             and 314.95(d)(2))
                                            Before receipt of an
                                             acknowledgement letter or
                                             paragraph IV acknowledgment
                                             letter:
                                                If an applicant
                                                submits a paragraph IV
                                                certification in an
                                                amendment to a 505(b)(2)
                                                application or ANDA, the
                                                applicant must send
                                                notice required by Sec.
                                                 314.52(a) or Sec.
                                                314.95(a), respectively,
                                                in accordance with the
                                                procedures in Sec.
                                                314.52(b) or Sec.
                                                314.95(b).
                                                If an ANDA
                                                applicant timely
                                                provides notice of
                                                paragraph IV
                                                certification in
                                                accordance with Sec.
                                                314.95(b), FDA will base
                                                its determination of
                                                whether the applicant is
                                                a first applicant on the
                                                date of submission of
                                                the amendment containing
                                                the paragraph IV
                                                certification.
                                            Amendment to a 505(b)(2)
                                             application or an ANDA
                                             (Sec.  Sec.   314.52(d)(3)
                                             and 314.95(d)(3))
                                             An applicant that
                                             submits an amendment or
                                             supplement to its 505(b)(2)
                                             application or ANDA to seek
                                             approval of a new strength
                                             must provide notice of any
                                             paragraph IV certification
                                             in accordance with Sec.
                                             Sec.   314.52(d)(1) and
                                             (d)(2) or Sec.  Sec.
                                             314.95(d)(1) and (d)(2), as
                                             applicable.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
  regulations, but should not be relied upon in place of the proposed
  regulation.

    We are proposing to revise Sec. Sec.  314.52(d) and 314.95(d)
(redesignated as Sec. Sec.  314.52(d)(1) and 314.95(d)(1),
respectively) to require that an applicant send notice of a paragraph
IV certification contained in an amendment to an application that has
been received for substantive review or in a supplement to an approved
application at the same time that the amendment or supplement is
submitted to FDA. Our proposed revisions clarify the requirement in our
current regulations for an applicant to send notice of a paragraph IV
certification at the same time that the amendment is submitted to FDA
by distinguishing between: (1) Amendments submitted after the
application has been received for substantive review as indicated by
the receipt of an acknowledgment letter (if, as to an ANDA, the
original application did not contain a paragraph IV certification) or
paragraph IV acknowledgment letter and (2) amendments submitted before
an application has been received for substantive review (see proposed
Sec. Sec.  314.52(d)(2) and 314.95(d)(2) and section II.D.1.b.i.). The
MMA amended the FD&C Act to require that notice of a paragraph IV
certification contained in a supplement to an approved 505(b)(2)
application or ANDA be sent at the same time that the supplement is
submitted to FDA, and our proposed revision to Sec. Sec.  314.52(d)(1)
and 314.95(d)(1) incorporates this requirement (see section
505(b)(3)(B)(ii) and (j)(2)(B)(ii)(II) of the FD&C Act).
    In proposed Sec. Sec.  314.52(d)(1) and 314.95(d)(1), we reiterate
the statutory requirement that notice of a paragraph IV certification
in an amendment or supplement must be provided regardless of whether
the applicant has already given notice with respect to another
paragraph IV certification contained in the 505(b)(2) application or
ANDA or in an amendment or supplement to the 505(b)(2) application or
ANDA. The phrase ``another paragraph IV certification'' may refer to a
previous paragraph IV certification to a different listed patent for
the listed drug relied upon or RLD or, for certain amendments and
supplements (see section II.F), a previous paragraph IV certification
to the same listed patent. For example, if an ANDA applicant submitted
a paragraph IV certification to the '246 patent (a listed patent
claiming the drug product for the listed drug relied upon) in its
original application, and subsequently submitted an amendment to its
pending ANDA to change the formulation, the ANDA applicant would be
required to provide a new patent certification to the '246 patent (see
proposed Sec.  314.96(d)(1) and section II.F.1). If this ANDA applicant
submitted a paragraph IV certification to the '246 patent in its
amendment, the ANDA applicant would be required to send notice of its
second paragraph IV certification to the '246 patent to the NDA holder
and each patent owner at the same time the amendment to the ANDA is
submitted to FDA.
    If an applicant submits an amendment containing a paragraph IV
certification to its 505(b)(2) application or ANDA before the applicant
has received an acknowledgment letter (if, as to an ANDA, the original
application did not contain a paragraph IV certification) or a
paragraph IV acknowledgment letter, proposed Sec. Sec.  314.52(d)(2)
and 314.95(d)(2) require that the applicant send notice of its
paragraph IV certification in accordance with the procedures described
in Sec. Sec.  314.52(b) and 314.95(b), respectively. In this
circumstance, the 505(b)(2) or ANDA applicant must send notice of the
paragraph IV certification contained in

its amendment on or after the date it receives an acknowledgment letter
or paragraph IV acknowledgment letter, but not later than 20 days after
the date of the postmark on the letter. This requirement reflects our
longstanding policy that notice of a paragraph IV certification may not
be sent unless and until we have notified the applicant that its
application has been filed or received, as appropriate (see section
II.D.1.a).
    It should be noted that a paragraph IV certification submitted in
an amendment after the 505(b)(2) application or ANDA is submitted but
before the applicant receives a paragraph IV acknowledgment letter is
considered part of the original 505(b)(2) application or ANDA solely
for the purpose of determining the appropriate timeframe for sending
notice of paragraph IV certification. The availability of a 30-month
stay for patent infringement litigation initiated within the statutory
timeframe in response to a paragraph IV certification submitted in an
amendment to a 505(b)(2) application or an ANDA continues to be
determined by whether the patent at issue was filed with FDA before the
date on which the original 505(b)(2) application or ANDA (excluding an
amendment or supplement) was submitted (see section 505(c)(3)(C) and
(j)(5)(B)(iii) of the FD&C Act; see also proposed Sec.  314.107(b)(2)
and section II.M.2.b). For purposes of determining an ANDA applicant's
eligibility for 180-day exclusivity and the date from which a first
ANDA applicant's compliance with section 505(j)(5)(D)(i)(IV) of the
FD&C Act is assessed, the date of the submission of the paragraph IV
certification is the date on which the amendment was submitted. An
amendment seeking approval for a different strength of a drug product
thus may have a different submission date than the original ANDA
submission for purposes of evaluating an ANDA applicant's eligibility
for 180-day exclusivity for that new drug product and the date from
which a first ANDA applicant's compliance with section
505(j)(5)(D)(i)(IV) of the FD&C Act is assessed.
    Proposed Sec. Sec.  314.52(d)(3) and 314.95(d)(3) require that an
applicant that submits an amendment or supplement to a 505(b)(2)
application or ANDA that contains a paragraph IV certification and
seeks approval for a different strength of the drug product must adhere
to the timing requirements for notice in Sec. Sec.  314.52(d)(1) or
(d)(2) and 314.95(d)(1) or (d)(2), as applicable. Unlike other
amendments and supplements to a 505(b)(2) application or ANDA, an
amendment or supplement seeking approval of a different strength may
refer to a different listed drug than the listed drug identified in the
original 505(b)(2) application or ANDA (see section 505(b)(4)(B) and
(j)(2)(D)(ii) of the FD&C Act). Accordingly, we have separately
described this type of amendment or supplement to clarify applicable
regulatory requirements.
    There are a few situations in which the relationship between an
acknowledgment letter or paragraph IV acknowledgment letter and the
timing of notice for a paragraph IV certification contained in an
amendment or supplement to a 505(b)(2) application or ANDA may seem
complicated. For example, in the case of a 505(b)(2) or ANDA applicant
that submits an original application containing a paragraph III
certification to a listed patent and receives an acknowledgment letter
(as distinguished from a paragraph IV acknowledgment letter) indicating
that the 505(b)(2) application or ANDA has been received for
substantive review, if the applicant subsequently submits an amendment
containing a paragraph IV certification to a listed patent, the
applicant need not wait to receive a paragraph IV acknowledgment letter
before sending notice in accordance with Sec.  314.52(d)(1) or Sec.
314.95(d)(1).
    Also, we note that FDA may send an acknowledgment letter for
certain types of supplements (e.g., a supplement to an ANDA seeking
approval for a new strength of a drug product; a 505(b)(2) supplement
to an NDA seeking approval for a new indication, new dosage regimen,
new route of administration, or a change from prescription use to OTC
status for all conditions of use). However, this practice would not
alter the 505(b)(2) or ANDA applicant's statutory obligation to send
notice of a paragraph IV certification at the time the supplement is
submitted to FDA (and not at the time the paragraph IV acknowledgment
letter for the supplement may be received).
    We interpret the requirement in proposed Sec.  314.52(d)(1) or
Sec.  314.95(d)(1) to send notice of a paragraph IV certification at
the same time that the amendment or supplement to the application is
submitted to FDA to mean that notice to the NDA holder and each patent
owner must be sent on the same day that the amendment or supplement to
the application is submitted to FDA. It should be noted that the
controlling date for purposes of first applicant eligibility is the
date on which the amendment or supplement to the ANDA containing a
paragraph IV certification is submitted (i.e., officially received
(date-stamped) by the OGD Document Room) as long as notice is timely
provided in accordance with the statute. Due to a technical difference
in the method by which FDA determines the date of submissions to FDA
(using a date of receipt rule) and the date on which an applicant sends
notice of a paragraph IV certification to the NDA holder and each
patent owner (using a date of mailing rule), these dates may differ.
For example, Applicant A submits an amendment containing a paragraph IV
certification to its ANDA on August 2 and sends notice of the paragraph
IV certification to the NDA holder and each patent owner on that same
day. The amendment to the ANDA is date-stamped by the OGD Document Room
on August 3. Applicant A has complied with the statutory requirement to
send notice of its paragraph IV certification at the same time the
amendment or supplement to the ANDA is submitted despite the difference
in the date on which the amendment was officially received and the date
on which the notice of paragraph IV certification was sent because both
the amendment and notice(s) were actually sent on the same day.
    If an ANDA applicant does not provide notice of a paragraph IV
certification on the same day that an amendment or supplement is
submitted, FDA will consider the paragraph IV certification to be
effective only as of the date that the applicant has both submitted the
amendment or supplement containing the paragraph IV certification and
sent the notice (see Purepac Pharmaceutical Co. v. Thompson, 354 F.3d
877 (D.C. Cir. 2004)).
    To qualify as a first applicant eligible for 180-day exclusivity
under section 505(j)(5)(B)(iv)(II)(bb) of the FD&C Act, an applicant
must, among other things, submit a paragraph IV certification on the
``first day on which a substantially complete application containing a
[paragraph IV certification] is submitted.'' Because daily electronic
updates to the Orange Book generally do not occur until the afternoon
(Eastern Standard Time), the opportunity to be a first applicant with
respect to a patent that is newly listed in the Orange Book (i.e., to
submit an amendment to the ANDA containing a paragraph IV certification
and send notice of the paragraph IV certification on that same day)
could be affected by, among other things, the time zone in which the
ANDA applicant resides. To ensure that all ANDA applicants
(irrespective of time zone) have a reasonable opportunity to be a first
applicant with respect to a newly listed patent, we are proposing that
any notice of paragraph

IV certification is invalid if it is sent before the first working day
after the day the patent is listed in the Orange Book (see proposed
Sec. Sec.  314.95(b)(2) and 314.94(a)(12)(viii)(C)(1)(ii), discussed in
section II.E.4). The term ``working day'' has the meaning provided in
21 CFR 1.377 (``any day from Monday through Friday, excluding Federal
holidays''). This approach is intended to promote equity among ANDA
applicants and reduce the burden on industry and on the Agency
associated with serial submissions of amendments and multiple notices
of paragraph IV certifications related to a newly-issued patent. When a
new patent is issued by the PTO, the NDA holder has 30 days within
which to submit the patent information to FDA for listing. An ANDA
applicant does not know if or when the patent may be submitted to FDA,
and when it is submitted, there may be a delay in the patent's
appearance in the Orange Book. Therefore, if an ANDA applicant
reasonably believes a patent could be listed for an RLD, it will often
submit a paragraph IV certification to FDA and send notice to the NDA
holder and patent owner each day during the 30-day period after
issuance of the new patent. ANDA applicants have adopted this practice
in an attempt to satisfy the certification and notice requirements on
the first date on which the patent is listed in the Orange Book and
thus qualify as a first applicant. FDA's proposal is intended to
eliminate the need for these burdensome serial certifications.
    The following example illustrates our approach: The NDA holder
submits Form FDA 3542 to the Office of Generic Drugs, Document Room,
Attention: Orange Book Staff, within 30 days after issuance of the '123
patent claiming the drug product Litigatolol. Form FDA 3542 is date-
stamped by the OGD Document Room on Friday, August 5 and listed in the
Orange Book, which is updated at 3 p.m. Eastern Standard Time on that
date. Applicant B and Applicant C have submitted ANDAs for Litigatolol
and have received acknowledgment letters indicating that their ANDAs
have been received for substantive review. Applicant B is located in
California and submits an amendment to its ANDA containing a paragraph
IV certification to the '123 patent and sends notice to the NDA holder
and each patent owner late in the afternoon, Pacific Time, on Friday,
August 5. Applicant C is located in New Jersey and would have been
unable to submit an amendment to its ANDA containing a paragraph IV
certification to the '123 patent and send notice to the NDA holder and
each patent owner before the end of the working day on Friday, August
5. Applicant C submits the amendment and sends notice on Monday, August
8. Prior to these amendments, no ANDA had contained a paragraph IV
certification to a patent listed for Litigatolol. Applicant B
prematurely submitted its amendment containing a paragraph IV
certification, and its notice of paragraph IV certification is invalid
because it was sent before the first full working day after the patent
is listed in the Orange Book. Only Applicant C has submitted the first
substantially complete ANDA containing a paragraph IV certification for
purposes of first applicant eligibility.
    It should be noted that if there is a delay between FDA's receipt
of new patent information and publication of the patent information in
the Orange Book, the actual date of publication of the patent
information in the Orange Book provides the date from which the
validity of the ANDA applicant's notice of paragraph IV certification
will be assessed for purposes of first applicant eligibility (compare
section II.D.3 regarding determination of a 505(b)(2) or ANDA
applicant's patent certification obligations and the availability of a
30-month stay based on patent information in FDA's possession).
    II.D.1.c. Certification of provision of notice. We are proposing to
amend Sec. Sec.  314.52(b) and 314.95(b) by revising and redesignating
certain text as new paragraph (b)(3). Proposed Sec. Sec.  314.52(b)(3)
and 314.95(b)(3) describe the current requirement for 505(b)(2) and
ANDA applicants, respectively, to amend their applications at the time
that they provide notice of a paragraph IV certification to include a
statement certifying that notice has been provided to the NDA holder
and each patent owner as required by Sec. Sec.  314.52(a) and 314.95(a)
and has met the content requirements for notice of a paragraph IV
certification as described in Sec. Sec.  314.52(c) and 314.95(c). We
are proposing to clarify that a copy of the notice of paragraph IV
certification itself does not need to be submitted to FDA in the
amendment.
    We describe acceptable methods for delivery of notice of paragraph
IV certification and documentation of timely delivery and receipt of
such notice in section II.D.4.
II.D.2. Notice Required for All Paragraph IV Certifications
    The MMA requires applicants submitting 505(b)(2) applications and
ANDAs to provide notice for all paragraph IV certifications submitted
to FDA on or after August 18, 2003, regardless of whether the applicant
had previously given notice of a paragraph IV certification contained
in its application or an amendment or supplement to the application
(see section 505(b)(3)(B) and (j)(2)(B)(ii) of the FD&C Act).
    We are proposing to require a 505(b)(2) or ANDA applicant to
provide a new notice of paragraph IV certification to a patent for
which it previously had provided notice if the applicant submits an
amendment or supplement to the 505(b)(2) application or ANDA for
certain changes to the proposed product that should be accompanied by a
new patent certification (see section II.F).
II.D.3. Contents of Notice
    We are proposing to revise Sec. Sec.  314.52(c) and 314.95(c)
regarding the contents of notice of a paragraph IV certification to
incorporate requirements added by the MMA and to support the efficient
enforcement of our regulations. We note, however, that the Agency
neither assesses the adequacy of the contents of a 505(b)(2) or ANDA
applicant's notice of paragraph IV certification nor the applicant's
stated basis for certifying that a listed patent is invalid,
unenforceable, or will not be infringed by its proposed drug product.
In our final rule implementing the patent and exclusivity provisions of
the Hatch-Waxman amendments, we stated that ``the agency does not have
the expertise or the desire to become involved in issues concerning
patent law and sufficiency of notice. . . . Disputes involving the
sufficiency of the notice [i.e., the detailed statement of the factual
and legal basis behind the applicant's opinion that the patent is
invalid, unenforceable, or not infringed] must be resolved by the
applicant, patent owner, and holder of the approved application rather
than by action on the part of FDA'' (59 FR 50338 at 50349, October 3,
1994).
    We also are revising Sec. Sec.  314.52(c) and 314.95(c) to require
the 505(b)(2) or ANDA applicant to cite section 505(b)(3)(D) and
(j)(2)(B)(iv), respectively, as amended by the MMA, in the notice of
paragraph IV certification.
    Table 7 summarizes the proposed changes related to content of a
notice of paragraph IV certification.

Table 7--Highlights of Proposed Changes Regarding Content of a Notice of
                     Paragraph IV Certification \1\
------------------------------------------------------------------------
                                                Proposed revisions to
            Current regulations                      regulations
------------------------------------------------------------------------
Content of a notice (Sec.  Sec.             Content of a notice (Sec.
 314.52(c)) and 314.95(c))                   Sec.   314.52(c)) and
                                             314.95(c))
 The 505(b)(2) or ANDA applicant     The 505(b)(2) or
 must cite section 505(b)(3)(B) or           ANDA applicant must cite
 505(j)(2)(B)(ii) of the FD&C Act, as        section 505(b)(3)(D) or
 appropriate, and the notice must also       505(j)(2)(B)(iv) of the
 include, but not be limited to, the         FD&C Act, as appropriate,
 following information:                      and the notice must also
                                             include, but is not limited
                                             to, the following
                                             information:
    --(1) A statement that a 505(b)(2)         --(1) A statement that a
     application submitted by the               505(b)(2) application
     applicant has been filed by FDA; or a      that contains any
     statement that FDA has received an         required BA or BE data
     ANDA submitted by the applicant            has been submitted by
     containing any required                    the applicant and filed
     bioavailability (BA) or                    by FDA; or a statement
     bioequivalence (BE) data or                that FDA has received an
     information.                               ANDA submitted by the
                                                applicant containing any
                                                required BA or BE data
                                                or information.
    --(2) The NDA or ANDA number.              --(2) The NDA or ANDA
                                                number.
    --(3) The established name, if any, of     --(3) A statement that
     the proposed drug product.                 the applicant has
    --(4) The active ingredient, strength,      received the
     and dosage form of the proposed drug       acknowledgment letter or
     product.                                   paragraph IV
                                                acknowledgment letter
                                                for the 505(b)(2)
                                                application or ANDA.
    --(5) The patent number and expiration     --(4) The established
     date, as submitted to the Agency or        name, if any, of the
     as known to the applicant, of each         proposed drug product.
     patent alleged to be invalid,          --(5) The active ingredient,
     unenforceable, or not infringed.        strength, and dosage form
    --(6) A detailed statement of the        of the proposed drug
     factual and legal basis of the          product.
     applicant's opinion that the patent    --(6) The patent number and
     is not valid, unenforceable, or will    expiration date of each
     not be infringed.                       patent on the list alleged
    --(7) If the applicant does not reside   to be invalid,
     or have a place of business in the      unenforceable, or not
     U.S., the name and address of an        infringed.
     agent in the U.S. authorized to        --(7) A detailed statement
     accept service of process for the       of the factual and legal
     applicant.                              basis of the applicant's
                                             opinion that the patent is
                                             not valid, unenforceable,
                                             or will not be infringed.
                                            --(8) If the applicant
                                             alleges that the patent
                                             will not be infringed and
                                             may later decide to file a
                                             civil action for
                                             declaratory judgment in
                                             accordance with section
                                             505(c)(3)(D) and
                                             505(j)(5)(C) of the FD&C
                                             Act, then the notice must
                                             be accompanied by an offer
                                             of confidential access to
                                             the 505(b)(2) application
                                             or ANDA for the sole and
                                             limited purpose of
                                             evaluating possible
                                             infringement of the patent
                                             that is the subject of the
                                             paragraph IV certification.
                                               --(9) If the applicant
                                                does not reside or have
                                                a place of business in
                                                the U.S., the name and
                                                address of an agent in
                                                the U.S. authorized to
                                                accept service of
                                                process for the
                                                applicant.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
  regulations, but should not be relied upon in place of the proposed
  regulation.

    II.D.3.a. Statement that any required bioavailability or
bioequivalence studies for a 505(b)(2) application have been submitted.
The MMA amended the FD&C Act to require that the notice of paragraph IV
certification for a 505(b)(2) application include a statement that ``an
application that contains data from bioavailability or bioequivalence
studies'' has been submitted to FDA (section 505(b)(3)(D)(i) of the
FD&C Act). This statutory provision parallels the content requirements
for notice of paragraph IV certification for an ANDA (see section
505(j)(2)(B)(iv)(I) of the FD&C Act). Consistent with our previous
implementation of the statutory requirement for ANDAs in Sec.
314.95(c), proposed Sec.  314.52(c)(1) requires that a notice of a
paragraph IV certification for a 505(b)(2) application state that data
from ``any required bioavailability or bioequivalence studies''
(emphasis added) have been submitted. This qualifier reflects that FDA
may exercise its scientific judgment to determine what bioavailability
and bioequivalence studies may be needed for certain 505(b)(2)
applications and ANDAs (see, e.g., Sec.  314.54(a)(1) and (a)(2)
(citing Sec. Sec.  314.50(d)(3) and 320.21(a)(2) and (f)); compare
Sec.  320.21(b)(2)).
    A 505(b)(2) application may seek to rely upon non-product-specific
published literature or other studies necessary for approval for which
the applicant has no right of reference or use. This type of 505(b)(2)
application generally would not require studies showing relative
bioavailability or bioequivalence because the 505(b)(2) application is
not relying upon the Agency's finding of safety and/or effectiveness
for a listed drug. In the absence of a listed drug, there is not likely
to be a specific drug for use as a comparator in a relative
bioavailability or bioequivalence study. However, such a 505(b)(2)
application must establish that reliance on the studies described in
the literature is scientifically appropriate. Further, a 505(b)(2)
application that did not rely upon a listed drug would not require a
patent certification or statement, and thus there would be no occasion
for a notice of paragraph IV certification.
    II.D.3.b. Statement confirming receipt of an acknowledgment letter
or a paragraph IV acknowledgment letter. We are proposing to revise
Sec. Sec.  314.52(c)(3) and 314.95(c)(3) to add a new requirement for
505(b)(2) and ANDA applicants, respectively, to facilitate compliance
with and enforcement of section 505(b)(3)(B)(i), (b)(3)(B)(ii),
(j)(2)(B)(ii)(I), and (j)(2)(B)(ii)(II) of the FD&C Act regarding the
timing of notice of paragraph IV certification. Proposed Sec. Sec.
314.52(c)(3) and 314.95(c)(3) require a 505(b)(2) and ANDA applicant,
respectively, to include a statement in its notice of paragraph IV
certification that the applicant has received an acknowledgment letter
or a paragraph IV acknowledgment letter for its 505(b)(2) application
or ANDA. This requirement is intended to ensure that a notice of
paragraph IV certification is not sent before FDA has determined that
the 505(b)(2) application or ANDA containing the certification is
acceptable for substantive review and has issued an acknowledgment
letter or a paragraph IV acknowledgment letter (see section II.D.1.a).
    II.D.3.c. Documentation that paragraph IV certification was
submitted and notice was sent only for patents listed in the Orange
Book. We are proposing to revise Sec. Sec.  314.52(c)(6) and
314.95(c)(6) to specify that notice of a paragraph IV certification
(and therefore the underlying paragraph IV certification as well) must
only be sent for a patent that is listed in the Orange Book for the
listed drug(s) relied upon

for a 505(b)(2) application or for the RLD for an ANDA. We are
proposing to add the phase ``on the list'' to proposed Sec. Sec.
314.52(c)(6) and 314.95(c)(6) to qualify the patents for which a notice
of paragraph IV certification must be sent.
    As discussed in section II.D.4.b, we are proposing to require an
ANDA applicant to include a dated printout of the Orange Book entry for
the RLD that includes the patent that is the subject of the notice of
paragraph IV certification in its amendment certifying that notice of
paragraph IV certification has been sent and documenting that notice
has been received (see proposed Sec.  314.95(e)). A 505(b)(2) applicant
may elect to submit a copy of the Orange Book patent listing for the
listed drug(s) relied upon with its 505(b)(2) application, amendment,
or supplement containing a paragraph IV certification to describe the
applicant's understanding of the most current patent information listed
in the Orange Book at the time of submission. We note, however, that a
505(b)(2) or ANDA applicant's patent certification obligations and the
availability of a 30-month stay under section 505(c)(3)(C) and
(j)(5)(B)(iii) of the FD&C Act are determined based on patent
information in FDA's possession, even if such information is not
accurately listed in the Orange Book (see Teva Pharms., USA, Inc. v.
Leavitt, 548 F.3d 103, at 105 (D.C. Cir. 2008) (``FDA insists reality
matters'')).
    In addition, we are proposing to delete the phrase ``as submitted
to the agency or as known to the applicant'' from Sec. Sec.
314.52(c)(6) and 314.95(c)(6), as this phrase is over-inclusive. It
does not accurately describe the universe of patents for which a
paragraph IV certification may be submitted and thus is inapplicable to
the content requirements for notice of a paragraph IV certification.
Although an applicant may submit a certification pursuant to section
505(b)(2)(A)(i) or 505(j)(2)(A)(vii)(I) of the FD&C Act (``paragraph I
certification'') with respect to patent information that has not been
filed with FDA and is not listed in the Orange Book, such a patent
could not be the basis for a paragraph IV certification.
    II.D.3.d. Offer of confidential access accompanying notice. The MMA
established conditions under which a 505(b)(2) or ANDA applicant may
bring a declaratory judgment action to obtain ``patent certainty''
(i.e., obtain a judicial determination of noninfringement, invalidity,
or unenforceability) with respect to a listed patent for which it has
given notice of a paragraph IV certification but has not been sued by
the NDA holder or any patent owner within the statutory timeframe (see
section 505(c)(3)(D) and (j)(5)(C) of the FD&C Act). As a precondition
to filing an action for declaratory judgment to establish patent
noninfringement (as distinguished from patent invalidity or
unenforceability), the applicant must provide a document offering the
NDA holder and each patent owner confidential access to the 505(b)(2)
application or ANDA for the sole and limited purpose of assessing
patent noninfringement (see section 505(c)(3)(D)(i)(III) and
(j)(5)(C)(i)(III) of the FD&C Act). Because this offer of confidential
access, if made, is required to accompany the notice of paragraph IV
certification, we are proposing to revise Sec. Sec.  314.52(c) and
314.95(c) to reference the statutory requirement for an offer of
confidential access (see section 505(c)(3)(D)(i)(I)(cc) and
(j)(5)(C)(i)(I)(cc) of the FD&C Act). Our proposed regulations do not
otherwise address the offer of confidential access because the process
for seeking a declaratory judgment does not involve FDA.
II.D.4. Documentation of Timely Sending and Receipt of Notice
    We are proposing to revise Sec. Sec.  314.52(e) and 314.95(e) to
clarify the requirements for submission of an amendment to a 505(b)(2)
application or ANDA, respectively, containing documentation of timely
sending of notice of paragraph IV certification and confirmation of
receipt of same by the NDA holder and each patent owner. In addition,
we are proposing to revise Sec. Sec.  314.52 and 314.95 to expand the
list of acceptable delivery methods that may be used to send notice of
paragraph IV certification to the NDA holder and each patent owner.
These proposed revisions are intended to facilitate compliance with the
statutory requirements regarding timing of notice of paragraph IV
certification and related regulatory provisions.
    Table 8 summarizes the proposed changes regarding documentation of
timely sending and receipt of notice of paragraph IV certification:

   Table 8--Highlights of Proposed Changes Regarding Documentation of
 Timely Sending and Receipt of Notice of Paragraph IV Certification \1\
------------------------------------------------------------------------
        Current regulations           Proposed revisions to regulations
------------------------------------------------------------------------
Notice of certification (Sec.  Sec.  Notice of certification (Sec.  Sec.
   314.52(a) and 314.95(a))             314.52(a) and 314.95(a))
 505(b)(2) or ANDA            505(b)(2) or ANDA
 applicant must send notice of        applicant must send notice of
 paragraph IV certification by        paragraph IV certification by
 registered or certified mail,        registered or certified mail,
 return receipt requested, to each    return receipt requested, or by a
 patent owner and the NDA holder.     designated delivery service, to
                                      each patent owner and the NDA
                                      holder.
                                      505(b)(2) or ANDA
                                      applicant may send notice by an
                                      alternative method only if FDA has
                                      agreed in advance that the method
                                      will produce an acceptable form of
                                      documentation.
Documentation of receipt of notice   Documentation of timely sending and
 (Sec.  Sec.   314.52(e) and          receipt of notice (Sec.  Sec.
 314.95(e))                           314.52(e) and 314.95(e))
 Applicant must amend its     Applicant must amend its
 505(b)(2) application or ANDA to     505(b)(2) application or ANDA to
 document the date of receipt of      provide documentation of the date
 the notice of paragraph IV           of receipt of the notice of
 certification by each patent owner   paragraph IV certification by each
 and NDA holder provided the          patent owner and NDA holder
 notice.                              provided the notice.
 Applicant must include a    --FDA will accept as adequate
 copy of the return receipt or        documentation of the date of
 other similar evidence of the date   receipt a return receipt,
 the notification was received.       signature proof of delivery by a
--FDA will accept as adequate         designated delivery service, or a
 documentation of the date of         letter acknowledging receipt by
 receipt a return receipt or a        the person provided notice.
 letter acknowledging receipt by
 the person provided the notice.
 An applicant may rely on    --Amendment must be submitted to
 another form of documentation only   FDA within 30 days after the last
 if FDA has agreed to such            date on which notice was received
 documentation in advance.            by a patent owner or NDA holder.

                                      Amendment also must
                                      include adequate documentation
                                      that notice was sent on a date
                                      that complies with the timeframe
                                      required by Sec.   314.52(b) or
                                      (d) or Sec.   314.95(b) or (d), as
                                      applicable.
                                     --FDA will accept a copy of the
                                      registered mail receipt, certified
                                      mail receipt, or receipt from a
                                      designated delivery service, as
                                      adequate documentation of the date
                                      of delivery.
                                      An ANDA applicant's
                                      amendment must include a dated
                                      printout of the Orange Book entry
                                      for the RLD that includes the
                                      patent that is the subject of the
                                      paragraph IV certification.
                                      An applicant may rely on
                                      another form of documentation only
                                      if FDA has agreed in advance.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
  regulations, but should not be relied upon in place of the proposed
  regulation.

    II.D.4.a. Acceptable methods of sending notice of paragraph IV
certification. A 505(b)(2) or ANDA applicant currently is required to
send notice of a paragraph IV certification to the NDA holder and each
patent owner by registered or certified mail, return receipt requested,
unless FDA agrees in advance to another method of delivery (see
Sec. Sec.  314.52(a) and (e) and 314.95(a) and (e)). We are proposing
to revise Sec. Sec.  314.52(a) and (e) and 314.95(a) and (e) to provide
applicants with the option of sending notice of paragraph IV
certification by a designated delivery service, as defined in proposed
Sec. Sec.  314.52(g)(1) and 314.95(g)(1). Section 505(b)(2) and ANDA
applicants often request permission to send notice of a paragraph IV
certification by a major commercial delivery service instead of the
U.S. Postal Service (for example, to send notice of a paragraph IV
certification to a patent owner who resides outside of the United
States). Because we routinely grant these requests, we are proposing to
amend our regulations to provide the option to all 505(b)(2) and ANDA
applicants to send notice of paragraph IV certification by the U.S.
Postal Service or a designated delivery service. We propose to define a
``designated delivery service'' in Sec. Sec.  314.52(g)(1) and
314.95(g)(1) to mean any delivery service provided by a trade or
business that the Agency determines: (1) Is available to the general
public throughout the United States; (2) records electronically to its
database, kept in the regular course of its business, or marks on the
cover in which any item referred to in this section is to be delivered,
the date on which such item was given to such trade or business for
delivery; and (3) provides overnight or 2-day delivery service
throughout the United States.
    This proposed definition is adapted from definition of ``designated
delivery service'' in 26 U.S.C. 7502(f)(2) (governing timely mailing
treated as timely filing and paying by the IRS). As noted in proposed
Sec. Sec.  314.52(g)(2) and 314.95(g)(2), FDA will periodically issue
guidance describing designated delivery services that meet these
criteria.
    Our proposal to revise Sec. Sec.  314.52(a) and (e) and 314.95(a)
and (e) to provide applicants with the option of sending notice of
paragraph IV certification by a designated delivery service, as defined
in proposed Sec. Sec.  314.52(g)(1) and 314.95(g)(1), differs from an
earlier proposal to provide additional methods of sending notice of
paragraph IV certification (see ``New Drugs for Human Use;
Clarification of Requirements for Patent Holder Notification; Proposed
Rule'' 63 FR 11174; March 6, 1998) (Patent Holder Notification proposed
rule). The Patent Holder Notification proposed rule would have
permitted a 505(b)(2) or ANDA applicant to send notice of paragraph IV
certification ``by mail or personal delivery'' (including overnight
delivery service, electronic mail, and facsimile) if the applicant
obtained a verification of receipt. We received comments objecting to
certain aspects of the Patent Holder Notification Proposed Rule--in
particular, notice by electronic methods of delivery such as electronic
mail or facsimile--and withdrew the proposed rule (see ``New Drugs for
Human Use; Clarification of Requirements for Patent Holder
Notification; Withdrawal'' 65 FR 12154; March 8, 2000) (Withdrawal of
Patent Holder Notification proposed rule). With respect to notification
by overnight delivery service, two comments on the Patent Holder
Notification proposed rule supported this alternate method of delivery
if a signed verification of receipt of notice by the NDA holder or each
patent owner was provided (see Docket No. FDA-1997-P-0417-0011 and FDA-
1997-P-0417-0012, available at http://www.regulations.gov). Another
comment objected to notification by overnight delivery service because
receipt of bulk deliveries (containing multiple envelopes and packages)
to large corporations is acknowledged by a single signature. This
commenter expressed concern that an overnight delivery service envelope
containing a notice of paragraph IV certification may not ensure timely
receipt by a responsible person. Given that receipt of notice of
paragraph IV certification begins a statutory 45-day period within
which a patent infringement action must be filed to obtain, under
certain circumstances, a 30-month stay, a signature acknowledging
receipt of the specific envelope was preferred by this commenter (see
Docket No. FDA-1997-P-0417-0010, available at http://www.regulations.gov).
    In light of the frequency with which FDA receives requests to send
notice by overnight delivery services, we invite comment on our current
proposal to provide applicants with the option of sending notice of
paragraph IV certification by a designated delivery service, as defined
in proposed Sec. Sec.  314.52(g)(1) and 314.95(g)(1).
    We also are proposing to add Sec. Sec.  314.52(a)(4) and
314.95(a)(4) and revise Sec. Sec.  314.52(e) and 314.95(e) to clarify
that a 505(b)(2) or ANDA applicant may send notice of paragraph IV
certification by an alternative method (i.e., a method other than
registered or certified mail, return receipt requested, or a designated
delivery service) only if FDA has agreed in advance that the method
will produce an acceptable form of documentation.
    In addition, we are proposing to revise the introductory text of
Sec.  314.52(a) to refer to each patent that claims the listed drug or
drugs relied upon or that claims a use for such listed drug or drugs
and for which the applicant submits a paragraph IV certification. This
revision is proposed

for clarity and does not represent a substantive change.
    II.D.4.b. Amendment documenting timely sending and confirmation of
receipt of notice of paragraph IV certification. We are proposing to
revise Sec. Sec.  314.52(e) and 314.95(e) to facilitate implementation
of section 505(b)(3)(B)(i), (b)(3)(B)(ii), (j)(2)(B)(ii)(I), and
(j)(2)(B)(ii)(II) of the FD&C Act and for the efficient enforcement of
the FD&C Act.
    A 505(b)(2) or ANDA applicant that has submitted one or more
paragraph IV certifications currently must submit an amendment to its
application documenting the date on which notice of paragraph IV
certification was received by the NDA holder and each patent owner (see
Sec. Sec.  314.52(e) and 314.95(e)). As discussed in section II.D.1.b,
the MMA amended the FD&C Act to require that a 505(b)(2) and ANDA
applicant provide notice of a paragraph IV certification in accordance
with the timeframes described in section 505(b)(3)(B)(i),
(b)(3)(B)(ii), (j)(2)(B)(ii)(I), and (j)(2)(B)(ii)(II) of the FD&C Act
(see proposed Sec. Sec.  314.52(b) and (d) and 314.95(b) and (d)). Our
proposed revisions to Sec. Sec.  314.52(e) and 314.95(e) require a
505(b)(2) and ANDA applicant, respectively, to establish compliance
with this statutory requirement by also submitting in its amendment
documentation that the notice of paragraph IV certification was sent on
a date that complies with the timeframe required by Sec.  314.52(b) or
(d) or Sec.  314.95(b) or (d), as applicable. For administrative
efficiency, we are proposing to require that a 505(b)(2) or ANDA
applicant submit the amendment containing documentation of timely
sending and receipt of notice of paragraph IV certification within 30
days after the last date on which notice was received by a person
described in Sec.  314.52(a) or Sec.  314.95(a), respectively.
    The proposed requirement for documentation that notice of paragraph
IV certification was timely sent can be satisfied by submitting a copy
of the registered mail receipt or certified mail receipt issued by the
U.S. Postal Service that bears a postmark documenting the date of
mailing or by submitting a copy of the receipt from a designated
delivery service, as defined in proposed Sec. Sec.  314.52(g) and
314.95(g). With respect to documentation of the date of receipt of
notice of paragraph IV certification, we are proposing to revise
Sec. Sec.  314.52(e) and 314.95(e) to include acceptance of signature
proof of delivery by a designated delivery service as adequate
documentation. A single document may be adequate to document both
timely sending and receipt of notice of paragraph IV certification if
it contains the information required by proposed Sec. Sec.  314.52(e)
and 314.95(e).
    In addition, we are proposing to require that ANDA applicants
include in their amendment a dated printout of the Orange Book entry
for the RLD that includes the patent that is the subject of the notice
of paragraph IV certification. This requirement is intended to ensure
that a paragraph IV certification that may qualify an ANDA applicant
for 180-day exclusivity is submitted only for a listed patent and is
not prematurely or inappropriately sent before the first working day
after the day the patent is listed in the Orange Book (see proposed
Sec. Sec.  314.95(b)(2) and 314.94(a)(12)(viii)(C)(1)(ii)).
    The following example illustrates our approach: The NDA holder
timely submits Form FDA 3542 to the Office of Generic Drugs, Document
Room, Attention: Orange Book Staff, at 4 p.m., Eastern Standard Time,
on the 30th day after issuance of the '456 patent claiming the drug
product Procrastinadipine. Form FDA 3542 is date-stamped by the Office
of Generic Drugs, Document Room on Friday, October 1 and listed in the
Orange Book on the afternoon of Monday, October 4. Applicant D and
Applicant E have submitted ANDAs for Procrastinadipine and each has
received an acknowledgment letter indicating that its ANDA has been
received for substantive review.
    Applicant D is aware that the '456 patent was issued by the PTO on
September 1 and understands that for the '456 patent to be timely filed
under section 505(c)(2) of the FD&C Act, the NDA holder must file the
patent information with FDA no later than October 1. Applicant D
submits an amendment to its ANDA containing a paragraph IV
certification to the '456 patent and sends notice to the NDA holder and
each patent owner on October 1 in an effort to have submitted the first
substantially complete ANDA containing a paragraph IV certification to
a patent listed for Procrastinadipine. However, Applicant D is unable
to submit the required printout (see proposed Sec.  314.95(b)(2)) of
the Orange Book entry for the RLD that includes the patent that is the
subject of the paragraph IV certification because the '456 patent has
not yet been listed in the Orange Book. Applicant E submits on Tuesday,
October 5 (i.e., the first working day after the day the patent is
listed in the Orange Book) an amendment to its ANDA containing a
paragraph IV certification to the '456 patent and the required printout
of the Orange Book entry and sends notice to the NDA holder and each
patent owner on that same day.
    Prior to these amendments, no ANDA had contained a paragraph IV
certification to a patent listed for Procrastinadipine. Applicant D's
notice of paragraph IV certification is premature and thus invalid
because the '456 patent had not yet been listed in the Orange Book.
Only Applicant E has submitted the first substantially complete ANDA
containing a paragraph IV certification for purposes of first applicant
eligibility.
II.D.5. Administrative Consequence for Late Notice
    The MMA does not specify a consequence for 505(b)(2) or ANDA
applicants that do not send notice of a paragraph IV certification
within the timeframe required by the FD&C Act (i.e., within 20 days
after the date of the postmark on the paragraph IV acknowledgment
letter or on the date that an amendment or supplement containing a
paragraph IV certification is submitted to FDA). In response to our
Request for MMA Comments, we received comments suggesting that we
create an administrative consequence for late notice (see, e.g., PhRMA
MMA Comment at 1 to 2). In light of the importance of the timing of
sending notice of paragraph IV certification to the statutory scheme,
we agree that it is appropriate to propose an administrative
consequence for ANDA applicants who are late in providing notice.
    After considering several suggestions for administrative
consequences, including those submitted to us in response to our
Request for MMA Comments, we are proposing to address ANDA applicants
that fail to timely provide notice of a paragraph IV certification by
moving forward the date of submission of the ANDA by the number of days
beyond the required time frame that the applicant delayed in sending
its notice (see proposed Sec.  314.101(b)(4)). Consequently, an ANDA
applicant may lose its first applicant status and thus its eligibility
for 180-day exclusivity as a result of providing late notice (see
section 505(j)(5)(B)(iv) of the FD&C Act), if another applicant submits
a substantially complete ANDA containing a paragraph IV certification
on the same first day and provides timely notice. Also, an ANDA
applicant that fails to timely provide notice of paragraph IV
certification may experience a delay in the review queue for its ANDA
consistent with the revised date of submission. We note that this
proposed administrative consequence

would not reduce the 30-month timeframe set forth in section
505(j)(5)(D)(i)(I)(aa)(BB) and (j)(5)(D)(i)(IV) of the FD&C Act in the
forfeiture calculus for a first applicant; rather, the 30-month period
would begin on the revised date of submission.
    We believe that the proposed administrative consequence for ANDA
applicants appropriately balances the purposes served by the
requirement for timely notice of paragraph IV certifications with the
legislative goal of speeding the availability of lower cost
alternatives to approved drugs. Certain options we considered as
alternatives did not seem to provide as measured a balance. For
example, we considered deeming paragraph IV certifications for which
notice had been provided after the statutory timeframe to not be
``lawfully maintained'' (see section 505(j)(5)(B)(iv)(bb) of the FD&C
Act). Under this interpretation, however, an ANDA applicant would
certainly lose its eligibility for 180-day exclusivity as a result of
sending late notice, regardless of the amount of time its notice was
delayed (e.g., even if its notice were one day late). We decline to
adopt this approach because it seems disproportionately punitive.
    We are not proposing a similar consequence for 505(b)(2) applicants
that fail to timely provide notice of a paragraph IV certification
because 505(b)(2) applicants are not eligible for 180-day exclusivity
and we are unable to extend the review clock as an administrative
consequence for an NDA (including a 505(b)(2) application) subject to
the Prescription Drug User Fee Act Reauthorization Performance Goals
and Procedures (see http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm119243.htm; see also 21 CFR 314.100). As
described below, we considered other possible administrative
consequences for any 505(b)(2) applicants that fail to provide notice
of a paragraph IV certification within the statutory timeframe;
however, we are declining to propose an administrative consequence at
this time.
    The implications of late notice of a paragraph IV certification by
a 505(b)(2) applicant differ from those of an ANDA applicant that may
otherwise be eligible for 180-day exclusivity. A 505(b)(2) application
that contains a paragraph IV certification could not be approved until
the 505(b)(2) applicant had provided notice of its paragraph IV
certification to the NDA holder and each patent owner and the
respective 45-day periods for each recipient of notice had expired
without the filing of a legal action for patent infringement (see Sec.
314.107(f)(2)). A 505(b)(2) applicant that provides late notice of a
paragraph IV certification risks that the NDA holder or patent owner
will file an action for patent infringement within the 45-day period
after notice, and that any resultant 30-month stay will delay approval
by a period of time commensurate with the 505(b)(2) applicant's delay
in providing notice of its paragraph IV certification. We considered
the suggestion, submitted in response to our Request for MMA Comments,
that we ``creat[e] an automatic regulatory presumption which could be
used by the court hearing the patent infringement action that the ANDA
or 505(b)(2) applicant `failed to reasonably cooperate in expediting
the action' within the meaning of [section 505(c)(3)(C) and
(j)(5)(B)(iii) of the FD&C Act]'' (see PhRMA MMA Comment at 2).
However, we decline to propose this approach because it is not
necessary to properly implement the statutory goal of adequate notice
and opportunity to defend certain intellectual property rights prior to
approval.

II.E. Amended Patent Certifications (Proposed Sec. Sec.  314.50(i)(6)
and 314.94(a)(12)(viii))

    We are proposing to revise Sec. Sec.  314.50(i)(6) and
314.94(a)(12)(viii) regarding submission of amended patent
certifications by 505(b)(2) and ANDA applicants, respectively, to
reflect revisions to the FD&C Act made by the MMA and for the efficient
enforcement of the FD&C Act. A 505(b)(2) or ANDA applicant would be
required to submit an amended patent certification to provide, for
example, a certification to a recently issued patent listed by the NDA
holder after submission of a 505(b)(2) application or ANDA that relies
upon the listed drug, or to change its certification to a patent for
which the applicant had previously submitted a patent certification. As
discussed in this section of the document, submission of an amended
patent certification also would be required for a reissued patent and
for a revision to a prior certification in the event that a patent or
patent information has been withdrawn from listing in the Orange Book.
    We are proposing to revise the introductory text of Sec.
314.94(a)(12)(viii) to remove the provision that restricts an ANDA
applicant from amending a paragraph IV certification to a paragraph III
certification in certain circumstances. Currently, Sec.
314.94(a)(12)(viii) provides that an ANDA applicant that has submitted
a paragraph IV certification may not amend its patent certification to
a paragraph III certification (delaying approval until the date on
which such patent will expire) if a patent infringement action has been
filed against another applicant that had submitted a paragraph IV
certification. The current regulation provides that an ANDA applicant
is permitted to amend its patent certification to a paragraph III
certification in these circumstances only if the Agency has determined
that no applicant is entitled to 180-day exclusivity or the patent
expired while patent infringement litigation was pending or before the
end of the 180-day exclusivity period. We have determined, however,
that it is not necessary to restrict submission of an amended patent
certification under these circumstances because 180-day exclusivity
does not extend beyond patent expiry. Accordingly, an applicant that
amended its paragraph IV certification to a paragraph III certification
would not be eligible for approval until patent expiration and thus
would not undermine a first applicant's 180-day exclusivity as to that
patent. The MMA specifically provides that a first applicant's 180-day
exclusivity would, in any event, terminate upon expiration of all of
the patents as to which the applicant submitted a paragraph IV
certification qualifying it for 180-day exclusivity (see section
505(j)(5)(D)(i)(VI) of the FD&C Act; see also Sec.
314.94(a)(12)(viii)).
    There are several circumstances in which amending to a paragraph
III certification is appropriate, including when an applicant is no
longer seeking approval before the patent expires or when required by
the terms of a settlement agreement between parties in patent
infringement litigation. This proposal would facilitate amendment of
paragraph IV certifications to paragraph III certifications in such
circumstances.
    We also are proposing to revise Sec. Sec.  314.50(i)(6)(i) and
314.94(a)(12)(viii) to require that a 505(b)(2) or ANDA applicant
submit an amended patent certification as an amendment to its pending
application (including a supplemental 505(b)(2) application or
supplemental ANDA (see Sec. Sec.  314.70(i) and 314.97(c),
respectively)) and not by letter. This requirement will facilitate
appropriate management of amended patent certifications.
    Table 9 summarizes the proposed changes regarding amended patent
certifications:

    Table 9--Highlights of Proposed Changes Regarding Amended Patent
                            Certifications\1\
------------------------------------------------------------------------
                                                Proposed revisions to
            Current regulations                      regulations
------------------------------------------------------------------------
Amended Certifications (Sec.  Sec.          Amended Certifications (Sec.
 314.50(i)(6) and 314.94(a)(12)(viii))        Sec.   314.50(i)(6) and
                                             314.94(a)(12)(viii))
 Amended patent certification must   Amended patent
 be submitted as an amendment to a pending   certification must be
 505(b)(2) application or ANDA or by         submitted as an amendment
 letter to an approved application.          to the 505(b)(2)
                                             application or ANDA and may
                                             no longer be submitted by
                                             letter.
Amended Certifications (Sec.                Amended Certifications (Sec.
 314.94(a)(12)(viii) only)                     314.94(a)(12)(viii) only)
 ANDA applicants restricted from     Deletion of
 amending a paragraph IV certification to    restriction on ANDA
 a paragraph III certification in certain    applicants from amending a
 circumstances when another ANDA applicant   paragraph IV certification
 has been sued for patent infringement.      to a paragraph III
                                             certification.
After a Finding of Infringement (Sec.       After a Finding of
 Sec.   314.50(i)(6)(i) and                  Infringement (Sec.  Sec.
 314.94(a)(12)(viii)(A))                     314.50(i)(6)(i) and
                                             314.94(a)(12)(viii)(A))
                                             Change from
                                             paragraph IV certification
                                             to paragraph III
                                             certification required
                                             after a final judgment is
                                             entered finding the patent
                                             to be infringed.
                                             Provision applies
                                             if patent infringement
                                             action initiated within 45
                                             days of receipt of notice
                                             of paragraph IV
                                             certification.
                                             Change from
                                             paragraph IV certification
                                             to paragraph III
                                             certification required
                                             after court enters final
                                             decision from which no
                                             appeal has been or can be
                                             taken, or signs settlement
                                             order or consent decree
                                             with a finding of
                                             infringement (unless the
                                             patent also is found
                                             invalid). An applicant may
                                             instead provide a statement
                                             under Sec.
                                             314.50(i)(1)(iii) or Sec.
                                             314.94(a)(12)(iii) with
                                             respect to a method-of-use
                                             patent if the 505(b)(2)
                                             application or ANDA is
                                             amended such that the
                                             applicant is no longer
                                             seeking approval for a
                                             method of use claimed by
                                             the patent.
                                             Provision applies
                                             if patent infringement
                                             action initiated after
                                             receipt of notice of
                                             paragraph IV certification,
                                             irrespective of whether the
                                             action is brought within
                                             the 45-day period.
After Removal of a Patent from the List     After Request to Remove a
 (Sec.  Sec.   314.50(i)(6)(ii) and          Patent or Patent
 314.94(a)(12)(viii)(B))                     Information from the List
 If a patent is removed from the     (Sec.  Sec.
 list, any applicant with a pending          314.50(i)(6)(ii) and
 application (including a tentatively        314.94(a)(12)(viii)(B))
 approved application with a delayed         If the list
 effective date) who has made a              reflects that an NDA holder
 certification with respect to such patent   has requested that a patent
 must amend its certification.               be removed from the list
 A patent that is the subject of a   and:
 lawsuit under Sec.   314.107(c) shall not  --no ANDA applicant is
 be removed from the list until FDA          eligible for 180-day
 determines either that no delay in          exclusivity based on a
 effective dates of approval is required     paragraph IV certification
 under that section as a result of the       to that patent, the patent
 lawsuit, that the patent has expired, or    will be removed and any
 that any such period of delay in            applicant with a pending
 effective dates of approval is ended.       505(b)(2) application or
 Applicant must submit a ``no        ANDA (including a
 relevant patents'' certification or, if     tentatively approved
 other relevant patents claim the drug,      505(b)(2) application or
 must amend the patent certification to      ANDA) who has certified to
 refer only to those relevant patents.       that patent must submit an
                                             amendment to withdraw the
                                             certification.
                                            --one or more first
                                             applicants are eligible for
                                             180-day exclusivity based
                                             on a paragraph IV
                                             certification to that
                                             patent, the patent shall
                                             remain listed until any 180-
                                             day exclusivity is
                                             extinguished.
                                             If one or more
                                             first applicants are
                                             eligible for 180-day
                                             exclusivity based on a
                                             paragraph IV certification
                                             to a patent that has been
                                             reissued, then the first
                                             applicant must submit a
                                             paragraph IV certification
                                             to the reissued patent
                                             within 30 days of listing
                                             to have lawfully maintained
                                             its paragraph IV
                                             certification for purposes
                                             of eligibility for 180-day
                                             exclusivity.
                                             A 505(b)(2)
                                             applicant is not required
                                             to provide or maintain a
                                             certification to a patent
                                             that remains listed only
                                             for purposes of a first
                                             applicant's 180-day
                                             exclusivity.
                                             After any
                                             applicable 180-day
                                             exclusivity period has
                                             ended, the patent will be
                                             removed and any pending
                                             ANDA (including a
                                             tentatively approved ANDA)
                                             that contains a
                                             certification to the patent
                                             must be amended to withdraw
                                             the certification.
                                             If removal of a
                                             patent from the list
                                             results in no patents
                                             listed for the listed
                                             drug(s) identified in the
                                             505(b)(2) application or
                                             ANDA, the applicant must
                                             submit an amended
                                             certification reflecting
                                             that there are no listed
                                             patents.
Late submission of patent information       Untimely filing of patent
 (Sec.  Sec.   314.50(i)(4) and              information (Sec.  Sec.
 314.94(a)(12)(vi))                          314.50(i)(4) and
                                             314.94(a)(12)(vi))
     If a patent on the listed       (see Table 3)
     drug is issued and the NDA holder for
     the listed drug does not submit the
     required information on the patent
     within 30 days of patent issuance, an
     applicant who submitted a 505(b)(2)
     application or an ANDA for that drug
     that contained an appropriate patent
     certification before the submission
     of the patent information is not
     required to submit an amended
     certification.

     An applicant whose 505(b)(2)
     application or ANDA is submitted
     after a late submission of patent
     information, or whose pending
     505(b)(2) application or ANDA was
     previously submitted but did not
     contain an appropriate patent
     certification at the time of the
     patent submission, must submit a
     certification under (Sec.
     314.50(i)(1)(i) or Sec.
     314.94(a)(12)(i) or a statement under
     Sec.   314.50(i)(1)(iii) or Sec.
     314.94(a)(12)(iii) as to that patent.
Patents Claiming the Drug Substance, Drug   Patents Claiming the Drug
 Product, or Method of Use (Sec.  Sec.       Substance, Drug Product, or
 314.50(i)(1)(i)(A) and                      Method of Use (Sec.  Sec.
 314.94(a)(12)(i)(A))                        314.50(i)(1)(i)(A) and
                                             314.94(a)(12)(i)(A))
     A 505(b)(2) application and     (No substantive
     ANDA are required to contain a patent   revisions)
     certification or statement for each    ............................
     patent issued by the PTO that, in the  ............................
     opinion of the applicant and to the    ............................
     best of its knowledge, claims the      ............................
     listed drug relied upon or RLD or      ............................
     that claims an approved use for such   ............................
     drug for which the applicant is        Other Amendments (Sec.  Sec.
     seeking approval and for which            314.50(i)(6)(iii)(A)(2)
     information is required to be filed     and
     under section 505(b) and (c) of the     314.94(a)(12)(viii)(C)(1)(i
     FD&C Act and Sec.   314.53.             i))
                                             Except as provided
                                             in Sec.  Sec.
                                             314.50(i)(4) and
                                             (i)(6)(iii)(B) and
                                             314.94(a)(12)(vi) and
                                             (a)(12)(viii)(C)(2)), an
                                             applicant must submit a
                                             patent certification or
                                             statement if, after
                                             submission of the 505(b)(2)
                                             application or ANDA, a new
                                             patent is issued by the PTO
                                             that, in the opinion of the
                                             applicant and to the best
                                             of its knowledge, claims
                                             the listed drug or RLD or
                                             that claims an approved use
                                             for such drug and for which
                                             information is required to
                                             be filed under section
                                             505(b) and (c) of the FD&C
                                             Act and Sec.   314.53.
                                             For a paragraph IV
                                             certification, the
                                             certification must not be
                                             submitted earlier than the
                                             first working day after the
                                             day the patent is published
                                             in the list.
Other Amendments (Sec.  Sec.                Other Amendments (Sec.  Sec.
 314.50(i)(6)(iii)(A) and                      314.50(i)(6)(iii)(A)(1)
 314.94(a)(12)(viii)(C)(1))                  and
                                             314.94(a)(12)(viii)(C)(1)(i
                                             ))
     [Amended patent certification   [Upon patent
     required upon patent expiration under   expiration, FDA will
     existing requirement for submission     consider the 505(b)(2) or
     of amended certification if, at any     ANDA applicant to have
     time before approval, the submitted     constructively changed its
     certification is no longer accurate.]   patent certification to a
                                             paragraph II
                                             certification.]
Other Amendments (Sec.  Sec.                Other Amendments (Sec.  Sec.
 314.50(i)(6)(iii)(B) and                      314.50(i)(6)(iii)(B) and
 314.94(a)(12)(viii)(C)(2))                  314.94(a)(12)(viii)(C)(2))
     An applicant is not required    An applicant is not
     to amend a submitted certification in   required to submit a
     response to patent information          supplement to change a
     submitted after approval of the         submitted certification in
     505(b)(2) application or ANDA (unless   response to patent
     a patent certification is required      information submitted after
     with a supplement to the 505(b)(2)      approval of the 505(b)(2)
     application or ANDA).                   application or ANDA (unless
                                             a patent certification is
                                             required with a supplement
                                             to the 505(b)(2)
                                             application or ANDA).
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
  regulations, but should not be relied upon in place of the proposed
  regulation.

II.E.1. Amended Patent Certifications After a Finding of Infringement
    We are proposing to amend Sec. Sec.  314.50(i)(6)(i) and
314.94(a)(12)(viii)(A) to reflect changes to the FD&C Act made by the
MMA that clarify the requirements for a 505(b)(2) or ANDA applicant,
respectively, to amend their paragraph IV certification after a
judicial finding of patent infringement. As further discussed in
section II.M, the MMA amended section 505(c)(3)(C) and (j)(5)(B)(iii)
of the FD&C Act to specify the types of court decisions that will
terminate a 30-month stay of approval, given that many patent
infringement actions previously had been concluded without a ``final
judgment'' regarding infringement being entered by a court. With
respect to a 505(b)(2) or ANDA applicant that had submitted a paragraph
IV certification resulting in a patent infringement action, the FD&C
Act provides that if, before the expiration of the 30-month stay of
approval, the district court hearing the patent infringement action
decides that the patent has been infringed and the district court's
judgment is either not appealed or is affirmed on appeal, the 505(b)(2)
application or ANDA may be approved on the date specified by the
district court that is not earlier than the date of expiration of the
patent (including any patent extension) and of any applicable
exclusivity (see section 505(c)(3)(C)(ii)(II) and
(j)(5)(B)(iii)(II)(bb) of the FD&C Act and 35 U.S.C. 271(e)(4)(A)).
    We are proposing to amend Sec. Sec.  314.50(i)(6)(i) and
314.94(a)(12)(viii)(A) to require that a 505(b)(2) and ANDA applicant,
respectively, submit an amendment to change its paragraph IV
certification to a paragraph III certification (stating that the patent
will expire on a specific date) or, if appropriate, to a statement
under section 505(b)(2)(B) or (j)(2)(A)(viii) of the FD&C Act if a
``court enters a final decision from which no appeal has been or can be
taken'' that the patent at issue has been infringed. After a final
court decision of patent infringement from which no appeal has been or
can be taken, a 505(b)(2) or ANDA applicant can no longer lawfully
maintain a paragraph IV certification that the patent is invalid or
will not be infringed by the manufacture, use, or sale of the drug for
which the 505(b)(2) application or ANDA has been submitted (see, e.g.,
Mylan Labs., Inc. v. Thompson, 389 F.3d 1272, 1281 (D.C. Cir. 2004)
(concluding that after the district court's finding of patent validity
and infringement, the ANDA applicant's paragraph IV certification was
``at variance with the legal reality'' and ``no longer accurate'')).
These proposed revisions to Sec. Sec.  314.50(i)(6)(i) and

314.94(a)(12)(viii)(A) reflect a change to the current text requiring a
505(b)(2) or ANDA applicant to amend its paragraph IV certification if
a ``final judgment'' has been entered finding the patent to be
infringed.
    Proposed Sec. Sec.  314.50(i)(6)(i) and 314.94(a)(12)(viii)(A) also
would require a 505(b)(2) and ANDA applicant, respectively, to submit
an amendment to change its paragraph IV certification to a paragraph
III certification or, if appropriate, to a statement under section
505(b)(2)(B) or 505(j)(2)(A)(viii) of the FD&C Act if a court signs a
settlement order or consent decree in the action that includes a
finding that the patent is infringed, unless the final decision,
settlement order or consent decree also finds the patent to be invalid.
For a first ANDA applicant, submission of an amendment that changes the
paragraph IV certification that qualified the applicant for 180-day
exclusivity to a paragraph III certification or a statement under
section 505(j)(2)(A)(viii) of the FD&C Act has implications for
continuing eligibility for 180-day exclusivity (see section
505(j)(5)(D)(i)(III) of the FD&C Act). We note, however, that if a
settlement is reached without a finding of patent infringement or
invalidity, then a paragraph IV certification may continue to be
appropriate. For example, if the 505(b)(2) or ANDA applicant is granted
a patent license such that the applicant would be permitted to obtain
approval and commence marketing prior to patent expiration, the
505(b)(2) or ANDA applicant would maintain its paragraph IV
certification with respect to the patent at issue and should submit an
amendment pursuant to proposed Sec. Sec.  314.50(i)(3) and
314.94(a)(12)(v) to advise the Agency of the patent licensing
agreement. Such an amendment must include a written statement by the
applicant that it has been granted a patent license and a written
statement from the patent owner confirming the licensing agreement and
consenting to approval of the application as of a specific date (see
proposed Sec. Sec.  314.50(i)(3) and 314.94(a)(12)(v)).
    We are proposing to apply the requirement that a 505(b)(2) or ANDA
applicant must submit an amendment to change its paragraph IV
certification to a paragraph III certification or, if appropriate, to a
statement under section 505(b)(2)(B) or 505(j)(2)(A)(viii) of the FD&C
Act after a judicial finding of patent infringement irrespective of
whether the patent infringement action was brought within 45 days of
receipt of the notice of paragraph IV certification (see proposed
Sec. Sec.  314.50(i)(6)(i) and 314.94(a)(12)(viii)(A)). A patent
infringement action initiated outside of the 45-day period following
receipt of a notice of paragraph IV certification is not eligible for a
30-month stay of approval while the patent infringement litigation is
pending (see Sec.  314.107(b)(3)). However, the rationale for an
amended patent certification in the event that the patent is found
valid and infringed applies with equal force to a legal action for
infringement of a listed patent that was brought outside of the 45-day
period (see 35 U.S.C. 271(e)(4)). Thus, we are proposing to remove the
phrase ``within 45 days of the receipt of notice sent under [Sec.
314.52 or Sec.  314.95, respectively]'' from the description of the
patent infringement action to which Sec. Sec.  314.50(i)(6)(i) and
314.94(a)(12)(viii)(A) apply. This proposed revision would clarify, for
example, that the approval of a 505(b)(2) application or ANDA that
contained a paragraph IV certification but was not subject to a 30-
month stay still may be delayed by the intervening grant of pediatric
exclusivity under section 505A(b)(1)(B) of the FD&C Act after a
judicial finding of infringement of the patent for which the paragraph
IV certification had been submitted (see Mylan Labs., Inc. v. Thompson,
332 F. Supp. 2d 106 (D.D.C.), aff'd, 389 F.3d 1272 (D.C. Cir. 2004);
see also proposed Sec.  314.107(b)(4) and (e)(1)(vi)).
    As explained in proposed Sec. Sec.  314.50(i)(6)(i) and
314.94(a)(12)(viii)(A), an applicant may change its paragraph IV
certification for a method-of-use patent to a statement under section
505(b)(2)(B) or 505(j)(2)(A)(viii) of the FD&C Act only if the
applicant amends its 505(b)(2) application or ANDA, respectively, such
that the applicant is no longer seeking approval for a method of use
claimed by the patent (see Sec. Sec.  314.50(i)(1)(iii) and
314.94(a)(12)(iii)).
II.E.2. Amended Certifications After Request by the NDA Holder To
Remove a Patent or Patent Information From the List
    We are proposing to revise Sec. Sec.  314.50(i)(6)(ii) and
314.94(a)(12)(viii)(B) to clarify the circumstances and timeframe in
which a 505(b)(2) or ANDA applicant, respectively, must submit an
amended patent certification to its 505(b)(2) application or ANDA after
an NDA holder has requested removal of a patent or patent information
from the list (``patent delisting''). These proposed revisions also
describe our current practice regarding patent delisting as it relates
to the eligibility of one or more first ANDA applicants for 180-day
exclusivity.
    An NDA holder may request removal of a patent or patent information
from the list in accordance with a court order or on its own
initiative, if it determines that the patent or patent information no
longer meets the statutory criteria for listing (see section 505(b)(1)
and (c)(2) of the FD&C Act). Since April 18, 2008, FDA has identified
in the Orange Book (the list) those patents for which an NDA holder has
withdrawn the patent and submitted a request for removal of the patent
from the list. We are proposing to revise Sec. Sec.  314.50(i)(6)(ii)
and 314.94(a)(12)(viii)(B) to state that if an NDA holder has requested
removal of a patent or patent information from the list, the patent or
patent information will be removed if no ANDA applicant has submitted a
paragraph IV certification to the patent or no ANDA applicant is
eligible for 180-day exclusivity. Upon removal of the patent or patent
information from the list, any applicant with a pending 505(b)(2)
application or ANDA (including a tentatively approved 505(b)(2)
application or ANDA) must submit an amendment to its application to
withdraw its certification to the patent.
    However, if an NDA holder has requested removal of a patent or
patent information from the list and one or more first ANDA applicants
are eligible for 180-day exclusivity, FDA will not remove the patent or
patent information from the list until we have determined that no first
applicant still is eligible for 180-day exclusivity (see section
505(j)(5)(D) of the FD&C Act regarding forfeiture of 180-day
exclusivity) or the 180-day exclusivity is extinguished (see proposed
Sec. Sec.  314.50(i)(6)(ii) and 314.94(a)(12)(viii)(B)). Otherwise, if
the NDA holder withdrew the patent or patent information for which a
first ANDA applicant had submitted the certification that qualified it
for 180-day exclusivity and FDA immediately removed the patent or
patent information from the list, the first applicant would be required
to withdraw its patent certification and could not ``lawfully
maintain'' its paragraph IV certification (as the ANDA would no longer
be considered to be one containing a paragraph IV certification) (see
section 505(j)(5)(B)(iv)(II)(bb) and (j)(5)(D)(i)(III) of the FD&C
Act). In addition, if FDA immediately removed a patent or patent
information from the list upon the NDA holder's request when one or
more first applicants were eligible for 180-day exclusivity, it could
result in ANDA applicants withdrawing corresponding patent
certifications

prematurely and thus undermining a first applicant's 180-day
exclusivity. We also are proposing to revise the heading for Sec. Sec.
314.50(i)(6)(ii) and 314.94(a)(12)(viii)(B) by replacing the phrase
``after removal of a patent'' with ``after request to remove a patent
or patent information'' to emphasize that FDA will not remove a patent
or patent information from the list until we have determined that no
first applicant is eligible for 180-day exclusivity.
    An NDA holder's withdrawal of a patent or patent information is
implicitly an acknowledgment that the standard for patent listing set
forth in section 505(b) and (c) of the FD&C Act can no longer be met.
Nevertheless, a patent for which the NDA holder has requested removal
may remain listed for 180-day exclusivity purposes. For a patent that
remains listed for purposes of 180-day exclusivity after an NDA holder
has withdrawn the patent or patent information and requested that FDA
remove the patent or patent information from the list, the requirements
for providing a patent certification will differ between 505(b)(2)
applicants and ANDA applicants. A 505(b)(2) applicant is neither
eligible for nor blocked by 180-day generic drug exclusivity.
Accordingly, we are proposing to revise Sec.  314.50(i)(6)(ii) to
exempt a 505(b)(2) applicant from the requirement to provide or
maintain a certification to a patent that is identified in the Orange
Book as remaining listed only for purposes of a first applicant's 180-
day generic drug exclusivity. Because one or more ANDA applicants may
be eligible for 180-day exclusivity, ANDA applicants are required to
provide an appropriate patent certification to each patent listed in
the Orange Book (except as provided in Sec.  314.94(a)(12)(vi)),
including to a patent that is listed with a notation indicating that
the NDA holder has requested removal of the patent or patent
information from the Orange Book. Once FDA has determined that no first
applicant is eligible for 180-day exclusivity, or such exclusivity is
extinguished, and has removed the patent information from the Orange
Book, an ANDA applicant must submit an amendment to its pending ANDA to
withdraw the certification.
    We are proposing to delete the statement in current Sec. Sec.
314.50(i)(6)(ii) and 314.94(a)(12)(viii)(B) regarding the timing of
removal of a patent or patent information that is the subject of a
patent infringement lawsuit under Sec.  314.107(c). This statement
would be replaced by the broader criterion, discussed earlier in this
section, that a patent will not be removed from the list until FDA has
determined that any 180-day exclusivity is extinguished. This proposed
revision reflects our current practice.
    We also are proposing to add a statement to emphasize that if a
505(b)(2) or ANDA applicant submits an amendment to withdraw a
paragraph IV certification, the 505(b)(2) application or ANDA will no
longer be considered to be one containing a paragraph IV certification
to the patent. In addition, we are proposing a conforming revision to
Sec.  314.94(a)(12)(viii) to clarify that once an amendment is
submitted to change a certification, the ANDA will no longer be
considered to contain the prior certification. This is consistent with
the Agency's practice for amended patent certifications for 505(b)(2)
applications (see Sec.  314.50(i)(6)).
    Finally, we are proposing to relocate within Sec. Sec.
314.50(i)(6)(ii) and 314.94(a)(12)(viii)(B) and revise the current
statement regarding submission of an amended patent certification after
removal of a patent from the list. This proposed revision is intended
to clarify rather than substantively change our current requirements.
If removal of a patent from the list results in there being no patents
listed for the listed drug(s) identified in the 505(b)(2) application
or the RLD identified in the ANDA, the applicant must submit an amended
certification under Sec.  314.50(i)(1)(ii) or Sec.  314.94(a)(12)(ii),
as appropriate, to reflect that there are no listed patents. We note,
however, that if a 505(b)(2) or ANDA applicant fails to submit an
amended patent certification after removal of a patent from the list,
the Agency will consider the 505(b)(2) or ANDA applicant to have
constructively withdrawn its patent certification to the delisted
patent (compare Ranbaxy Labs. Ltd. v. FDA, 307 F. Supp. 2d 15, 21
(D.D.C.), aff'd, 2004 U.S. App. LEXIS 8311 (D.C. Cir. 2004); see also
section II.E.4). With respect to any patents that remain listed for the
listed drug(s) identified in the 505(b)(2) application or for the RLD
identified in the ANDA, it is expected that the applicant would
maintain an accurate patent certification consistent with current
regulatory requirements (see Sec. Sec.  314.50(i)(6)(iii) and
314.94(a)(12)(viii)(C)). We seek comment on this approach.
II.E.3. Amended Certifications Upon Patent Reissuance
    In section II.B.1.e, we describe certain proposed revisions to our
regulations to clarify our requirements regarding an NDA holder's
submission of patent information related to reissued patents. Because
the listing of a reissued patent may require submission of an amended
patent certification by a 505(b)(2) or ANDA applicant under our current
regulations, we are describing in this section of the document an
applicant's patent certification obligations with respect to a reissued
patent.
    Sections 314.50(i)(6)(iii) and 314.94(a)(12)(viii)(C) require that
a 505(b)(2) and ANDA applicant submit an amended patent certification
if, at any time before approval of the 505(b)(2) application or ANDA,
the applicant learns that the submitted certification is no longer
accurate. As a general rule, we require a 505(b)(2) or ANDA applicant
to provide an appropriate patent certification or statement with
respect to a reissued patent, unless either the original patent or the
reissued patent was not timely filed by the NDA holder for listing in
the Orange Book (see Sec. Sec.  314.50(i)(4) and 314.94(a)(12)(vi)). As
noted in section II.B.1.e, if a 505(b)(2) or ANDA applicant is not
required to provide a patent certification or statement to the original
patent because it was untimely filed (and late-listed as to the pending
505(b)(2) application or ANDA), the 505(b)(2) or ANDA applicant would
not be required to provide a patent certification or statement to the
reissued patent even if timely filed following reissuance.
    We require a 505(b)(2) or ANDA applicant to provide an amended
patent certification or statement to the reissued patent, even though a
patent certification or statement may already have been submitted for
the original patent, because the scope of claims may be narrowed or, in
certain circumstances, broadened upon reissuance of the patent (see 35
U.S.C. 251). A change in the scope of the patent claims may result in
the reissued patent being listed in the Orange Book with a revised
designation by the NDA holder regarding whether the patent claims the
drug substance, drug product, and/or a method of use, or the reissued
patent may be listed with a revised use code. Accordingly, submission
of an amendment to a pending 505(b)(2) application or ANDA is necessary
to provide an appropriate patent certification or statement to the
reissued patent, even if the type of patent certification (e.g., a
paragraph III certification) does not differ from that submitted for
the original patent.
    If an ANDA applicant submitted a paragraph IV certification to the
original listed patent and continues to opine that the reissued patent
is invalid or will not be infringed by the manufacture, use, or sale of
the drug for which the application is submitted, then we are

proposing that the applicant must submit an amendment to its pending
ANDA that contained a paragraph IV certification to the reissued patent
within 30 days of the date of listing of the reissued patent in the
Orange Book to lawfully maintain its paragraph IV certification for
purposes of eligibility for 180-day exclusivity (see proposed Sec.
314.94(a)(12)(viii)(B)). Both 505(b)(2) and ANDA applicants are
required to provide notice of the paragraph IV certification to the
reissued patent and comply with other applicable regulatory
requirements at the time of submission of the amendment containing the
paragraph IV certification. We seek comment on this proposal.
    An amended patent certification to the reissuance of an original
patent for which a paragraph IV certification previously was submitted
may have implications for the 30-month stay provisions of the FD&C Act:
     If a 505(b)(2) or ANDA applicant submitted a paragraph IV
certification to the original patent and a patent infringement action
was initiated within 45 days of its notice of the paragraph IV
certification to the original patent, the resulting 30-month stay would
not be affected solely by reissuance of the patent, recertification,
and renotification and would continue subject to Sec.  314.107.
     If a 505(b)(2) or ANDA applicant submitted a statement
under section 505(b)(2)(B) or section 505(j)(2)(A)(viii) of the FD&C
Act, respectively, or a paragraph III certification to the original
patent and subsequently submitted a paragraph IV certification to the
reissued patent, a 30-month stay would be available if a patent
infringement action was initiated within 45 days of its notice of the
paragraph IV certification to the reissued patent.
     If a 505(b)(2) or ANDA applicant had previously submitted
a paragraph IV certification to the original patent and no patent
infringement action was initiated within 45 days of receipt of notice,
no subsequent patent infringement action with respect to the reissued
patent can give rise to a 30-month stay.

This approach reflects our proposal to treat the original patent and
the reissued patent as a ``single bundle'' of patent rights, albeit
patent rights that have changed with reissuance, such that the patent
information listed for the reissued patent would have been submitted
under 505(b)(1) or 505(c)(2) of the FD&C Act at the time of listing of
the original patent for purposes of section 505(c)(3)(C) and
(j)(5)(B)(iii) of the FD&C Act. Although we recognize that a reissued
patent may have a broadened scope of claims if applied for within 2
years from the grant of the original patent (see 35 U.S.C. 251), our
proposal to consider the original patent and reissued patent together
for purposes of administering the patent certification requirements of
the FD&C Act and any 30-month stay of approval or 180-day exclusivity
that relates to a paragraph IV certification is intended to provide a
consistent and predictable approach to implementation of the FD&C Act.
If FDA were to propose a different approach to the availability of a
30-month stay based on a paragraph IV certification to a reissued
patent with broadened claims, the implementation of such an approach
would require resources and patent expertise that FDA currently does
not possess and would be inconsistent with the Agency's ministerial
role in patent listing. In any event, we do not expect that the
scenario described here will occur frequently.
    An amended patent certification to the reissuance of an original
patent for which a paragraph IV certification previously was submitted
also may have implications for the 180-day exclusivity provisions of
the FD&C Act. As described previously in this section of the document,
if a one or more first ANDA applicants is eligible for 180-day
exclusivity based on a paragraph IV certification to the original
patent and the patent is reissued, the first ANDA applicant would be
required to submit a paragraph IV certification to the reissued patent
within 30 days of listing to be considered by FDA to have lawfully
maintained its paragraph IV certification for purposes of section
505(j)(5)(B)(iv)(II)(bb) and (j)(5)(D)(i)(III) of the FD&C Act. We note
that the original patent, which qualified the first applicant for 180-
day exclusivity, would remain listed in the Orange Book until FDA
determined that any 180-day exclusivity is extinguished. Consistent
with our current practice regarding requests for patent delisting, the
original patent that qualified a first applicant for 180-day
exclusivity also would remain listed in the Orange Book even if the
scope of the reissued patent is narrowed such that the patent is no
longer eligible for listing pursuant to section 505(b)(1) or 505(c)(2)
of the FD&C Act and the NDA holder has requested, as required, that the
patent be delisted from the Orange Book (see proposed Sec.
314.53(f)(2) and section II.B.4.b). Given that FDA will continue to
list a patent that qualified a first applicant for 180-day exclusivity
under specified circumstances even if the patent has been withdrawn by
the NDA holder on its own initiative or after a judicial finding of
invalidity or unenforceability, the fact that the original patent
technically is surrendered upon reissuance is not relevant to FDA's
assessment of a first applicant's continued eligibility for 180-day
exclusivity. However, in recognition of the surrender of the original
patent upon reissuance, we require a first applicant to maintain a
paragraph IV certification to the reissued patent. If a first applicant
submitted only a paragraph III certification or a 505(j)(2)(A)(viii)
statement to the reissued patent, we would consider the first applicant
to have amended or withdrawn its paragraph IV certification to the
patent for which it qualified for 180-day exclusivity under section
505(j)(5)(D)(i)(III) of the FD&C Act.
    If no applicant had submitted a paragraph IV certification to the
original patent, the first ANDA applicant to submit a paragraph IV
certification to the reissued patent could be eligible for 180-day
exclusivity, if no other applicant already has qualified as a first
applicant based on an earlier paragraph IV certification to another
listed patent. However, if a first applicant who qualifies as such
based on a paragraph IV certification to the original patent forfeits
180-day exclusivity, 180-day exclusivity would not be available to a
subsequent applicant that submitted a paragraph IV certification to the
reissued patent (see section 505(j)(5)(D)(iii)(II) of the FD&C Act).
II.E.4. Other Amended Certifications
    Sections 314.50(i)(6)(iii) and 314.94(a)(12)(viii)(C) require a
505(b)(2) and ANDA applicant, respectively, to amend a submitted
certification if, at any time before approval of the application, the
applicant learns that the submitted certification is no longer
accurate. In Dr. Reddy's Labs., Inc. v. Thompson, the district court
held that our regulations ``imposing a duty upon ANDA applicants to
assure its certifications are accurate until the date of final approval
is supported by [the] . . . express FDA authority [in section
505(j)(4)(J) and (K) of the FD&C Act]'' (302 F. Supp. 2d 340, 355
(D.N.J. 2003)) (see also section 505(e) of the FD&C Act).
    Over the years, many 505(b)(2) and ANDA applicants have neglected
to amend a previously submitted patent certification after the patent
has expired. The Agency's longstanding position has been that a patent
is relevant for purposes of 180-day exclusivity determinations ``until
the end of the term of the patent or applicable 180-day

exclusivity period, whichever occurs first'' (1994 final rule, 59 FR
50338 at 50348). Section 505(j)(5)(D)(i)(VI) of the FD&C Act, added by
the MMA, is consistent with FDA's longstanding position that 180-day
exclusivity is extinguished upon expiration of the patent(s) on which
exclusivity is based (see Docket No. FDA-2004-N-0062-0006 (comment
submitted by PhRMA) at 5, available at http://www.regulations.gov).
    Accordingly, we are proposing to codify our longstanding position
that if an applicant that previously submitted a paragraph III
certification, a paragraph IV certification, or a statement under
section 505(b)(2)(B) or (j)(2)(A)(viii) of the FD&C Act with respect to
a listed patent fails to amend its patent certification to a paragraph
II certification upon patent expiration, the Agency will consider the
505(b)(2) or ANDA applicant to have constructively changed its patent
certification to a paragraph II certification (see, e.g., Ranbaxy Labs.
Ltd. v. FDA, 307 F. Supp. 2d 15, 21 (D.D.C.), aff'd, 2004 U.S. App.
LEXIS 8311 (D.C. Cir. 2004) (finding that upon patent expiration an
ANDA applicant's paragraph IV certifications ``became invalid, and
either converted as a matter of law to Paragraph II certifications or
became inaccurate, thereby creating both an obligation on [the ANDA
applicant's] . . . part to amend its ANDAs to reflect patent expiry and
an inability on the part of the FDA to approve the ANDAs in their
inaccurate form'')). This approach also will clarify that any pediatric
exclusivity will delay approval of a 505(b)(2) application or ANDA upon
patent expiry under section 505A(b)(1)(B) and (c)(1)(B) of the FD&C
Act, regardless of whether an applicant has amended its certification
to a paragraph II certification.
    We also are proposing to amend Sec. Sec.  314.50(i)(6)(iii)(A) and
314.94(a)(12)(viii)(C)(1) by revising and redesignating the current
text as paragraph (1) and paragraph (i), respectively, and adding a new
paragraph (2) and paragraph (ii) to expressly codify the requirement
for a 505(b)(2) and ANDA applicant to submit a patent certification to
a newly issued patent. Proposed Sec. Sec.  314.50(i)(6)(iii)(A)(2) and
314.94(a)(12)(viii)(C)(1)(ii) state that, except as provided in
Sec. Sec.  314.50(i)(4) and (i)(6)(iii)(B) and 314.94(a)(12)(vi) and
(a)(12)(viii)(C)(2)), an applicant must submit a patent certification
or statement if, after submission of the 505(b)(2) application or ANDA,
a new patent is issued by the PTO that, in the opinion of the applicant
and to the best of its knowledge, claims the listed drug or RLD or that
claims an approved use for such drug and for which information is
required to be filed under section 505(b) and (c) of the FD&C Act and
Sec.  314.53.
    A 505(b)(2) and ANDA applicant currently are required to submit a
patent certification or statement for each patent issued by the PTO
that, in the opinion of the applicant and to the best of its knowledge,
claims the listed drug or RLD or that claims an approved use for such
drug for which the applicant is seeking approval and for which
information is required to be filed under section 505(b) and (c) of the
FD&C Act and Sec.  314.53. Although the general requirement to submit a
patent certification to a newly issued patent is established by
Sec. Sec.  314.50(i)(1)(i)(A) and 314.94(a)(12)(i)(A) and implicit in
the exceptions for late submission of patent information, we are
proposing to expressly codify the requirement to submit a patent
certification to a newly issued patent in the section of the
regulations directed to amended patent certification.
    As discussed in section II.D.1.b.ii, we are proposing that a patent
certification or statement by an ANDA applicant must not be submitted
earlier than the first working day after the day the patent is
published in the Orange Book (see proposed Sec.
314.94(a)(12)(viii)(C)(1)(ii)). Thus, for a paragraph IV certification,
the certification must not be submitted earlier than the first working
day after the day the patent is published in the Orange Book. This
proposal is intended to discourage burdensome serial submissions of
paragraph IV certifications and ensure that all ANDA applicants
(irrespective of time zone) have a reasonable opportunity to be a first
applicant with respect to a newly listed patent (see also proposed
Sec.  314.95(b)(2)).
    In addition, we are proposing to revise Sec. Sec.
314.50(i)(6)(iii) and 314.94(a)(12)(viii)(C) to technically correct,
but not substantively change, the reference to the lack of a
requirement to ``amend'' a submitted patent certification after
approval of a 505(b)(2) application or ANDA, respectively. We are
proposing to correct this statement to indicate that an applicant is
not required to submit a supplement solely to change a submitted patent
certification after approval of the application. This revision also
reflects that any changes to an application after approval would be
made in a supplement to the application and not in an amendment, as the
current regulation describes.

II.F. Patent Certification Requirements for Amendments and Supplements
to 505(b)(2) Applications and ANDAs (Proposed Sec. Sec.  314.60,
314.70, 314.96, and 314.97)

    We are proposing to add Sec. Sec.  314.60(f), 314.70(i), 314.96(d),
and 314.97(c) to clarify and augment the patent certification
requirements for amendments and supplements described in Sec. Sec.
314.50(i)(6)(iii) and 314.94(a)(12)(viii)(C). Proposed Sec. Sec.
314.60(f) and 314.96(d) would require an applicant to also submit a
patent certification described in Sec. Sec.  314.50(i) or
314.94(a)(12), as appropriate, if approval is sought for any of the
following types of amendments to an original 505(b)(2) application or
ANDA: (1) To add a new indication or other condition of use; (2) to add
a new strength; (3) to make other than minor changes in product
formulation; or (4) to change the physical form or crystalline
structure of the active ingredient.
    Currently, an applicant that submits an amendment to a pending
505(b)(2) application or supplement or a pending ANDA or supplement is
required to amend its patent certification if, at any time before
approval, the applicant learns that the previously submitted patent
certification is no longer accurate with respect to the pending
application or supplement, as amended (see Sec. Sec.  314.50(i)(6)(iii)
and 314.94(a)(12)(viii)(C), respectively, and section II.E.4). For
example, an amendment to change the formulation of a proposed product
in a 505(b)(2) application or ANDA would require a revised patent
certification if, in the applicant's opinion and to the best of its
knowledge, the new formulation would infringe a listed patent for which
it previously had filed a paragraph IV certification.
    Some NDA holders have expressed concern that a 505(b)(2) or ANDA
applicant may change its proposed product in an amendment to a pending
application, but not update its patent certification to correspond to
the proposed product as changed by the amendment. For example, in 2003,
FDA received a citizen petition submitted on behalf of Biovail
Corporation requesting, among other things, that FDA require submission
of a new patent certification upon amendment of the chemistry,
manufacturing, and controls section of an ANDA (Docket No. FDA-2003-P-
0519 (Biovail Petition), available at http://www.regulations.gov; see
also PhRMA comment to Docket No. FDA-2002-N-0279-0061 at 9 to 10,
available at http://www.regulations.gov). The

Biovail Petition recognized that even if the ANDA (or 505(b)(2))
applicant continued to assert that a paragraph IV certification was the
appropriate patent certification for the changed product, the factual
and legal basis of the applicant's opinion that the patent will not be
infringed may have changed in light of the changes in product
formulation (see Biovail Petition at 4 to 5). Biovail maintained that
``[r]equiring a new patent certification whenever the CMC portion of an
ANDA is amended will allow the NDA holder and patent owner to ensure
that the impact of the amendment on patent infringement issues is
addressed promptly'' (Supplement to Biovail Petition at 1).
    We agree that certain changes to a proposed product submitted in a
505(b)(2) application or ANDA should be accompanied by a new patent
certification (see section II.F.2). To address these concerns and
further clarify our requirements for submission of new patent
certifications with an amendment to a 505(b)(2) application or ANDA, we
are proposing to add Sec. Sec.  314.60(f) and 314.96(d). If an
applicant submits an amendment to a 505(b)(2) application or ANDA for
any of the categories of changes described in these provisions and does
not submit a new patent certification, the applicant will be required
to verify that the proposed change described in the amendment is not
the type of change for which a new patent certification is required
(e.g., the proposed formulation change meets the criteria for a
``minor'' formulation change). We seek comment on this proposal.
    We also are proposing to add Sec. Sec.  314.70(i) and 314.97(c),
and make conforming revisions to Sec. Sec.  314.50(i)(6)(iii)(B) and
314.94(a)(12)(viii)(C)(2), to clarify our requirements for submission
of new patent certifications with a supplement to a 505(b)(2)
application or ANDA. Proposed Sec. Sec.  314.70(i) and 314.97(c) would
require an applicant to also submit a patent certification described in
Sec.  314.50(i) or 314.94(a)(12), as appropriate, if approval is sought
for either of the following types of supplements to a 505(b)(2)
application or ANDA: (1) To add a new indication or other condition of
use or (2) to add a new strength.
    FDA is not proposing to require a patent certification with a
supplement to change the formulation or to change the physical form or
crystalline structure of the active ingredient of a product approved in
a 505(b)(2) application or ANDA. It is not necessary for FDA to use its
limited resources to require patent certifications under these
circumstances because the NDA holder for a listed drug and any patent
owner can monitor postapproval changes in the formulation or active
ingredient of a marketed drug product and address any patent-related
concerns without the involvement of FDA. With respect to NDA
supplements, it should be noted that these patent certification
requirements apply to 505(b)(2) supplements, irrespective of whether
the original application to which the supplement was submitted was
approved as a stand-alone 505(b)(1) application or a 505(b)(2)
application. A supplement to a 505(b)(2) application of the type
described in proposed Sec.  314.70(i) is generally a 505(b)(2)
supplement.
    Table 10 summarizes the proposed changes related to patent
certification requirements for amendments and supplements to 505(b)(2)
applications and ANDAs:

 Table 10--Highlights of Proposed Changes Regarding Patent Certification
  Requirements for Amendments and Supplements to 505(b)(2) Applications
                              and ANDAs \1\
------------------------------------------------------------------------
                                                Proposed revisions to
            Current regulations                      regulations
------------------------------------------------------------------------
Amended certifications--Other amendments    Amended certifications--
 (Sec.  Sec.   314.50(i)(6)(iii),            Other amendments (Sec.
 314.94(a)(12)(viii)(C))                     Sec.   314.50(i)(6)(iii),
                                             314.94(a)(12)(viii)(C))
     Except as otherwise provided,   Except as otherwise
     an applicant must amend a submitted     provided, an applicant must
     certification if, at any time before    amend a submitted
     approval of the 505(b)(2) application   certification if, at any
     or ANDA, the applicant learns that      time before approval of the
     the submitted certification is no       505(b)(2) application or
     longer accurate.                        ANDA, the applicant learns
                                             that the submitted
                                             certification is no longer
                                             accurate.
                                            Patent certification
                                             requirements (Sec.  Sec.
                                             314.60(f) and 314.96(d)).
                                             Except as provided
                                             below, an amendment to a
                                             505(b)(2) application or
                                             ANDA is required to contain
                                             patent certifications
                                             described in Sec.  Sec.
                                             314.50(i) or 314.94(a)(12),
                                             respectively, if approval
                                             is sought for any of the
                                             following types of
                                             amendments or supplements:
                                               --(1) To add a new
                                                indication or other
                                                condition of use;
                                               --(2) to add a new
                                                strength;
                                               --(3) to make other than
                                                minor changes in product
                                                formulation; or
                                               --(4) to change the
                                                physical form or
                                                crystalline structure of
                                                the active ingredient.
                                            Patent certification
                                             requirements (Sec.  Sec.
                                             314.70(i) and 314.97(c)).
                                             Except as provided
                                             below, a supplement to a
                                             505(b)(2) application or
                                             ANDA is required to contain
                                             patent certifications
                                             described in Sec.  Sec.
                                             314.50(i) or 314.94(a)(12),
                                             respectively, if approval
                                             is sought for either of the
                                             following types of
                                             supplements:
                                               --(1) To add a new
                                                indication or other
                                                condition of use; or
                                               --(2) to add a new
                                                strength.
                                             A supplement to a
                                             505(b)(2) application that
                                             seeks approval to add a new
                                             indication or other
                                             condition of use is
                                             required to contain patent
                                             certifications described in
                                             Sec.   314.50(i) only for
                                             patents that are identified
                                             as claiming an approved
                                             use. If the method-of-use
                                             patent is identified as
                                             also claiming the drug
                                             substance or drug product,
                                             the patent certification
                                             also must address the drug
                                             substance and/or drug
                                             product claims.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
  regulations, but should not be relied upon in place of the proposed
  regulation.

    We invite comment on this proposal and whether a new patent
certification should be required with the submission of other types of
amendments or supplements to a 505(b)(2) application or ANDA that may
change the drug product in a manner that could be protected by patent.
II.F.1. Types of Amendments or Supplements for Which Patent
Certification is Required
    II.F.1.a. Amendments or supplements to add a new indication or
other condition of use. Proposed Sec. Sec.  314.60(f)(1),
314.70(i)(1)(i), 314.96(d)(1), and 314.97(c)(1) require a 505(b)(2) or
ANDA applicant to submit a new patent certification with an amendment
or supplement to add a new indication or other condition of use for the
drug product that is the subject of the 505(b)(2) application or ANDA.
Although most requests for approval of a different indication or
condition of use by a 505(b)(2) applicant could not be made as an
amendment to the 505(b)(2) application (see Separate Marketing
Application Guidance at 4 to 5), there are certain scenarios in which
an applicant may submit an amendment to a 505(b)(2) application (or
ANDA) for a new indication or other condition of use. For example, a
505(b)(2) or ANDA applicant seeking approval for a drug product for
which the indication has changed from prescription status to OTC use
for the listed drug relied upon or RLD, as applicable, would be
required to submit a new patent certification with an amendment or
supplement to the application. These patent certification requirements
are currently encompassed by Sec. Sec.  314.50(i)(6)(iii) and
314.94(a)(12)(viii)(C). Proposed Sec. Sec.  314.60(f)(1),
314.70(i)(1)(i), 314.96(d)(1), and 314.97(c)(1) would parallel the
requirements for submission of patent information by an NDA applicant
seeking approval of a supplement to add a new indication or other
condition of use (see proposed Sec.  314.53(d)(2)(ii)).
    Currently, an applicant is required to submit a patent
certification or statement with a 505(b)(2) supplement that seeks
approval for a new indication or other condition of use (``efficacy
supplement''). We are proposing to reduce the current patent
certification requirements with respect to a supplement to a 505(b)(2)
application that seeks approval for a new indication or other condition
of use. Proposed Sec.  314.70(i)(2) states that a supplement to a
505(b)(2) application that only seeks approval to add a new indication
or other condition of use is required to contain patent certifications
described in Sec.  314.50(i) only for patents that are identified as
claiming an approved use. This proposed change preserves the NDA
holder's intellectual property rights without requiring the 505(b)(2)
applicant to submit a duplicative certification to patents listed in
the Orange Book for the listed drug relied upon that have not been
identified by the NDA holder as claiming a method of use and would not
be implicated by the efficacy supplement. We note, however, that if a
method-of-use patent is identified as also claiming the drug substance
or drug product, a statement under section 505(b)(2)(B) of the FD&C Act
would not be sufficient. The 505(b)(2) applicant's patent certification
also must address the drug substance and/or drug product claims in the
patent.
    II.F.1.b. Amendments or supplements to add a new strength or change
an existing strength. Proposed Sec. Sec.  314.60(f)(2),
314.70(i)(1)(ii), 314.96(d)(2), and 314.97(c)(2) would codify our
current requirements with respect to an applicant's submission of a new
patent certification with an amendment or supplement to add a new
strength for the drug product that is the subject of the 505(b)(2)
application or ANDA. As noted in section II.A.2.q, it is our
longstanding practice to regard different strengths of a drug product
as different drug products (see Apotex, Inc. v. Shalala, 53 F. Supp. 2d