enters an order requiring that the date of approval be delayed for an
already approved 505(b)(2) application or ANDA, FDA will convert the
approval to a tentative approval, if appropriate. This scenario may
occur, for example, if a patent infringement action is initiated after
the 45-day period described in section 505(c)(3)(C) and (j)(5)(B)(iii)
of the FD&C Act and results in a judgment of patent infringement.
Proposed Sec.  314.107(b)(4) would expressly describe FDA's practice of
giving effect to the court order under 35 U.S.C. 271(e)(4)(A),
irrespective of whether the order relates to a patent associated with a
30-month stay of approval (see, e.g., Mylan Labs., Inc. v. Thompson,
389 F.3d 1272 (D.C. Cir. 2004)).
    We also are proposing to amend references to ``receiv[ing] final
approval'' and making an approval ``effective'' to refer instead to
receipt of an approval letter (see sections II.A.2.dd and II.I).
II.M.3. Subsequent ANDA Submission (Proposed Sec.  314.107(c))
    Section 1102 of the MMA amended section 505(j)(5) of the FD&C Act
to modify the conditions under which a 180-day period of exclusivity is
granted and to establish conditions under which a first applicant would
forfeit the 180-day exclusivity period. As noted in section I.D, we are
currently implementing the 180-day exclusivity provisions of the MMA
directly from the statute and will determine if additional rulemaking
is necessary in the future. At this time, we are proposing to revise
Sec.  314.107(c) to remove provisions that have been superseded by the
statute, as revised by the MMA, and to generally conform with the
statute.
    Table 13 summarizes the proposed changes related to submission of
an ANDA containing a paragraph IV certification by a subsequent ANDA
applicant.

   Table 13--Highlights of Proposed Changes Regarding Subsequent ANDA
                             Submission \1\
------------------------------------------------------------------------
                                                Proposed revisions to
            Current regulations                      regulations
------------------------------------------------------------------------
Subsequent ANDA submission (Sec.            Subsequent ANDA submission
 314.107(c)(1),(3))                          (Sec.   314.107(c)(1))
 If an ANDA contains a paragraph     If an ANDA contains
 IV certification and the ANDA is for a      a paragraph IV
 generic copy of the same listed drug for    certification for a
 which one or more substantially complete    relevant patent and the
 ANDAs were previously submitted             ANDA is not that of a first
 containing a paragraph IV certification     applicant, the ANDA is
 to the same patent, approval of the         regarded as that of a
 subsequent ANDA will be made effective no   subsequent applicant.
 sooner than 180 days from whichever of      The ANDA of a
 the following dates is earlier:             subsequent applicant will
--(i) The date the applicant submitting      not be approved during the
 the first application first commences       period when any first
 commercial marketing of its drug product;   applicant for the drug
 or                                          product is eligible for 180-
--(ii) The date of a decision of the court   day exclusivity or during
 holding the relevant patent invalid,        the 180-day exclusivity
 unenforceable, or not infringed.            period of a first
                                             applicant.
                                             Any applicable 180-
                                             day exclusivity period can
                                             not extend beyond the
                                             expiration of the patent
                                             upon which the 180-day
                                             exclusivity period was
                                             based.
 For purposes of Sec.
 314.107(c)(1), if FDA concludes that the
 applicant submitting the first ANDA is
 not actively pursuing approval, FDA will
 make the approval of subsequent ANDAs
 immediately effective if they are
 otherwise eligible for an immediately
 effective approval.
Subsequent ANDA submission (Sec.            Definitions (Sec.
 314.107(c)(2))                              314.3(b))
 For purposes of Sec.                First applicant is
 314.107(c)(1), the `applicant submitting    an applicant that, on the
 the first application' is the applicant     first day on which a
 that submits an ANDA that is both           substantially complete ANDA
 substantially complete and contains a       containing a paragraph IV
 certification that the patent was           certification is submitted
 invalid, unenforceable, or not infringed    for approval of a drug,
 prior to the submission of any other        submits a substantially
 application for the same listed drug that   complete ANDA that
 is both substantially complete and          contains, and for which the
 contains the same certification.            applicant lawfully
 A `substantially complete'          maintains, a paragraph IV
 application must contain the results of     certification for the drug.
 any required bioequivalence studies, or,    Substantially
 if applicable, a request for a waiver of    complete application is an
 such studies.                               ANDA that on its face is
                                             sufficiently complete to
                                             permit a substantive review
                                             and contains all the
                                             information required under
                                             section 505(j)(2)(A) of the
                                             FD&C Act and Sec.   314.94.
Subsequent ANDA submission (Sec.            Subsequent ANDA submission
 314.107(c)(4))                              (Sec.   314.107(c)(2))
     For purposes of Sec.            For purposes of
     314.107(c)(1)(i), the applicant         Sec.   314.107(c)(1), a
     submitting the first ANDA shall         first applicant must submit
     notify FDA of the date that it          a supplement to its ANDA
     commences commercial marketing of its   notifying FDA within 30
     drug product.                           days of the date of first
                                             commercial marketing of its
                                             drug product.
     If an applicant does not        If an applicant
     promptly notify FDA of such date, the   does not notify FDA, as
     effective date of approval shall be     required above, of this
     deemed to be the date of the            date, the date of first
     commencement of first commercial        commercial marketing will
     marketing.                              be deemed to be the date of
                                             the drug product's
                                             approval.
     Commercial marketing           Definitions (Sec.
     commences with the first date of        314.3(b))
     introduction or delivery for            Commercial
     introduction into interstate commerce   marketing is the
     outside the control of the              introduction or delivery
     manufacturer of a drug product,         for introduction into
     except for investigational use under    interstate commerce of a
     part 312 of this chapter, but does      drug product described in
     not include transfer of the drug        an approved ANDA, outside
     product for reasons other than sale     the control of the ANDA
     within the control of the               holder, except for
     manufacturer or application holder.     investigational use under
                                             part 312 of this chapter,
                                             but does not include
                                             transfer of the drug
                                             product for reasons other
                                             than sale to parties
                                             identified in the approved
                                             ANDA.
------------------------------------------------------------------------
\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.  314.107(c)(1) to incorporate the
term ``first applicant,'' as defined by section
505(j)(5)(B)(iv)(II)(bb) of the FD&C Act and in proposed Sec.  314.3(b)
(see section II.A.2.q), and to distinguish a ``first applicant'' from a
``subsequent applicant.'' An ANDA has been submitted by a subsequent
applicant if the ANDA has not been submitted by a first applicant and
contains a paragraph IV certification to a relevant patent that has
been listed for the drug product for which a first applicant has
submitted an ANDA. A subsequent applicant's ANDA will not be approved
during the period when any first applicant for the drug product is
eligible for 180-day exclusivity or during the 180-day exclusivity
period of a first applicant (see section 505(j)(5)(B)(iv)(I) of the
FD&C Act). By including the period during which any first applicant is
eligible for 180-day exclusivity, proposed Sec.  314.107(c)(1)
clarifies that a subsequent ANDA for the drug product may not be
approved while a first applicant is eligible for 180-day exclusivity as
long as a forfeiture event has not occurred with respect to that first
applicant (see section 505(j)(2)(D)(ii) of the FD&C Act). These
proposed revisions replace the current text of Sec.  314.107(c)(1),
superseded by statute, which describe a patent-by-patent analysis to
determine eligibility for 180-day exclusivity and events that would
trigger the start of the 180-day period under the pre-MMA statutory
scheme.
    We are proposing to delete the definition of the ``applicant
submitting the first application'' in current Sec.  314.107(c)(2)
because it has been superseded by the statutory definition added by the
MMA. We are proposing to incorporate the MMA's definition of the term
``first applicant,'' with minor editorial changes and additional
clarifying text, into Sec.  314.3(b) (see section
505(j)(5)(B)(iv)(II)(bb) of the FD&C Act and section II.A.2.q). We also
are proposing to delete Sec.  314.107(c)(3), which described the
potential consequences of a first applicant's failure to actively
pursue approval of its ANDA because this regulation has been superseded
by the statutory provisions that specify events that will result in
forfeiture of the 180-day exclusivity period by a first applicant (see
section 505(j)(5)(D) of the FD&C Act).
    The MMA amended the FD&C Act to modify the types of events that can
trigger the start of the 180-day exclusivity period for a first
applicant (see section 505(j)(5)(B)(iv)(I) of the FD&C Act; see also
section 1102(b)(3) of the MMA). Section 505(j)(5)(B)(iv)(I) of the FD&C
Act provides that the period of 180-day exclusivity will begin on the
``date of the first commercial marketing of the drug (including the
commercial marketing of the listed drug) by any first applicant.'' This
commercial marketing trigger differs from the version of section
505(j)(5)(B)(iv)(I) in effect prior to enactment of the MMA, which
provided that the 180-day exclusivity period will begin on the earlier
of two events, one of which was the date the Secretary receives notice
from the applicant of the first commercial marketing of the drug
eligible for 180-day exclusivity. We are proposing to revise Sec.
314.107(c)(4) to conform with these changes to the FD&C Act and
redesignate this provision as Sec.  314.107(c)(2) (``redesignated Sec.
314.107(c)(2)'').
    In light of the change in the commercial marketing trigger from the
date on which FDA receives notice from the applicant of the first
commercial marketing to the date of the first commercial marketing of
the drug, we are proposing to revise redesignated Sec.  314.107(c)(2)
to require a first applicant to submit correspondence to its ANDA
notifying FDA within 30 days of the date of first commercial marketing
of the drug product (see current Sec.  314.107(c)(4)). This proposal to
require notification within 30 days of the date of first commercial
marketing is intended to facilitate the efficient enforcement of the
FD&C Act and provide adequate notice to subsequent applicants that have
received tentative approval and are awaiting expiration of the period
of 180-day exclusivity. If the first applicant does not notify FDA
within this timeframe, we are proposing to deem the date of first
commercial marketing to be the date of the drug product's approval.
This may have the effect of shortening the 180-day period of
exclusivity in a manner similar to current Sec.  314.107(c)(4).
    We also are proposing to revise redesignated Sec.  314.107(c)(2) to
remove the description of ``commercial marketing.'' As explained in
section II.A.2.l, we are proposing to define ``commercial marketing''
in Sec.  314.3(b) with certain modifications, as compared to current
Sec.  314.107(c)(4), to the scope of the exclusion for transfer of the
drug product for reasons other than sale.
II.M.4. Delay of Approval Due to Exclusivity (Proposed Sec.
314.107(d))
    We are proposing to revise Sec.  314.107(d) to clarify that
approval of a 505(b)(2) application or ANDA may be delayed by orphan
drug exclusivity and pediatric exclusivity in addition to the
exclusivities described in Sec.  314.108. Proposed Sec.  314.107(d)
explains that when approval of a 505(b)(2) application or ANDA is
delayed under Sec.  314.107 and Sec.  314.108, 21 CFR 316.31 (orphan
drug exclusivity), or section 505A of the FD&C Act (pediatric
exclusivity), the 505(b)(2) application or ANDA will be approved on the
latest of the dates specified under these provisions. We also have made
conforming revisions to proposed Sec.  314.107(d) that are described
elsewhere in section II.M.
II.M.5. Notification of Court Actions or Documented Agreement (Proposed
Sec.  314.107(e))
    We are proposing to revise Sec.  314.107(e) to expand the scope of
documentation that an applicant must submit to FDA regarding court
actions and settlements related to patents. These changes are intended
to ensure that FDA is promptly advised of court actions and documented
agreements that may affect the timing of approval of a 505(b)(2)
application or ANDA for the efficient administration of the FD&C Act.
FDA does not have the resources to monitor the numerous court actions
that are pending at any given time which may affect the date of
approval of a 505(b)(2) application or ANDA that is otherwise eligible
for approval.
    Table 14 summarizes the proposed changes related to notification of
court actions or documented agreements.

Table 14--Highlights of Proposed Changes Regarding Notification of Court
                   Actions or Documented Agreements\1\
------------------------------------------------------------------------
                                              Proposed revisions to
          Current regulations                      regulations
------------------------------------------------------------------------
Notification of court actions (Sec.      Notification of court actions
 314.107(e))                              or documented agreements (Sec.
                                            314.107(e)(1) and (e)(2))

 Applicant must submit a copy     Applicant must submit
 of the entry of the order or judgment    the following information to
 to the Office of Generic Drugs or to     FDA, as applicable:
 the appropriate division in the Office  --a copy of any judgment by the
 of New Drugs, as applicable, within 10   court (district court or
 working days of a final judgment.        mandate of the court of
                                          appeals) or settlement order
                                          or consent decree signed and
                                          entered by the court (district
                                          court or court of appeals)
                                          finding a patent described in
                                          Sec.   314.107(b)(3) invalid,
                                          unenforceable, or not
                                          infringed, or finding the
                                          patent valid and infringed,
                                          and written notification of
                                          whether any such court action
                                          has been appealed;
                                            --A copy of any order
                                             entered by the court
                                             terminating the 30-month or
                                             7\1/2\-year period
                                             described in Sec.
                                             314.107(b)(3)(i) and
                                             (b)(3)(ii);
                                            --A copy of any documented
                                             agreement described in Sec.
                                               314.107(b)(3)(vi);
                                            --A copy of any preliminary
                                             injunction described in
                                             Sec.   314.107(b)(3)(v),
                                             and a copy of any
                                             subsequent court order
                                             lifting the injunction; and
                                            --A copy of any court order
                                             pursuant to 35 U.S.C.
                                             271(e)(4)(A) ordering that
                                             a 505(b)(2) application or
                                             ANDA may be approved no
                                             earlier than the date
                                             specified (irrespective of
                                             whether the injunction
                                             relates to a patent
                                             described in Sec.
                                             314.107(b)(3)).
                                          All required
                                          information must be sent to
                                          the Office of Generic Drugs or
                                          to the appropriate division in
                                          the Office of New Drugs, as
                                          applicable, within 14 days of:
                                            --the date of entry by the
                                             court,
                                            --the date of appeal or
                                             expiration of the time for
                                             appeal, or
                                            --the date of documented
                                             agreement, as applicable.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
  regulations, but should not be relied upon in place of the proposed
  regulation.

    Proposed Sec.  314.107(e)(1)(i) would require a 505(b)(2) or ANDA
applicant to submit a copy of any judgment by the court (district court
or mandate of the court of appeals) finding a patent described in Sec.
314.107(b)(3) invalid, unenforceable, or not infringed, or finding the
patent valid and infringed. This proposed requirement imposes a duty on
505(b)(2) and ANDA applicants to notify FDA regarding any court
judgment regardless of whether or not the action for patent
infringement has resulted in a substantive determination by the court
regarding validity, enforceability, and/or infringement of the patent.
    In addition, we are proposing to require 505(b)(2) and ANDA
applicants to submit to FDA a copy of certain documented agreements and
court actions other than judgments to facilitate FDA's administration
of the FD&C Act. Proposed Sec.  314.107(e)(1)(i) would require a
505(b)(2) or ANDA applicant to submit a copy of a settlement order or
consent decree signed and entered by the court (district court or court
of appeals) finding a patent described in proposed Sec.  314.107(b)(3)
invalid, unenforceable, or not infringed, or finding the patent valid
and infringed. It should be noted that this proposal would require
submission of written documentation that the parties have entered into
a settlement that has terminated the patent infringement litigation,
but does not require applicants to send copies of the actual settlement
agreement to FDA (compare section 1112 of the MMA (requiring that
generic drug applicants file certain agreements with the FTC)).
Proposed Sec.  314.107(e)(1)(ii) would require a 505(b)(2) or ANDA
applicant to submit written notification of whether or not any action
by the court described in Sec.  314.107(e)(1)(i) has been appealed
within the time permitted for an appeal. Proposed Sec.
314.107(e)(1)(iii) and (e)(1)(iv) would require a 505(b)(2) or ANDA
applicant to submit a copy of any order entered by the court
terminating the 30-month or 7\1/2\-year period described in proposed
Sec.  314.107(b)(3)(i) and (b)(3)(ii), and any documented agreement
described in proposed Sec.  314.107(b)(3)(vi). Proposed Sec.
314.107(e)(1)(v) would require a 505(b)(2) or ANDA applicant to submit
a copy of any preliminary injunction described in Sec.
314.107(b)(3)(v), and a copy of any subsequent court order lifting the
injunction. Proposed Sec.  314.107(e)(1)(vi) would require a 505(b)(2)
or ANDA applicant to submit a copy of any court order pursuant to 35
U.S.C. 271(e)(4)(A) ordering that a 505(b)(2) application or ANDA may
be approved no earlier than the date specified (irrespective of whether
the injunction relates to a patent described in Sec.  314.107(b)(3)).
This revision is intended to conform with proposed Sec.  314.107(b)(4)
(see section II.M.2.d). These court actions and documented agreements
also may affect the timing of approval of a 505(b)(2) application or
ANDA and frequently are unpublished. If an applicant is unsure whether
a particular court action or documented agreement requires notification
to FDA under proposed Sec.  314.107(e), we recommend submission.
    We also are proposing to modify the timeframe for a 505(b)(2) or
ANDA applicant to submit the required information to the appropriate
division in OND or to OGD, as applicable, to ensure timely notification
to FDA. Proposed Sec.  314.107(e)(2) would require submission of all
required information within 14 calendar days of entry by the court, the
date of appeal or expiration of the time for appeal, or the date of
written agreement, as applicable. We are proposing to change the
timeframe for submission of required information from 10 working days
to 14 calendar days for clarity and consistency with other counting
conventions used in part 314.
II.M.6. Computation of the 45-Day Time Clock (Proposed Sec.
314.107(f))
    We are proposing to revise Sec.  314.107(f) to clarify the
computation of the 45-day period after receipt of notice of paragraph
IV certification and to enhance the requirements for notifying FDA of
any legal action filed

within this timeframe. Table 15 summarizes the proposed changes related
to the 45-day period after receipt of notice of paragraph IV
certification. We seek comment on the proposed notification requirement
and alternative ways for FDA to monitor compliance with the FD&C Act.

  Table 15--Highlights of Proposed Changes Regarding the 45-Day Period
        After Receipt of Notice of Paragraph IV Certification \1\
------------------------------------------------------------------------
                                                Proposed revisions to
            Current regulations                      regulations
------------------------------------------------------------------------
Computation of 45-day time clock (Sec.      Computation of 45-day time
 314.107(f)(1))                              clock (Sec.
                                             314.107(f)(1))
 The 45-day clock described in       The 45-day clock
 Sec.   314.107(b)(3) begins on the day      described in Sec.
 after the date of receipt of the            314.107(b)(3) as to each
 applicant's notice of certification by      recipient required to
 the patent owner or its representative,     receive notice of paragraph
 and by the approved application holder.     IV certification under Sec.
                                              Sec.   314.52 or 314.95
                                             begins on the day after the
                                             date of receipt of the
                                             applicant's notice of
                                             certification by each
                                             recipient.
Computation of 45-day time clock (Sec.      Notification of filing of
 314.107(f)(2))                              legal action (Sec.
                                             314.107(f)(2)(i) to
                                             (f)(2)(ii))
 The 505(b)(2) or ANDA applicant     The 505(b)(2) or
 must notify FDA immediately of the filing   ANDA applicant must notify
 of any legal action filed within 45 days    FDA in writing within 14
 of receipt of the notice of                 days of the filing of any
 certification.                              legal action filed within
                                             45 days of receipt of the
                                             notice of certification by
                                             any recipient.
 The notification to FDA of the      The notification to
 legal action must include, among other      FDA of the legal action
 things: (iv) A certification that an        must include, among other
 action for patent infringement identified   things: (iv) A statement
 by number, has been filed in an             that an action for patent
 appropriate court on a specified date.      infringement, identified by
 A patent owner or its               the court, case number and
 representative may also notify FDA of the   the patent number(s) of the
 filing of any legal action for patent       patent(s) at issue in the
 infringement.                               action, has been filed in
                                             an appropriate court on a
                                             specified date.
                                             A patent owner or
                                             NDA holder (or their
                                             representatives) may also
                                             notify FDA of the filing of
                                             any legal action for patent
                                             infringement.
Computation of 45-day time clock (Sec.      Notification of filing of
 314.107(f)(2))                              legal action (Sec.
                                             314.107(f)(2)(iii))
 If the 505(b)(2) or ANDA            If the 505(b)(2) or
 applicant or the patent owner or its        ANDA applicant, the patent
 representative does not notify FDA in       owner(s), the NDA holder,
 writing before the expiration of the 45-    or their representatives do
 day time period or the completion of the    not notify FDA in writing
 Agency's review of the application,         before the expiration of
 whichever occurs later, that a legal        the 45-day time period or
 action for patent infringement was filed    the completion of the
 within 45 days of receipt of the notice     Agency's review of the
 of certification, approval of the           505(b)(2) application or
 505(b)(2) application or ANDA will be       ANDA, whichever occurs
 made effective immediately upon             later, that a legal action
 expiration of the 45 days or upon           for patent infringement was
 completion of FDA's review and approval     filed within 45 days of
 of the application, whichever is later.     receipt of the notice of
                                             paragraph IV certification,
                                             the 505(b)(2) application
                                             or ANDA may be approved
                                             upon expiration of the 45-
                                             day period (if the
                                             505(b)(2) or ANDA applicant
                                             confirms that a legal
                                             action for patent
                                             infringement has not been
                                             filed) or upon completion
                                             of FDA's review of the
                                             505(b)(2) application or
                                             ANDA, whichever is later.
Computation of 45-day time clock (Sec.      Waiver (Sec.
 314.107(f)(3))                              314.107(f)(3))
 If the patent owner or approved     If the patent owner
 application holder who is an exclusive      or NDA holder who is an
 patent licensee waives its opportunity to   exclusive patent licensee
 file a legal action for patent              (or their representatives)
 infringement within 45 days of a receipt    waives its opportunity to
 of the notice of certification and the      file a legal action for
 patent owner or approved application        patent infringement within
 holder who is an exclusive patent           45 days of a receipt of the
 licensee submits to FDA a valid waiver      notice of certification and
 before the 45 days elapse, approval of      the patent owner or NDA
 the ANDA or the 505(b)(2) application       holder who is an exclusive
 will be made effective upon completion of   patent licensee (or their
 FDA's review and approval of the            representatives) submits to
 application. FDA will only accept a         FDA a valid waiver before
 waiver in the form specified in Sec.        the 45 days elapse, the
 314.107(f)(3)).                             505(b)(2) application or
                                             ANDA may be approved upon
                                             completion of the Agency's
                                             review of the application.
                                             FDA will only accept a
                                             waiver in the form
                                             specified in Sec.
                                             314.107(f)(3), as proposed
                                             for revision.
------------------------------------------------------------------------
\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.  314.107(f)(1) to clarify that the
45-day period after receipt of notice of paragraph IV certification is
calculated for each recipient required to be notified under Sec. Sec.
314.52(a) and 314.95(a). This proposed revision would codify FDA's
longstanding interpretation of section 505(b)(3) and (j)(2)(B) of the
FD&C Act, as amended by the MMA. This interpretation ensures that each
person required to receive notice under Sec.  314.52 or Sec.  314.95,
as applicable, also receives the full 45-day period in order to
evaluate whether to initiate an action for patent infringement and
obtain a 30-month (or 7\1/2\-year) stay of approval while litigation is
pending. Accordingly, a 505(b)(2) or ANDA applicant's notice of
paragraph IV certification may result in more than one ``45-day clock''
if the NDA holder and patent owners(s) are different entities and
receive notice of paragraph IV certification on different days.
    Proposed Sec.  314.107(f)(2) would require that a 505(b)(2) or ANDA
applicant notify FDA in writing within 14 calendar days of the filing
of any legal action filed within 45 days of receipt of the notice of
certification. We are proposing to replace the current requirement for
``immediate'' notification to establish a date certain by which the
applicant must send written notification to FDA. This revision is
intended to enhance compliance and conform with proposed Sec.
314.107(e), which would require a 505(b)(2) or ANDA applicant to submit
notification of court actions and documented agreements (and a copy of
certain court actions) to FDA within 14 calendar days of entry by the
court, the date of appeal or expiration of the time for appeal, or the
date of documented agreement, as applicable (see section II.M.5).
    We also are proposing to revise Sec.  314.107(f)(2)(iv)
(redesignated as Sec.  314.107(f)(2)(i)(D)) to eliminate the
requirement that the notification to the Agency include a
``certification'' that an action has been filed. This requirement has
resulted in confusion, and the Agency has concluded that a written
``statement'' containing the necessary information is adequate. We are
proposing to require that this statement contain the patent number(s)
of the listed patent(s) at issue in the patent infringement action, in
addition to the court and case number. The patent number(s) of the
listed patent(s) at issue in the litigation will assist FDA in its
administration of the approval

requirements for 505(b)(2) applications and ANDAs.
    We are proposing to expressly state that an NDA holder or its
representative also may notify FDA of the filing of any legal action
for patent infringement, irrespective of whether the NDA holder is an
exclusive patent licensee and initiated the patent infringement action.
The notification must be sent to the appropriate office or division and
contain the information described in proposed Sec.  314.107(f)(2)(i).
    Proposed Sec.  314.107(f)(2)(iii) clarifies that a 505(b)(2)
application or ANDA may be approved upon expiration of the 45-day
period (if the 505(b)(2) or ANDA applicant confirms that a legal action
for patent infringement has not been filed within the 45-day period) or
upon completion of FDA's review of the 505(b)(2) application or ANDA,
whichever is later. This provision would apply, for example, if an
applicant changed a paragraph III certification or a statement pursuant
to section 505(b)(2)(B) or 505(j)(2)(A)(viii), as applicable, to a
paragraph IV certification during review of the 505(b)(2) application
or ANDA and the 45-day period had not elapsed by the time the office or
division was ready to take an action on the application. It is unlikely
that this provision would be implicated in most cases, however, because
a 505(b)(2) or ANDA applicant is required by statute to provide notice
of paragraph IV certification not later than 20 days after the date of
the postmark on the acknowledgment letter or paragraph IV
acknowledgment letter, and review of an application would not be
expected to be completed before the 45-day period for each recipient
had ended. The proposed revisions to Sec.  314.107(f)(2)(iii) and
(f)(3) would replace the current references to the approval of a
505(b)(2) application or ANDA being made effective because this text
incorrectly suggests that FDA might issue an approval letter that would
become effective at some date in the future (see section II.A.2.dd and
II.I). In addition, proposed Sec.  314.107(f)(2)(iii) clarifies that
FDA would not approve a 505(b)(2) application or ANDA upon expiration
of the 45-day period unless the 505(b)(2) or ANDA applicant had
confirmed that a legal action for patent infringement had not been
filed.
    Proposed Sec.  314.107(f)(3) would permit a representative of the
patent owner or NDA holder who is an exclusive patent licensee to waive
the opportunity to file a patent infringement action within the 45-day
period. This revision is intended to conform with other sections of
part 314, including Sec. Sec.  314.52 and 314.95 which permit notice of
paragraph IV certification to be sent to a representative designated by
the patent owner to receive notice and the NDA holder's attorney,
agent, or other authorized official.
    Finally, we are proposing to revise the title to Sec.  314.107(f)
and add titles to paragraphs (f)(1), (f)(2), and (f)(3) of that section
for administrative convenience.
II.M.7. Conversion of Approval to Tentative Approval (Proposed Sec.
314.107(g))
    We are proposing to add Sec.  314.107(g) to clarify that if FDA
issues an approval letter in error or a court enters an order requiring
that the date of approval be delayed for an already approved 505(b)(2)
application or ANDA, FDA will convert the approval to a tentative
approval if appropriate.
    An approved application may be converted to tentatively approved
status if a court determines that a listed patent has been infringed by
a 505(b)(2) or ANDA applicant and issues an order pursuant to 35 U.S.C.
271(e)(4) requiring that the effective date of approval shall not be
earlier than the date on which the infringed patent will expire,
including any pediatric exclusivity that may attach to that patent
(see, e.g., Mylan Labs., Inc. v. Thompson, 389 F.3d 1272 (D.C. Cir.
2004)). In addition, FDA will convert an approval to tentatively
approved status if the approval letter was issued in error (for
example, if an ANDA applicant failed to notify FDA of an adverse
decision in patent infringement litigation).

II.N. Assessing Bioavailability and Bioequivalence for Drugs Not
Intended To Be Absorbed Into the Bloodstream (Proposed Sec.  320.23)

    The MMA amends section 505(j)(8) of the FD&C Act to explicitly
authorize FDA to establish methods for assessing bioavailability and
bioequivalence for drugs that are not absorbed into the bloodstream
(see section 505(j)(8)(A)(ii) and (j)(8)(C) of the FD&C Act). These
amendments essentially codify our existing practice of establishing
such methods, as reflected in current Sec. Sec.  320.23(a)(1) and
320.24 and in our implementation of these regulations.
    Our proposal would revise the text of Sec.  320.23 to more
precisely reflect the text of section 505(j)(8) of the FD&C Act.
However, these proposed revisions are not intended to change our
current interpretation of Sec.  320.23, as the amendments to section
505(j)(8) of the FD&C Act are intended to codify our existing
interpretation (see section 1103(b) of the MMA, which specifically
states that the amendments made to section 505(j)(8) of the FD&C Act
``do[] not alter the standards for approval of [ANDAs].'').

II.O. Miscellaneous

II.O.1. Clarifying Revisions and Editorial Changes
    We are proposing several clarifying revisions and editorial changes
throughout the sections of parts 314 and 320 that are the subject of
this rulemaking. These changes are intended to promote consistency
throughout our regulations, incorporate ``plain language,'' employ
grammatically correct phrasing, and otherwise clarify the text of these
regulations. Examples of proposed revisions that are not otherwise
described in this document are provided below.
     Change ``means'' to ``is'' after each term described in
the definitions section (see proposed Sec.  314.3(b));
     change ``shall'' to ``must'' as appropriate (see generally
part 314);
     change ``are required'' to ``must'' because an applicant
is always required to comply with applicable regulations (see proposed
Sec.  314.50(d)(5));
     change ``prior to the submission of'' to ``before
submitting'' for clarity (see proposed Sec.  314.50(d)(5));
     change ``claims no uses'' to ``does not claim a use'' to
correct grammar (see proposed Sec. Sec.  314.52(a) and 314.95(a)); and
     change ``each amendment to Sec.  314.50(d)(1)'' to ``each
amendment to a section of the NDA described in Sec.  314.50(d)(1)'' for
clarity (see proposed Sec.  314.60(d)).
    In the codified section of this proposed rule, we have indicated
proposed editorial changes as amendatory instructions to remove and add
text. In some instances, however, it was necessary to print an entire
paragraph to indicate proposed changes that are only editorial changes
and would not affect substantive portions of the proposed rule.
    We also are proposing to correct statutory citations in part 314
that have changed due to a series of amendments to the FD&C Act (see,
e.g., proposed Sec. Sec.  314.52(c), 314.60(c), and 314.95(c) and (f)).
II.O.2. Effect of Other Rulemaking
    In anticipation of the Agency's business process efforts to move
all submissions to FDA to electronic submission, we are proposing
certain revisions to provisions that clearly contemplate submission of
paper to facilitate the transition to electronic submissions and reduce
the volume of conforming revisions that may be needed in the future.
Examples of these proposed revisions are provided below:

     Change ``in a form other than hard copy, for example, on
microfiche or computer tapes'' to ``in an alternate form'' to reflect
advances in technology and facilitate the transition to electronic
submissions (see proposed Sec.  314.50(f)(4));
     delete references to ``mailing cover'' (see proposed
Sec. Sec.  314.53(d)(6) and 314.70(b)(4)); and
     change ``cover letter'' to ``submission'' (see proposed
Sec.  314.70(a)(6)).
    FDA is committed to adapting its business practices to evolving
technology, including using the significant advancements in Web-based,
electronic systems. We anticipate that Web-based filing of most
submissions eventually will be required. We anticipate that when such a
change to an electronic submission system is implemented, future
guidance will address any technical questions related to such
submissions. Until such time, the sponsor or applicant must submit them
in the manner described in the regulations and to the appropriate FDA
location identified in the regulations.

III. Legal Authority

    The MMA and sections 505, 505A, 527, and 701 (21 U.S.C. 360cc and
371) of the FD&C Act provide the principal legal authority for this
proposed rule. Section 505(b) of the FD&C Act describes the contents of
an NDA and 505(b)(2) application, including patent listing and patent
certification requirements. Section 505(j) of the FD&C Act describes
the contents of an ANDA, including bioequivalence information, patent
certification requirements, and criteria for a petitioned ANDA. Section
505(b) and (j) of the FD&C Act restrict certain amendments and
supplements to a 505(b)(2) application or an ANDA. Section 505(b), (c),
and (j) of the FD&C Act describe the timing of approval for 505(b)(2)
applications and ANDAs that are subject to the patent and marketing
exclusivity protections accorded the listed drug(s) relied upon and the
RLD, respectively. Section 505(j) also describes the availability of
180-day exclusivity for a first ANDA applicant.
    Section 505A of the FD&C Act describes the availability of
pediatric exclusivity and describes the effect of such exclusivity on
approval of 505(b)(2) applications and ANDAs. Section 527 of the FD&C
Act describes the effect of orphan exclusivity on approval of 505(b)(2)
applications and ANDAs.
    Thus, sections 505, 505A, and 527 of the FD&C Act, in conjunction
with our general rulemaking authority in section 701(a) of the FD&C
Act, serve as our principal legal authority for this proposal.

IV. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct Agencies to assess all
costs and benefits of available regulatory alternatives and, when
regulation is necessary, to select regulatory approaches that maximize
net benefits (including potential economic, environmental, public
health and safety, and other advantages; distributive impacts; and
equity).
    The Regulatory Flexibility Act requires Agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. We do not believe this proposed rule would result in
a significant impact on a substantial number of small entities, but the
impacts are uncertain. Because we are uncertain whether the proposed
rule would have a significant economic impact on a substantial number
of small entities, this and other sections of the preamble and the full
preliminary regulatory impact analysis constitute the Agency's
regulatory flexibility analysis.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that Agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $141 million, using the most current (20132) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
proposed rule to result in any 1-year expenditure that would meet or
exceed this amount.
    This proposed rule would implement portions of the MMA in a manner
that preserves the balance struck in the 1984 Hatch-Waxman Amendments
between encouraging the availability of less expensive generic drugs
and bringing innovative new drugs to market. This rule would also
revise and clarify procedures related to the approval of 505(b)(2)
applications and ANDAs to reduce uncertainty among drug firms, reduce
costs to industry, and reduce demands on FDA resources responding to
industry inquiries.
    FDA has been implementing the MMA directly from the statute for
several years and based on this experience has identified opportunities
to clarify MMA provisions through the adoption of codified language. To
the extent that clarified regulatory language improves certainty among
regulated entities, this proposal, if promulgated, would reduce
industry compliance costs and Agency enforcement costs. The full
discussion of economic impacts is available in docket FDA-2011-N-0830
and at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm (Ref. 1).

IV.A. Summary of the Benefits and Costs of the Proposed Rule

    Although many provisions of this proposed rule would codify current
practice, elements of this proposal would lead to changes that generate
additional benefits and costs. This proposed rule would affect
applicants and application holders for NDAs (including 505(b)(2)
applications) and ANDAs. Provisions of this rule would affect the
submission of patent information by NDA holders for listing in the
Orange Book and the submission by 505(b)(2) and ANDA applicants of a
patent certification or statement addressing the listed patent(s) for
the listed drug(s) relied upon or RLD, respectively. This proposed rule
would also affect, for those certifying that a listed patent is
invalid, unenforceable, or not infringed (paragraph IV certification),
the requirements for the provision of notice of the paragraph IV
certification to each patent owner and the NDA holder for the listed
drug. The proposed rule would also affect other requirements associated
with 505(b)(2) applications and ANDAs.
    This proposed rule would revise certain aspects of the regulations
on listing of patent information, patent certification requirements,
and a 30-month stay of approval. It would also update regulations
pertaining to the type of bioavailability and bioequivalence data that
can be used to support 505(b)(2) applications and ANDAs. These proposed
revisions to the Agency's regulations in parts 314 and 320 would
implement portions of Title XI of the MMA and facilitate compliance
with and enforcement of the FD&C Act.
    We present a summary of benefits and costs in Table 16. The
estimated annual monetized benefits of this proposed rule are $194,314,
and estimated annual monetized costs are $91,371. We have also
identified, but are unable to

quantify, impacts from proposed changes to submitted patent information
and the implementation of an administrative consequence for failing to
provide notice within the timeframe specified by the MMA.

                                                  Table 16--Economic Data: Costs and Benefits Statement
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Units
                                                                      Primary      Low        High   ---------------------------------------
                              Category                                estimate   estimate   estimate      Year       Discount      Period       Notes
                                                                                dollars        rate       covered
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits
    Annualized Monetized $millions/year............................      $0.19      $0.19      $0.19  ...........           7%       Annual  ...........
                                                                         $0.19      $0.19      $0.19  ...........           3%       Annual  ...........
    Annualized Quantified..........................................  .........  .........  .........  ...........           7%       Annual  ...........
                                                                                ...........
    Qualitative....................................................  .........  .........  .........  ...........           3%       Annual  ...........
Costs
    Annualized Monetized $millions/year............................      $0.09      $0.09      $0.09         2012           7%       Annual  ...........
                                                                         $0.09      $0.09      $0.09         2012           3%       Annual  ...........
    Annualized Quantified..........................................  .........  .........  .........  ...........           7%  ...........  ...........

    Qualitative....................................................  .........  .........  .........  ...........           3%               ...........
Transfers
    Federal Annualized Monetized $millions/year....................  .........  .........  .........  ...........           7%  ...........        None.
                                                                     .........  .........  .........  ...........           3%               ...........
    From/To........................................................      From:        To:
    Other Annualized Monetized $millions/year......................  .........  .........  .........  ...........           7%  ...........        None.

    From/To........................................................      From:        To:                                   3%
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects
State, Local, or Tribal Government: Not applicable
Small Business: For firms with 25 to 49 employees, which is a more likely lower bound for firms submitting 505(b)(2) applications, the unit cost of this
 provision would be less than 0.05 percent of average shipments.
Wages: No estimated effect
Growth: No estimated effect
--------------------------------------------------------------------------------------------------------------------------------------------------------

IV.B. Summary of Regulatory Flexibility Analysis

    FDA conducted a regulatory flexibility analysis of the impact of
the proposed rule on small entities. Statistics on the classification
of firms by employment size from the U.S. Bureau of the Census show
that in 2005, at least 85 percent of pharmaceutical manufacturing
entities had fewer than 500 employees and would have been considered
small by the U.S. Small Business Administration (Ref. 2).
    We have provided monetized estimates for $194,314 in benefits and
$91,371 in costs. These costs of this proposed rule are generally small
unit costs incurred across many entities. Our estimated unit costs for
all but one item are less than $190 per unit. In table 17, we express
the unit cost of an amendment to a patent certification in terms of
hundredths of a percent of average establishment shipments. Excluding
one item (505(b)(2) applicants providing a patent certification to a
pharmaceutically equivalent drug product), there are costs of $83,146
attributable to about 1,200 units. Some affected entities would face
multiple unit costs of some type in a year, but even this circumstance
would not approach a significant impact on a substantial number of
small entities. For a unit cost of $190 to amount to 1 percent of
average shipments among establishment with fewer than 5 employees, the
entity would have to incur that cost more than 40 times.

   Table 17--Small Entity Characteristics and the Impact of Unit Costs
                   Attributable to This Proposed Rule
------------------------------------------------------------------------

------------------------------------------------------------------------
                                          Pharmaceutical Preparation
                                                 Manufacturing
                                                (NAICS 325412)
------------------------------------------------------------------------
No. of Employees....................                <5             20-49
Total Value of Shipments ($1,000)...           187,933           978,494
No. of Establishments...............               228               109
Average Value of Shipments ($)......           824,268         8,977,009
Unit Costs of Identifying a                      0.50%            0.046%
 Pharmaceutically Equivalent Drug
 Product as a Listed Drug Relied
 Upon per Sec.   314.50(i)(1)(i)(C)
 as a Percentage of the Average
 Value of Shipments.................
------------------------------------------------------------------------

V. Paperwork Reduction Act of 1995

    This proposed rule contains information collection requirements
that are subject to public comment and review by the Office of
Management and Budget (OMB) under the Paperwork Reduction Act of 1995
(44 U.S.C. 3501-3520). We describe these provisions below in this
section of the document with an estimate of the annual reporting
burden. Our estimate includes the time for reviewing instructions,
searching existing data sources, gathering and maintaining the data
needed, and completing and reviewing each collection of information.

    We invite comments on these topics: (1) Whether the proposed
collection of information is necessary for the proper performance of
FDA's functions, including whether the information will have practical
utility; (2) the accuracy of FDA's estimate of the burden of the
proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information to be collected; and (4) ways
to minimize the burden of the collection of information on respondents,
including through the use of automated collection techniques, when
appropriate, and other forms of information technology.
    Title: Abbreviated New Drug Applications and 505(b)(2)
Applications; Proposed Revisions to Implement Portions of the Medicare
Prescription Drug, Improvement, and Modernization Act of 2003 and Other
Changes.
    Description of Respondents: Respondents to this collection of
information are NDA applicants (including 505(b)(2) applicants) and
ANDA applicants, patent owners, and their representatives.
    Burden Estimate: This proposed rule would implement portions of
Title XI of the MMA that pertain to a 505(b)(2) or ANDA applicant's
provision of notice of paragraph IV certification to each patent owner
and the NDA holder; the availability of 30-month stays of approval on
505(b)(2) applications and ANDAs that are otherwise ready to be
approved; submission of amendments and supplements to 505(b)(2)
applications and ANDAs; and the types of bioavailability and
bioequivalence data that can be used to support these applications.
This proposed rule also would amend certain regulations regarding
505(b)(2) applications and ANDAs to facilitate compliance with and
efficient enforcement of the FD&C Act.
    FDA currently has OMB approval for the collection of information
entitled ``Application for Food and Drug Administration Approval to
Market a New Drug'' (OMB control number 0910-0001). This collection of
information includes, among other things:
     The requirements in Sec. Sec.  314.50(i) and 314.94(a)(12)
for submission of an appropriate patent certification or statement in a
505(b)(2) application or ANDA;
     the requirements in Sec. Sec.  314.52 and 314.95 for a
505(b)(2) or ANDA applicant to send notice of any paragraph IV
certification to each patent owner and the NDA holder and amend its
505(b)(2) application or ANDA to certify that notice has been provided
and to document receipt of the notice;
     the content requirements in Sec.  314.54 for a 505(b)(2)
application;
     the requirements in Sec. Sec.  314.60 and 314.96 for
applicants that amend an unapproved 505(b)(2) application or ANDA,
respectively;
     the requirements in Sec. Sec.  314.70 and 314.97 for
supplements submitted to FDA for certain changes to an approved
505(b)(2) application or ANDA;
     the requirements in Sec. Sec.  314.90 and 314.99 for
applicants that request waivers from FDA for compliance with Sec. Sec.
314.50 through 314.81 or Sec. Sec.  314.92 through 314.99,
respectively;
     the procedures in Sec.  314.107(c) by which a first
applicant notifies FDA of the date of first commercial marketing;
     the requirement in Sec.  314.107(e) for an applicant to
submit to FDA a copy of certain court decisions related to a patent
that is the subject of a paragraph IV certification;
     the requirement in Sec.  314.107(f) for a 505(b)(2) or
ANDA applicant to notify FDA immediately of the filing of any legal
action within 45 days of receipt of the notice of paragraph IV
certification by each patent owner or the NDA holder; and
     the requirement in Sec.  314.107(f) for a patent owner or
NDA holder who is an exclusive patent licensee that waives its
opportunity to file a legal action for patent infringement within the
45-day period to submit to FDA a waiver in the specified format.
    FDA has OMB approval for the collection of information entitled
``General Administrative Procedures: Citizen Petitions; Petition for
Reconsideration or Stay of Action; Advisory Opinions'' (OMB control
number 0910-0183). This collection of information includes, among other
things, the requirements in Sec.  314.93 for submitting a suitability
petition in accordance with 21 CFR 10.20 and 10.30.
    FDA also has received OMB approval for the collection of
information entitled ``Applications for Food and Drug Administration
Approval to Market a New Drug: Patent Submission and Listing
Requirements and Application of 30-Month Stays on Approval of
Abbreviated New Drug Applications Certifying That a Patent Claiming a
Drug is Invalid or Will Not Be Infringed'' (OMB control number 0910-
0513). This collection of information includes the requirements in
Sec.  314.50(h) for submission of patent information in an NDA, an
amendment, or a supplement, as described in Sec.  314.53. Section
314.53 requires that an applicant submitting an NDA, an amendment, or a
supplement, except as provided in Sec.  314.53(d)(2), submit on Forms
FDA 3542a and 3542 the required patent information described in this
section.
    We are not reestimating these approved burdens. Only the reporting
burdens associated with the MMA's amendments to the FD&C Act and the
proposed changes to parts 314 and 320 are estimated.
    Under section 505(b), (c), and (j) of the FD&C Act and this
proposed rule, the following information would be submitted to FDA but
is not currently approved by OMB under the PRA:
    Proposed Sec.  314.50(i)(1)(i)(C) would require a 505(b)(2)
applicant to submit an appropriate patent certification or statement
for each patent listed in the Orange Book for a drug product(s) that is
pharmaceutically equivalent to the proposed drug product for which the
505(b)(2) application is submitted. Proposed Sec.  314.54 would require
a 505(b)(2) applicant to identify a pharmaceutically equivalent product
as a listed drug relied upon and to comply with applicable regulatory
requirements. Generally, 505(b)(2) applications submitted for a
proposed drug product for which there is an approved pharmaceutical
equivalent already cite the pharmaceutically equivalent product as a
listed drug relied upon to support approval. Therefore, we are not
estimating a new burden for proposed Sec.  314.54 at this time. Based
on our experience reviewing 505(b)(2) applications, we estimate that
proposed Sec.  314.50(i)(1)(i)(C) may result in approximately two
instances per year in which an applicant is required to identify a
pharmaceutically equivalent drug product as a listed drug relied upon
and comply with applicable regulatory requirements (including
submission of an appropriate patent certification or statement for each
patent listed in the Orange Book for the pharmaceutically equivalent
listed drug relied upon). Based on an estimated average of 2.6 patents
by each NDA holder for listing in the Orange Book, we estimate that
there will be 5.2 responses per year, and the burden hours associated
with this requirement in proposed Sec.  314.50(i)(1)(i)(C) will be
approximately 2 hours per response. If the patent certification
submitted pursuant to proposed Sec.  314.50(i)(1)(i)(C) is a paragraph
IV certification, the applicant also must comply with the requirements
in Sec.  314.52 for notice of paragraph IV certification, which add

approximately 80 hours (15.33 hours per response) to the currently
approved burden hours. This estimate reflects other proposals described
in this section of the document that would reduce the currently
approved burden for Sec.  314.52 from 16 hours per response to 15 hours
per response, and the additional content requirement in proposed Sec.
314.52(c) that would increase the estimated burden by 0.33 hours per
response. As previously noted, we are not reestimating approved burdens
in this document. Accordingly, the estimate provided for Sec.
314.52(a), (b), (c), and (e) reflects the additional burden that may
arise from the requirement in proposed Sec.  314.50(i)(1)(i)(C) if the
505(b)(2) applicant submits a paragraph IV certification. We separately
describe and estimate the burden of the additional content requirement
in proposed Sec.  314.52(c) for the estimated average of seven
505(b)(2) applications filed per year that contain one or more
paragraph IV certification.
    Proposed Sec. Sec.  314.50(i)(6) and 314.94(a)(12)(viii) would
require a 505(b)(2) or ANDA applicant to amend its patent certification
from a paragraph IV certification to a paragraph III certification
after the court enters a final decision from which no appeal has been
or can be taken, or signs a settlement order or consent decree with a
finding of infringement (unless the patent also is found invalid).
Proposed Sec. Sec.  314.50(i)(6) and 314.94(a)(12)(viii) also would
require a 505(b)(2) or ANDA applicant to submit an amended patent
certification in certain circumstances after the NDA holder has
requested to remove a patent or patent information from the list. Based
on our experience and review of selected court decisions, we estimate
that there are approximately 12 instances per year in which a party has
submitted a court decision or order with a finding of infringement. In
addition, there are approximately 24 instances per year in which the
NDA holder has requested to remove a patent or patent information from
the list and the patent or patent information has been removed. Based
on our experience, we estimate that this requirement may result in
approximately 36 and 108 instances per year in which an applicant
amends its 505(b)(2) application or ANDA, respectively, to submit a
revised patent certification, and the burden hours associated with this
requirement will be approximately 2 hours per response. Proposed
Sec. Sec.  314.50(i)(6)(iii)(A)(2) and 314.94(a)(12)(vi)(C)(1)(ii)
would expressly codify the current requirement for a 505(b)(2) or ANDA
applicant to submit a patent certification or statement if, after
submission of the application, 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 an approved use for such listed drug and for
which information is required to be filed by the NDA holder. The burden
hours associated with compliance with current provisions of Sec. Sec.
314.50(i)(1) through (i)(6) and 314.94(a)(12)(i) through (a)(12)(viii)
are described in the burden hours estimate currently approved under OMB
control number 0910-0001.
    Proposed Sec. Sec.  314.52(a) and 314.95(a) would 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, and
thereby reduce the burden on applicants to submit, under current
Sec. Sec.  314.52(a) and (e), a request to FDA to use common alternate
delivery methods. We receive approximately 205 written inquiries per
year from 505(b)(2) or ANDA applicants requesting permission to send
notice of paragraph IV certification by an overnight delivery service.
Proposed Sec. Sec.  314.52(a) and 314.95(a) would eliminate the
requirement to submit a request to use a designated delivery service,
as defined in proposed Sec. Sec.  314.52(f) and 314.95(f). We estimate
that approximately 95 percent of these written inquiries will no longer
be required because the alternate delivery method would fall within the
definition of a ``designated delivery service'' in proposed Sec. Sec.
314.52(g) and 314.95(g).
    Proposed Sec. Sec.  314.52(c) and 314.95(c) would require that
notice of paragraph IV certification contain a statement that the
applicant has received the acknowledgment letter or the paragraph IV
acknowledgment letter, as applicable. In addition, proposed Sec.
314.52(c) would require that the notice of paragraph IV certification
contain a statement that a 505(b)(2) application that contains any
required bioavailability or bioequivalence data has been submitted by
the applicant and filed by FDA, as required by section 505(b)(3)(D)(i)
of the FD&C Act. We estimate that these additional content requirements
for the notice of paragraph IV certification would increase the burden
of providing notice of paragraph IV certification by approximately 20
minutes. Based on an estimated average of 7 505(b)(2) applications
filed per year that contain one or more paragraph IV certifications and
209 ANDAs received per year that contain one or more paragraph IV
certifications, we estimate that there will be 21 and 627 responses per
year, and the burden hours associated with this requirement will be
approximately 20 minutes per response.
    Proposed Sec. Sec.  314.52(d)(1) and 314.95(d)(1) would require
notice of paragraph IV certification regardless of whether notice has
already been provided for another paragraph IV certification contained
in the 505(b)(2) application or ANDA or an amendment or supplement to
the 505(b)(2) application or ANDA, as required by section
505(b)(3)(B)(ii) and (j)(2)(B)(ii)(II) of the FD&C Act. Since enactment
of the MMA, FDA has regulated directly from the statute and required
notice of paragraph IV certification in these circumstances. Thus, the
burden associated with this statutory requirement is reflected in the
burden hours estimate for Sec. Sec.  314.52 and 314.95 currently
approved under OMB control number 0910-0001.
    Proposed Sec. Sec.  314.52(e) and 314.95(e) would permit a
505(b)(2) or ANDA applicant to submit a single amendment containing
documentation of timely sending and receipt of notice of paragraph IV
certification. Currently, an applicant is required to amend its
505(b)(2) application or ANDA both at the time of sending notice of
paragraph IV certification and after the notice was received by each
patent owner and the NDA holder (see current Sec. Sec.  314.52(b) and
(e) and 314.95(b) and (e)). Proposed Sec.  314.95(e) also would require
an ANDA applicant to include in its amendment a dated printout of the
Orange Book entry for the RLD. FDA has OMB approval for the burden
hours estimate of 16 hours per response for the estimated 260 responses
submitted annually to comply with Sec. Sec.  314.52 and 314.95 (see OMB
control number 0910-0001). We estimate that 2 hours of the 16 hours per
response are attributable to compliance with current Sec. Sec.
314.52(b) and (e) and 314.95(b) and (e). We estimate that the burden
hours associated with the requirement in proposed Sec. Sec.  314.52(e)
and 314.95(e) (including submission of the dated printout of the Orange
Book entry) would be approximately 1 hour per response for each of the
estimated 7 and 209 responses per year by our updated estimate of 7
505(b)(2) applicants and 209 ANDA applicants whose applications were
filed or received, as applicable, by FDA and contained one or more
paragraph IV certifications. Therefore, the proposal would reduce the
currently approved burden for Sec. Sec.  314.52 and 314.95 by 1 hour.
    Proposed Sec.  314.53(c)(2) would decrease the patent information
that NDA applicants are currently required to submit for listing in the
Orange Book.

Proposed Sec.  314.53(c)(2) would require an NDA applicant to submit
information on a previously submitted patent only if a patent is a
reissued patent of a patent previously submitted for listing for the
NDA or supplement. Proposed Sec.  314.53(c)(2) would require submission
of patent information on whether a drug substance patent claims a
polymorph only if such patent claims only a polymorph that is the same
active ingredient described in the NDA or supplement. Proposed Sec.
314.53(c)(2) also would provide that an applicant that submits
information for a patent that claims either the drug substance or drug
product and meets the requirements for patent listing on that basis is
not required to provide information on whether that patent also claims
the drug product or drug substance, respectively. The information
collection resulting from current Sec.  314.50(h) (citing Sec.  314.53)
and Form FDA 3542a has been approved by OMB under control number 0910-
0153 for FDA's estimate of 20 hours per response. We estimate the
proposed revisions to our regulations will reduce the time needed to
complete Form FDA 3542a by approximately 3 hours per response.
    Proposed Sec.  314.53(d)(2) would enable FDA to reduce duplicative
submission of patent information and require such information only for
a supplement to change the dosage form or route of administration, to
change the strength, to change the drug product from prescription to
OTC use, or to correct previously submitted patent information that
differently or no longer claims the changed product.
    Proposed Sec.  314.53(f)(2) would expressly require correction or
change of patent information if the NDA holder determines that a patent
or patent claim no longer meets the statutory requirements for listing,
if the NDA holder is required by court order to amend patent
information or withdraw a patent from the list, or if the term of a
listed patent is extended under 35 U.S.C. 156(e). We estimate that
these corrections and changes of patent information would result in
approximately 62 submissions of Form FDA 3542 or other written
submission, as provided in proposed Sec.  314.53(f)(2)(iv), by
approximately 39 NDA holders. We further estimate that the burden hours
associated with the requirement in proposed Sec.  314.53(f)(2) would be
approximately 1 hour per response.
    Section 505(b)(4)(A) and (j)(2)(D)(i) of the FD&C Act generally
prohibit the submission of certain types of changes in an amendment or
a supplement to a 505(b)(2) application or an ANDA, respectively.
Proposed Sec. Sec.  314.60(e) and 314.70(h) would prohibit an applicant
from amending or supplementing a 505(b)(2) application to seek approval
of a drug that has been modified to have a different active ingredient,
different route of administration, different dosage form, or certain
differences in excipients that the drug proposed in the original
submission of the 505(b)(2) application. These changes must be
requested in a new 505(b)(2) application. This proposed requirement
conforms with FDA's current policy regarding the types of proposed
changes to a drug product that should be submitted as a separate
application (see Separate Marketing Application Guidance). Accordingly,
the burden associated with this statutory requirement is reflected in
the burden hours estimate for Sec. Sec.  314.50 and 314.94 currently
approved under OMB control number 0910-0001 for 505(b)(2) applications
and ANDAs, respectively.
    Proposed Sec. Sec.  314.60(f), 314.70(i), 314.96(d), and 314.97(c)
would require an applicant to submit a patent certification if approval
is sought for either of the following types of amendments or
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.
Proposed Sec. Sec.  314.60(f) and 314.96(d) also would require an
applicant to submit a patent certification if approval is sought for
either of the following types of amendments to a 505(b)(2) application
or ANDA: (1) To make other than minor changes in product formulation or
(2) to change the physical form or crystalline structure of the active
ingredient. Although currently the submission of a patent certification
is required 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 (thus
the burden hours are currently approved under OMB control number 0910-
0001), the patent certification requirements would be broadened under
this proposed rule. We estimate that this requirement may result in
approximately six and four instances per year in which an applicant is
required to submit a patent certification with an amendment or
supplement, respectively, to its 505(b)(2) application. We further
estimate that this requirement may result in approximately 95 and 16
instances per year in which an applicant is required to submit a patent
certification with an amendment or supplement, respectively, to its
ANDA. The burden hours associated with these requirements are estimated
to be approximately 2 hours per response.
    Proposed Sec. Sec.  314.96(c) and 314.97(b) would prohibit an ANDA
applicant from amending or supplementing an ANDA to seek approval of a
drug referring to a listed drug that is different from the RLD
identified in the ANDA. An applicant must submit a change of the RLD in
a new ANDA. We estimate that approximately one ANDA applicant per year
will be required to submit a new ANDA instead of submitting an
amendment for a change of the RLD. We also estimate that approximately
one ANDA applicant per year will be required to submit a new ANDA
instead of submitting a supplement for a change of the RLD. We further
estimate that the burden of submitting an ANDA and complying with
applicable regulatory requirements, including any required study to
demonstrate bioequivalence to the new RLD, will be approximately 288
hours for each of the estimated two responses per year.
    Proposed Sec.  314.107(e) would expand the scope of the court
actions and documented agreements related to a patent described in
Sec.  314.107(b)(3) that are required to be submitted to FDA. Proposed
Sec.  314.107(e) also would require submission of any court order
pursuant to 35 U.S.C. 271(e)(4)(A) ordering that a 505(b)(2)
application or ANDA may be approved no earlier than the date specified.
FDA has OMB approval for the burden hours estimate of 30 minutes per
response for the estimated 98 responses submitted annually by 25
505(b)(2) or ANDA applicants to comply with Sec.  314.107(e) (see OMB
control number 0910-0001). Based on our experience, we estimate that
140 505(b)(2) and ANDA applicants will be required to submit a copy of
a court action, documented agreement, or written notification of appeal
in approximately 310 instances per year. We continue to estimate that
the burden associated with submitting a copy of these documents to FDA
is approximately 30 minutes per response.
    The estimated burden of the burden of this collection of
information is described in Table 18.

                                 Table 18--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                   Number of                     Average burden
        21 CFR section             Number of     responses per   Total annual     per response      Total hours
                                  respondents     respondent       responses       (in hours)
----------------------------------------------------------------------------------------------------------------
314.50(i)(1)..................               2             2.6             5.2  2...............            10.4
314.50(i)(6)..................              36               1              36  2...............              72
314.52(a), (b), (c), and (e)..               2             2.6             5.2  15.33...........            79.7
314.52(c).....................               7               3              21  0.33 (20                       7
                                                                                minutes)..
314.53(f).....................              39             1.5              62  1...............              62
314.60(f).....................               6               1               6  2...............              12
314.70(i).....................               4               1               4  2...............               8
314.94(a)(12).................             108               1             108  2...............             216
314.95(c).....................             209               3             627  0.33 (20                     209
                                                                                minutes)..
314.96(c).....................               1               1               1  288.............             288
314.96(d).....................              95               1              95  2...............             190
314.97(b).....................               1               1               1  288.............             288
314.97(c).....................              16               1              16  2...............              32
314.107(e)....................             140             2.2             310  0.5 (30                      155
                                                                                minutes)..
    Total Reporting Burden      ..............  ..............  ..............  ................          1629.1
     Hours.
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    We have submitted the information collection requirements of this
rule to OMB for review. Interested persons are requested to send
comments regarding information collection to the Office of Information
and Regulatory Affairs, OMB (see ADDRESSES).

VI. Environmental Impact

    The Agency has determined under 21 CFR 25.30(h) and 25.31(a) and
(g) that this action is of a type that does not individually or
cumulatively have a significant effect on the human environment.
Therefore, neither an environmental assessment nor an environmental
impact statement is required.

VII. Effective Date

    FDA proposes that any final rule based on this proposal become
effective 60 days after publication in the Federal Register.
    We intend to apply this rule, if finalized, to any new submission
received by FDA on or after the effective date. This proposed rule
provides sufficient notice to all interested parties, including NDA
holders, NDA applicants (including 505(b)(2) applicants), and ANDA
applicants to adjust their submissions and actions by the time we issue
any final rule. However, we invite comments on how a final rule should
be implemented.

VIII. Federalism

    FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the proposed rule, if finalized, would not contain policies that would
have substantial direct effects on the States, on the relationship
between the National Government and the States, or on the distribution
of power and responsibilities among the various levels of government.
Accordingly, the Agency tentatively concludes that the proposed rule
does not contain policies that have federalism implications as defined
in the Executive order and, consequently, a federalism summary impact
statement is not required.

IX. Request for Comments

    Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) either electronic or written comments regarding this
document. It is only necessary to send one set of comments. Identify
comments with the docket number found in brackets in the heading of
this document. Received comments may be seen in the Division of Dockets
Management between 9 a.m. and 4 p.m., Monday through Friday, and will
be posted to the docket at http://www.regulations.gov.

X. References

    The following references have been placed on display in the
Division of Dockets Management (see ADDRESSES), and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
(FDA has verified the Web site addresses, but we are not responsible
for any subsequent changes to the Web sites after this document
publishes in the Federal Register.)

    1. Preliminary Regulatory Impact Analysis, Initial Regulatory
Flexibility Analysis, and Unfunded Mandates Reform Act Analysis for
Abbreviated New Drug Applications and 505(b)(2) Applications;
Proposed Rule, available at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.
    2. U.S. Department of Commerce, Bureau of the Census, Economic
Census, Manufacturing Industry Series, Pharmaceutical Preparation
Manufacturing, Table 4, EC02-311-325412 (RV), 2002.

List of Subjects

21 CFR Part 314

    Administrative practice and procedure, Confidential business
information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 320

    Drugs, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, FDA proposes
to amend 21 CFR parts 314 and 320 as follows:

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

0
1. The authority citation for 21 CFR part 314 is revised to read as
follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 356,
356a, 356b, 356c, 360cc, 371, 374, 379e.
0
2. Section 314.3 is revised to read as follows:

Sec.  314.3  Definitions.

    (a) The definitions and interpretations contained in section 201 of
the Federal Food, Drug, and Cosmetic Act apply to

those terms when used in this part and part 320 of this chapter.
    (b) The following definitions of terms apply to this part and part
320 of this chapter:
    180-day exclusivity period is the 180-day period beginning on the
date of the first commercial marketing of the drug (including the
commercial marketing of the reference listed drug) by any first
applicant. The 180-day period ends on the day before the date on which
an ANDA submitted by an applicant other than a first applicant could be
approved.
    Abbreviated application, abbreviated new drug application, or ANDA
is the application described under Sec.  314.94, including all
amendments and supplements to the application.
    Acknowledgment letter is a written, postmarked communication from
FDA to an applicant stating that the Agency has determined that a
505(b)(2) application or ANDA is sufficiently complete to permit a
substantive review. An acknowledgment letter indicates that the
505(b)(2) application is regarded as filed or the ANDA is regarded as
received.
    Act is the Federal Food, Drug, and Cosmetic Act (section 201 et
seq. (21 U.S.C. 301 et seq.)).
    Active ingredient is any component that is intended to furnish
pharmacological activity or other direct effect in the diagnosis, cure,
mitigation, treatment, or prevention of disease, or to affect the
structure or any function of the body of man or other animals. The term
includes those components that may undergo chemical change in the
manufacture of the drug product and be present in the drug product in a
modified form intended to furnish the specified activity or effect.
    Active moiety is the molecule or ion, excluding those appended
portions of the molecule that cause the drug to be an ester, salt
(including a salt with hydrogen or coordination bonds), or other
noncovalent derivative (such as a complex, chelate, or clathrate) of
the molecule, responsible for the physiological or pharmacological
action of the drug substance.
    ANDA holder is the applicant that owns an approved ANDA.
    Applicant is any person who submits an NDA (including a 505(b)(2)
application) or ANDA or an amendment or supplement to an NDA or ANDA
under this part to obtain FDA approval of a new drug and any person who
owns an approved NDA (including a 505(b)(2) application) or ANDA.
    Application, new drug application, or NDA is the application
described under Sec.  314.50, including all amendments and supplements
to the application. An NDA refers to ``stand-alone'' applications
submitted under section 505(b)(1) of the Federal Food, Drug, and
Cosmetic Act and to 505(b)(2) applications.
    505(b)(2) application is an NDA submitted under section 505(b)(1)
of the Federal Food, Drug, and Cosmetic Act for a drug for which the
investigations described in section 505(b)(1)(A) of the Federal Food,
Drug, and Cosmetic Act and relied upon by the applicant for approval of
the NDA were not conducted by or for the applicant and for which the
applicant has not obtained a right of reference or use from the person
by or for whom the investigations were conducted.
    Approval letter is a written communication to an applicant from FDA
approving an NDA or an ANDA.
    Assess the effects of the change is to evaluate the effects of a
manufacturing change on the identity, strength, quality, purity, and
potency of a drug product as these factors may relate to the safety or
effectiveness of the drug product.
    Authorized generic drug is a listed drug, as defined in this
section, that has been approved under section 505(c) of the Federal
Food, Drug, and Cosmetic Act and is marketed, sold, or distributed
directly or indirectly to the retail class of trade with labeling,
packaging (other than repackaging as the listed drug in blister packs,
unit doses, or similar packaging for use in institutions), product
code, labeler code, trade name, or trademark that differs from that of
the listed drug.
    Bioavailability is the rate and extent to which the active
ingredient or active moiety is absorbed from a drug product and becomes
available at the site of drug action. For drug products that are not
intended to be absorbed into the bloodstream, bioavailability may be
assessed by scientifically valid measurements intended to reflect the
rate and extent to which the active ingredient or active moiety becomes
available at the site of drug action.
    Bioequivalence is the absence of a significant difference in the
rate and extent to which the active ingredient or active moiety in
pharmaceutical equivalents or pharmaceutical alternatives becomes
available at the site of drug action when administered at the same
molar dose under similar conditions in an appropriately designed study.
Where there is an intentional difference in rate (e.g., in certain
extended release dosage forms), certain pharmaceutical equivalents or
alternatives may be considered bioequivalent if there is no significant
difference in the extent to which the active ingredient or moiety from
each product becomes available at the site of drug action. This applies
only if the difference in the rate at which the active ingredient or
moiety becomes available at the site of drug action is intentional and
is reflected in the proposed labeling, is not essential to the
attainment of effective body drug concentrations on chronic use, and is
considered medically insignificant for the drug. For drug products that
are not intended to be absorbed into the bloodstream, bioequivalence
may be assessed by scientifically valid measurements intended to
reflect the rate and extent to which the active ingredient or active
moiety becomes available at the site of drug action.
    Bioequivalence requirement is a requirement imposed by FDA for in
vitro and/or in vivo testing of specified drug products that must be
satisfied as a condition of marketing.
    Class 1 resubmission is the resubmission of an NDA or efficacy
supplement, following receipt of a complete response letter, that
contains one or more of the following: Final printed labeling, draft
labeling, certain safety updates, stability updates to support
provisional or final dating periods, commitments to perform
postmarketing studies (including proposals for such studies), assay
validation data, final release testing on the last lots used to support
approval, minor reanalyses of previously submitted data, and other
comparatively minor information.
    Class 2 resubmission is the resubmission of an NDA or efficacy
supplement, following receipt of a complete response letter, that
includes any item not specified in the definition of ``Class 1
resubmission,'' including any item that would require presentation to
an advisory committee.
    Commercial marketing is the introduction or delivery for
introduction into interstate commerce of a drug product described in an
approved ANDA, outside the control of the ANDA holder, except for
investigational use under part 312 of this chapter, but does not
include transfer of the drug product for reasons other than sale to
parties identified in the approved ANDA.
    Complete response letter is a written communication to an applicant
from FDA usually describing all of the deficiencies that the Agency has
identified in an NDA or ANDA that must be satisfactorily addressed
before it can be approved.
    Component is any ingredient intended for use in the manufacture of
a drug product, including those that may not appear in such drug
product.

    Date of approval is the date on the approval letter from FDA
stating that the NDA or ANDA is approved. ``Date of approval'' refers
only to a final approval and not to a tentative approval.
    Dosage form is the physical manifestation containing the active and
inactive ingredients that delivers a dose of the drug product. This
includes such factors as:
    (1) The physical appearance of the drug product,
    (2) The physical form of the drug product prior to dispensing to
the patient,
    (3) The way the product is administered, and
    (4) The design features that affect frequency of dosing.
    Drug product is a finished dosage form, e.g., tablet, capsule, or
solution that contains a drug substance, generally, but not
necessarily, in association with one or more other ingredients.
    Drug substance is an active ingredient that is intended to furnish
pharmacological activity or other direct effect in the diagnosis, cure,
mitigation, treatment, or prevention of disease or to affect the
structure or any function of the human body, but does not include
intermediates used in the synthesis of such ingredient.
    Efficacy supplement is a supplement to an approved NDA proposing to
make one or more related changes from among the following changes to
product labeling:
    (1) Add or modify an indication or claim;
    (2) Revise the dose or dose regimen;
    (3) Provide for a new route of administration;
    (4) Make a comparative efficacy claim naming another drug product;
    (5) Significantly alter the intended patient population;
    (6) Change the marketing status from prescription to over-the-
counter use;
    (7) Provide for, or provide evidence of effectiveness necessary
for, the traditional approval of a product originally approved under
subpart H of part 314; or
    (8) Incorporate other information based on at least one adequate
and well-controlled clinical study.
    FDA is the Food and Drug Administration.
    First applicant is an applicant that, on the first day on which a
substantially complete ANDA containing a paragraph IV certification is
submitted for approval of a drug, submits a substantially complete ANDA
that contains, and for which the applicant lawfully maintains, a
paragraph IV certification for the drug.
    Inactive ingredient is any component other than an active
ingredient.
    Listed drug is a new drug product that has been approved under
section 505(c) of the Federal Food, Drug, and Cosmetic Act for safety
and effectiveness or under section 505(j) of the Federal Food, Drug,
and Cosmetic Act, which has not been withdrawn or suspended under
section 505(e)(1) through (e)(5) or section 505(j)(6) of the Federal
Food, Drug, and Cosmetic Act, and which has not been withdrawn from
sale for what FDA has determined are reasons of safety or
effectiveness. Listed drug status is evidenced by the drug product's
identification in the current edition of FDA's ``Approved Drug Products
With Therapeutic Equivalence Evaluations'' (the list) as an approved
drug. A drug product is deemed to be a listed drug on the date of the
approval letter for the NDA or ANDA for that drug product.
    NDA holder is the applicant that owns an approved NDA.
    Newly acquired information is data, analyses, or other information
not previously submitted to the Agency, which may include (but is not
limited to) data derived from new clinical studies, reports of adverse
events, or new analyses of previously submitted data (e.g., meta-
analyses) if the studies, events, or analyses reveal risks of a
different type or greater severity or frequency than previously
included in submissions to FDA.
    Original application, original NDA is a pending NDA for which FDA
has never issued a complete response letter or approval letter, or an
NDA that was submitted again after FDA had refused to file it or after
it was withdrawn without being approved.
    Paragraph IV acknowledgment letter is a written, postmarked
communication from FDA to an applicant stating that the Agency has
determined that a 505(b)(2) application or ANDA containing a paragraph
IV certification is sufficiently complete to permit a substantive
review. A paragraph IV acknowledgment letter indicates that the
505(b)(2) application is regarded as filed or the ANDA is regarded as
received.
    Paragraph IV certification is a patent certification of invalidity,
unenforceability, or noninfringement described in Sec.
314.50(i)(1)(i)(A)(4) or Sec.  314.94(a)(12)(i)(A)(4).
    Patent owner is the owner of the patent for which information is
submitted for an NDA.
    Pharmaceutical alternatives are drug products that contain the
identical therapeutic moiety, or its precursor, but not necessarily in
the same amount or dosage form or as the same salt or ester. Each such
drug product individually meets either the identical or its own
respective compendial or other applicable standard of identity,
strength, quality, and purity, including potency and, where applicable,
content uniformity, disintegration times, and/or dissolution rates.
    Pharmaceutical equivalents are drug products in identical dosage
forms and route(s) of administration that contain identical amounts of
the identical active drug ingredient, i.e., the same salt or ester of
the same therapeutic moiety, or, in the case of modified release dosage
forms that require a reservoir or overage or such forms as prefilled
syringes where residual volume may vary, that deliver identical amounts
of the active drug ingredient over the identical dosing period; do not
necessarily contain the same inactive ingredients; and meet the
identical compendial or other applicable standard of identity,
strength, quality, and purity, including potency and, where applicable,
content uniformity, disintegration times, and/or dissolution rates.
    Postmark is an independently verifiable evidentiary record of the
date on which a document is transmitted, in an unmodifiable format, to
another party. For postmarks made by the U.S. Postal Service or a
designated delivery service, the date of transmission is the date on
which the document is received by the domestic mail service of the U.S.
Postal Service or by a designated delivery service. For postmarks
documenting an electronic event, the date of transmission is the date
(in a particular time zone) that FDA sends the electronic transmission
on its host system as evidenced by a verifiable record. If the sender
and the intended recipient are located in different time zones, it is
the sender's time zone that provides the controlling date of electronic
transmission.
    Reference listed drug is the listed drug identified by FDA as the
drug product upon which an applicant relies in seeking approval of its
ANDA.
    Reference standard is the drug product selected by FDA that an
applicant seeking approval of an ANDA must use in conducting an in vivo
bioequivalence study required for approval.
    Resubmission is submission by the applicant of all materials needed
to fully address all deficiencies identified in the complete response
letter. An NDA or ANDA for which FDA issued a complete response letter,
but which was withdrawn before approval and later submitted again, is
not a resubmission.
    Right of reference or use is the authority to rely upon, and
otherwise

use, an investigation for the purpose of obtaining approval of an NDA,
including the ability to make available the underlying raw data from
the investigation for FDA audit, if necessary.
    Same drug product formulation is the formulation of the drug
product submitted for approval and any formulations that have minor
differences in composition or method of manufacture from the
formulation submitted for approval, but are similar enough to be
relevant to the Agency's determination of bioequivalence.
    Specification is the quality standard (i.e., tests, analytical
procedures, and acceptance criteria) provided in an approved NDA or
ANDA to confirm the quality of drug substances, drug products,
intermediates, raw materials, reagents, components, in-process
materials, container closure systems, and other materials used in the
production of a drug substance or drug product. For the purpose of this
definition, acceptance criteria means numerical limits, ranges, or
other criteria for the tests described.
    Strength is the amount of drug substance contained in, delivered,
or deliverable from a drug product, which includes:
    (1)(i) The total quantity of drug substance in mass or units of
activity in a dosage unit or container closure (e.g., weight/unit dose,
weight/volume or weight/weight in a container closure, or units/volume
or units/weight in a container closure); and/or, as applicable.
    (ii) The concentration of the drug substance in mass or units of
activity per unit volume or mass (e.g., weight/weight, weight/volume,
or units/volume); or
    (2) Such other criteria the Agency establishes for determining the
amount of drug substance contained in, delivered, or deliverable from a
drug product if the weights and measures described in paragraph (i) of
this definition do not apply (e.g., certain drug-device combination
products for which the amount of drug substance is emitted per use or
unit time).
    Substantially complete application is an ANDA that on its face is
sufficiently complete to permit a substantive review and contains all
the information required under section 505(j)(2)(A) of the Federal
Food, Drug, and Cosmetic Act and Sec.  314.94.
    Tentative approval is notification that an NDA or ANDA otherwise
meets the requirements for approval under the Federal Food, Drug, and
Cosmetic Act, but cannot be approved because there is a 7-year period
of orphan exclusivity for a listed drug under section 527 of the
Federal Food, Drug, and Cosmetic Act and Sec.  316.31 of this chapter,
or that a 505(b)(2) application or ANDA otherwise meets the
requirements for approval under the Federal Food, Drug, and Cosmetic
Act, but cannot be approved until the conditions in Sec.
314.107(b)(1)(iii), (b)(3), or (c) are met; because there is a period
of exclusivity for the listed drug under Sec.  314.108; because there
is a period of pediatric exclusivity for the listed drug under section
505A of the Federal Food, Drug, and Cosmetic Act, or because a court
order pursuant to 35 U.S.C. 271(e)(4)(A) orders that the application
may be approved no earlier than the date specified. A drug product that
is granted tentative approval is not an approved drug and will not be
approved until FDA issues an approval letter after any necessary
additional review of the NDA or ANDA.
    The list is the list of approved drug products published in FDA's
current ``Approved Drug Products With Therapeutic Equivalence
Evaluations,'' available electronically on FDA's Web site at http://www.fda.gov/cder.
    Therapeutic equivalents are approved drug products that are
pharmaceutical equivalents and for which bioequivalence has been
demonstrated. Therapeutic equivalents can be expected to have the same
clinical effect and safety profile when administered to patients under
the conditions specified in the labeling.
0
3. Section 314.50 is amended by:
0
a. Removing from paragraph (a) introductory text, paragraphs (a)(5),
(d)(1)(v), (d)(5)(v), and (d)(5)(vi)(a), paragraph (e)(2) introductory
text, and paragraphs (f)(3), (g)(2), and (k) the word ``shall'' each
time it appears and adding in its place the word ``must'';
0
b. Removing from paragraphs (a)(5), (b), (c)(1), (c)(2)(i), and
(c)(2)(iv) through (c)(2)(viii), paragraph (d) introductory text,
paragraphs (d)(1)(i), (d)(1)(ii)(a), (d)(1)(iii) through (d)(1)(v),
(d)(3)(ii), and (d)(5)(iv), paragraph (e)(1)(i) introductory text,
paragraph (e)(2), paragraph (f) introductory text, paragraphs (f)(1)
through (f)(3), (g)(2), (j)(4)(i), (j)(4)(ii), and (k), paragraph (l)
heading, paragraph (l)(1) introductory text, and paragraphs (l)(2) and
(l)(4) the word ``application'' each time it appears and adding in its
place ``NDA'';
0
c. Removing from paragraph (j) introductory text the word ``shall'' and
adding in its place the word ``must'' and removing the phrase ``new
drug application'' and adding in its place ``NDA''; and
0
d. Revising the section heading and section introductory text,
paragraphs (a)(1) and (d)(5)(vi)(b), paragraph (e)(1) introductory
text, paragraphs (f)(4), (g)(3), and (i), paragraph (j)(4) introductory
text, the first two sentences of paragraph (j)(4)(iii), and paragraph
(l)(3).
    The revisions read as follows:

Sec.  314.50  Content and format of an NDA.

    NDAs and supplements to approved NDAs are required to be submitted
in the form and contain the information, as appropriate for the
particular submission, required under this section. Three copies of the
NDA are required: An archival copy, a review copy, and a field copy. An
NDA for a new chemical entity will generally contain an application
form, an index, a summary, five or six technical sections, case report
tabulations of patient data, case report forms, drug samples, and
labeling, including, if applicable, any Medication Guide required under
part 208 of this chapter. Other NDAs will generally contain only some
of those items, and information will be limited to that needed to
support the particular submission. These include an NDA of the type
described in section 505(b)(2) of the Federal Food, Drug, and Cosmetic
Act, an amendment, and a supplement. The NDA is required to contain
reports of all investigations of the drug product sponsored by the
applicant, and all other information about the drug pertinent to an
evaluation of the NDA that is received or otherwise obtained by the
applicant from any source. FDA will maintain guidance documents on the
format and content of NDAs to assist applicants in their preparation.
    (a) * * *
    (1) The name and address of the applicant; the date of the NDA; the
NDA number if previously issued (for example, if the NDA is a
resubmission or an amendment or supplement); the name of the drug
product, including its established, proprietary, code, and chemical
names; the dosage form and strength; the route of administration; the
identification numbers of all INDs (as defined in Sec.  312.3(b) of
this chapter) that are referenced in the NDA; the identification
numbers of all drug master files and other applications under this part
that are referenced in the NDA; and the drug product's proposed
indications for use.
* * * * *
    (d) * * *
    (5) * * *
    (vi) * * *
    (b) The applicant must, under section 505(i) of the Federal Food,
Drug, and Cosmetic Act, update periodically its pending NDA with new
safety information learned about the drug that

may reasonably affect the statement of contraindications, warnings,
precautions, and adverse reactions in the draft labeling and, if
applicable, any Medication Guide required under part 208 of this
chapter. These ``safety update reports'' must include the same kinds of
information (from clinical studies, animal studies, and other sources)
and must be submitted in the same format as the integrated summary in
paragraph (d)(5)(vi)(a) of this section. In addition, the reports must
include the case report forms for each patient who died during a
clinical study or who did not complete the study because of an adverse
event (unless this requirement is waived). The applicant must submit
these reports:
    (1) 4 months after the initial submission;
    (2) In a resubmission following receipt of a complete response
letter; and
    (3) At other times as requested by FDA. Before submitting the first
such report, applicants are encouraged to consult with FDA regarding
further details on its form and content.
* * * * *
    (e) * * * (1) Upon request from FDA, the applicant must submit the
samples described below to the places identified in the Agency's
request. FDA generally will ask applicants to submit samples directly
to two or more Agency laboratories that will perform all necessary
tests on the samples and validate the applicant's analytical
procedures.
* * * * *
    (f) * * *
    (4) Applicants are invited to meet with FDA before submitting an
NDA to discuss the presentation and format of supporting information.
If the applicant and FDA agree, the applicant may submit tabulations of
patient data and case report forms in an alternate form.
    (g) * * *
    (3) If an applicant who submits an NDA under section 505(b) of the
Federal Food, Drug, and Cosmetic Act obtains a ``right of reference or
use,'' as defined under Sec.  314.3(b), to an investigation described
in clause (A) of section 505(b)(1) of the Federal Food, Drug, and
Cosmetic Act, the applicant must include in its NDA a written statement
signed by the owner of the data from each such investigation that the
applicant may rely on in support of the approval of its NDA, and
provide FDA access to, the underlying raw data that provide the basis
for the report of the investigation submitted in its NDA.
* * * * *
    (i) Patent certification--(1) Contents. A 505(b)(2) application is
required to contain the following:
    (i) Patents claiming drug substance, drug product, or method of
use. (A) A certification with respect to each patent issued by the U.S.
Patent and Trademark Office that, in the opinion of the applicant and
to the best of its knowledge, claims the drug substance or drug product
on which investigations that are relied upon by the applicant for
approval of its 505(b)(2) application were conducted 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 Federal Food, Drug, and
Cosmetic Act and Sec.  314.53. For each such patent, the applicant must
provide the patent number and certify, in its opinion and to the best
of its knowledge, one of the following circumstances:
    (1) That the patent information has not been submitted to FDA. The
applicant must entitle such a certification ``Paragraph I
Certification'';
    (2) That the patent has expired. The applicant must entitle such a
certification ``Paragraph II Certification'';
    (3) The date on which the patent will expire. The applicant must
entitle such a certification ``Paragraph III Certification''; or
    (4) That the patent is invalid, unenforceable, or will not be
infringed by the manufacture, use, or sale of the drug product for
which the 505(b)(2) application is submitted. The applicant must
entitle such a certification ``Paragraph IV Certification''. This
certification must be submitted in the following form:

    I, (name of applicant), certify that Patent No. ______ (is
invalid, unenforceable, or will not be infringed by the manufacture,
use, or sale of) (name of proposed drug product) for which this
505(b)(2) application is submitted.

    The certification must be accompanied by a statement that the
applicant will comply with the requirements under Sec.  314.52(a) with
respect to providing a notice to each owner of the patent or its
representative and to the holder of the approved NDA for the drug
product which is claimed by the patent or a use of which is claimed by
the patent and with the requirements under Sec.  314.52(b) with respect
to sending the notice and under Sec.  314.52(c) with respect to the
content of the notice.
    (B) If the drug on which investigations that are relied upon by the
applicant were conducted is itself a licensed generic drug of a
patented drug first approved under section 505(b) of the Federal Food,
Drug, and Cosmetic Act, the appropriate patent certification under this
section with respect to each patent that claims the first-approved
patented drug or that claims an approved use for such a drug.
    (C) If, before the date of submission of the 505(b)(2) application,
there is an approved drug product that is pharmaceutically equivalent
to the drug product for which the 505(b)(2) application is submitted,
an appropriate patent certification under this section with respect to
each patent that claims the drug substance or drug product or that
claims an approved use for such drug.
    (ii) No relevant patents. If, in the opinion of the applicant and
to the best of its knowledge, there are no patents described in
paragraph (i)(1)(i) of this section, a certification in the following
form:

    In the opinion and to the best knowledge of (name of applicant),
there are no patents that claim the drug or drugs on which
investigations that are relied upon in this 505(b)(2) application
were conducted or that claim a use of such drug or drugs.

    (iii) Method-of-use patent. (A) If information that is submitted
under section 505(b) or (c) of the Federal Food, Drug, and Cosmetic Act
and Sec.  314.53 is for a method-of-use patent, and the labeling for
the drug product for which the applicant is seeking approval does not
include any indications or other conditions of use that are covered by
the use patent, a statement explaining that the method-of-use patent
does not claim any of the proposed indications or other conditions of
use.
    (B) If the labeling of the drug product for which the applicant is
seeking approval includes an indication or other condition of use that,
according to the patent information submitted under section 505(b) or
(c) of the Federal Food, Drug, and Cosmetic Act and Sec.  314.53 or in
the opinion of the applicant, is claimed by a use patent, the applicant
must submit an applicable certification under paragraph (i)(1)(i) of
this section.
    (2) [Reserved]
    (3) Licensing agreements. If a 505(b)(2) application is for a drug
or method of using a drug claimed by a patent and the applicant has a
licensing agreement with the patent owner, the applicant must submit a
certification under paragraph (i)(1)(i)(A)(4) of this section
(``Paragraph IV Certification'') as to that patent and a statement that
it has been granted a patent license. If the patent owner consents to
approval of the 505(b)(2) application (if otherwise justified) as of a
specific date, the 505(b)(2) application must contain a written
statement from the patent owner that it has a licensing agreement with

the applicant and that it consents to approval of the 505(b)(2)
application as of a specific date.
    (4) Untimely filing of patent information. If a patent described in
paragraph (i)(1)(i) of this section is issued and the holder of the
approved NDA for the patented drug does not file with FDA the required
information on the patent within 30 days of issuance of the patent, an
applicant who submitted a 505(b)(2) application that, before the
submission of the patent information, contained an appropriate patent
certification is not required to submit an amended certification to
address the patent that is late-listed with respect to the pending
505(b)(2) application. Except as provided in Sec.  314.53(f)(1), an NDA
holder's amendment to the description of the approved method(s) of use
claimed by the patent will be considered untimely filing of patent
information if:
    (i) The amendment is submitted more than 30 days after patent
issuance and it is not related to a corresponding change in approved
product labeling; or
    (ii) The amendment is submitted more than 30 days after a
corresponding change in approved product labeling. An applicant whose
505(b)(2) application is filed after the NDA holder's untimely filing
of patent information or whose 505(b)(2) application was previously
filed but did not contain an appropriate patent certification at the
time of the patent submission must submit a certification under
paragraph (i)(1)(i) of this section or a statement under paragraph
(i)(1)(iii) of this section as to that patent.
    (5) Disputed patent information. If an applicant disputes the
accuracy or relevance of patent information submitted to FDA, the
applicant may seek a confirmation of the correctness of the patent
information in accordance with the procedures under Sec.  314.53(f).
Unless the patent information is withdrawn or changed, the applicant
must submit an appropriate certification for each relevant patent.
    (6) Amended certifications. A certification submitted under
paragraphs (i)(1)(i) through (i)(1)(iii) of this section may be amended
at any time before the approval of the 505(b)(2) application. An
applicant must submit an amended certification as an amendment to a
pending 505(b)(2) application. If an applicant with a pending 505(b)(2)
application voluntarily makes a patent certification for an untimely
filed patent, the applicant may withdraw the patent certification for
the untimely filed patent. Once an amendment for the change in
certification has been submitted, the 505(b)(2) application will no
longer be considered to be one containing the prior certification.
    (i) After finding of infringement. An applicant who has submitted a
paragraph IV certification and is sued for patent infringement must
submit an amendment to change its certification if a court enters a
final decision from which no appeal has been or can be taken, or 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. In its amendment, the applicant must certify under paragraph
(i)(1)(i)(A)(3) of this section that the patent will expire on a
specific date or, with respect to a patent claiming a method of use,
the applicant may instead provide a statement under paragraph
(i)(1)(iii) of this section if the applicant amends its 505(b)(2)
application such that the applicant is no longer seeking approval for a
method of use claimed by the patent.
    (ii) After request to remove a patent or patent information from
the list. If the list reflects that an NDA holder has requested that a
patent be removed from the list and no ANDA applicant is eligible for
180-day exclusivity based on a paragraph IV certification to that
patent, the patent will be removed and any applicant with a pending
505(b)(2) application (including a tentatively approved 505(b)(2)
application) who has made a certification with respect to such patent
must submit an amendment to withdraw its certification. In the
amendment, the applicant must state the reason for withdrawing the
certification (that the patent has been removed from the list). If the
list reflects that an NDA holder has requested that a patent be removed
from the list and 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. 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 for its ANDA. Once
an amendment to withdraw the certification has been submitted, the
505(b)(2) application will no longer be considered to be one containing
a paragraph IV certification to the patent. 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, the applicant must
submit an amended certification reflecting that there are no listed
patents.
    (iii) Other amendments. (A) Except as provided in paragraphs (i)(4)
and (i)(6)(iii)(B) of this section:
    (1) An applicant must amend a submitted certification if, at any
time before the approval of the 505(b)(2) application, the applicant
learns that the submitted certification is no longer accurate; and
    (2) An applicant must submit a certification or statement under
paragraph (i)(1) of this section if, after submission of the 505(b)(2)
application, a new patent is issued by the U.S. Patent and Trademark
Office that, in the opinion of the applicant and to the best of its
knowledge, claims a listed drug relied upon or that claims an approved
use for such listed drug for which information is required to be filed
under section 505(b) and (c) of the Federal Food, Drug, and Cosmetic
Act and Sec.  314.53.
    (B) An applicant is not required to submit a supplement to change a
submitted certification when information on an otherwise applicable
patent is submitted after the approval of the 505(b)(2) application,
except as provided in Sec.  314.70(i).
    (j) * * *
    (4) If the applicant claims exclusivity under Sec.  314.108(b)(4)
or (b)(5), the following information to show that the NDA contains
``new clinical investigations'' that are ``essential to approval of the
application or supplement'' and ``were conducted or sponsored by the
applicant'':
* * * * *
    (iii) * * * If the applicant was the sponsor named in the Form FDA
1571 for an IND under which the new clinical investigation(s) that is
essential to the approval of its NDA was conducted, identification of
the IND by number. If the applicant was not the sponsor of the IND
under which the clinical investigation(s) was conducted, a
certification that the applicant or its predecessor in interest
provided substantial support for the clinical investigation(s) that is
essential to the approval of its NDA, and information supporting the
certification. * * *
* * * * *
    (l) * * *
    (3) Field copy. The applicant must submit a field copy of the NDA
that contains the technical section described in paragraph (d)(1) of
this section, a copy of the application form required under paragraph
(a) of this section, a copy of the summary required under paragraph (c)
of this section, and a certification that the field copy is a true copy
of the technical section described in paragraph (d)(1) of this section

contained in the archival and review copies of the NDA.
* * * * *
0
4. Section 314.52 is revised to read as follows:

Sec.  314.52  Notice of certification of invalidity or noninfringement
of a patent.

    (a) Notice of certification. For 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,
the applicant must send notice of such certification by registered or
certified mail, return receipt requested, or by a designated delivery
service, as defined in paragraph (g) of this section to each of the
following persons:
    (1) Each owner of the patent that is the subject of the
certification or the representative designated by the owner to receive
the notice. The name and address of the patent owner or its
representative may be obtained from the U.S. Patent and Trademark
Office; and
    (2) The holder of the approved NDA under section 505(b) of the
Federal Food, Drug, and Cosmetic Act for each drug product which is
claimed by the patent or a use of which is claimed by the patent and
for which the applicant is seeking approval, or, if the NDA holder does
not reside or maintain a place of business within the U.S., the NDA
holder's attorney, agent, or other authorized official. The name and
address of the NDA holder or its attorney, agent, or authorized
official may be obtained from the Orange Book Staff, Office of Generic
Drugs, 7620 Standish Pl., Rockville, MD 20855.
    (3) This paragraph does not apply to a use patent that does not
claim a use for which the applicant is seeking approval.
    (4) An 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.
    (b) Sending the notice. (1) Except as provided under paragraph (d)
of this section, the applicant must send the notice required by
paragraph (a) of this section on or after the date it receives a
paragraph IV acknowledgment letter from FDA, but not later than 20 days
after the date of the postmark on the paragraph IV acknowledgment
letter. The 20-day clock described in this paragraph begins on the day
after the date of the postmark on the paragraph IV acknowledgment
letter. When the 20th day falls on Saturday, Sunday, or a Federal
holiday, the 20th day will be the next day that is not a Saturday,
Sunday, or Federal holiday.
    (2) Any notice required by paragraph (a) of this section is invalid
if it is sent before the applicant's receipt of a paragraph IV
acknowledgment letter. The applicant will not have complied with this
paragraph until it sends valid notice.
    (3) At the same time it sends the notice required by paragraph (a)
of this section, the applicant must submit to FDA an amendment to its
505(b)(2) application that includes a statement certifying that the
notice has been provided to each person identified under paragraph (a)
of this section and that the notice met the content requirement under
paragraph (c) of this section. A copy of the notice itself need not be
submitted to the Agency.
    (c) Content of a notice. In the notice, the applicant must cite
section 505(b)(3)(D) of the Federal Food, Drug, and Cosmetic Act and
must include, but is not limited to, the following information:
    (1) A statement that a 505(b)(2) application that contains any
required bioavailability or bioequivalence studies has been submitted
by the applicant and filed by FDA.
    (2) The NDA number.
    (3) A statement that the applicant has received the paragraph IV
acknowledgment letter for the 505(b)(2) application.
    (4) The established name, if any, as defined in section 502(e)(3)
of the Federal Food, Drug, and Cosmetic Act, of the proposed drug
product.
    (5) The active ingredient, strength, and dosage form of the
proposed drug product.
    (6) The patent number and expiration date of each patent on the
list alleged to be invalid, unenforceable, or not infringed.
    (7) A detailed statement of the factual and legal basis of the
applicant's opinion that the patent is not valid, unenforceable, or
will not be infringed. The applicant must include in the detailed
statement:
    (i) For each claim of a patent alleged not to be infringed, a full
and detailed explanation of why the claim is not infringed.