patent claim(s). An NDA holder may submit a revised use code based on a
patent-specific decision by either a Federal district court, the Court
of Appeals for the Federal Circuit, or the U.S. Supreme Court. We
decline to broaden the scope of this provision to allow for use code
changes to be considered timely filed based solely on changes in patent
law or interpretation that are not specific to the patent for which the
use code was submitted because we are not experts in patent law and
would be unable to evaluate arguments that could effectively remove the
limitation for untimely filing of method-of-use patent information.
    Our clarifying revisions to the regulations are expected to address
concerns about how to set use codes, and there is no need to reevaluate
our proposal on this basis.
    To facilitate implementation of this provision, FDA is revising
Sec.  314.53(c)(2)(i)(K) and (c)(2)(ii)(L) to require that if the
patent has been submitted previously for listing, the NDA holder must
identify all change(s) from the previously submitted patent information
and specify whether the change is related to the patent (e.g., patent
term extension or patent-specific decision by the USPTO or a Federal
court) or related to an FDA action or procedure (e.g., FDA approval of
a supplement that changes the approved conditions of use of the drug).
This information will assist the Orange Book staff in updating listed
patent information where appropriate and replaces the current
requirement that an applicant only identify whether the expiration date
is a new expiration date.
    We also are making technical amendments in Sec. Sec.  314.50(i)(4)
and 314.94(a)(12)(vi) to explain that a 505(b)(2) or ANDA applicant
generally is not required to submit a patent certification or statement
to address the patent or patent information that is late-listed with
respect to the pending 505(b)(2) application or ANDA. Although a patent
certification or statement generally would not be required in this
circumstance, we would permit an applicant to submit and maintain a
patent certification (including a paragraph IV certification) or a
statement pursuant to section 505(b)(2)(B) or 505(j)(2)(B)(viii) of the
FD&C Act, if desired. For example, an ANDA applicant may wish to submit
a paragraph IV certification to challenge the method-of-use patent with
the revised use code if the applicant may be eligible for 180-day
exclusivity based on that certification.
    V.B.2.c. Where to send submissions of Forms FDA 3542a and 3542
(Sec.  314.53(d)(4)). We proposed to clarify that patent information
submitted on Form FDA 3542a with the filing of an NDA, amendment, or
supplement must be submitted to the CDER Central Document Room, and
should not be submitted to the Orange Book staff (see proposed Sec.
314.53(d)(4)(i); see also Sec. Sec.  314.50(h) and 314.70(f)). We also
proposed to require that patent information submitted on Form FDA 3542
upon and after approval of an NDA or supplement be submitted directly
to the Orange Book staff through the OGD Document Room. Our proposal to
designate the OGD Document Room as the official repository for
submission of Form FDA 3542 was intended to facilitate prompt listing
of patent information in the Orange Book after Form FDA 3542 has been
officially

received by the Agency (see proposed Sec.  314.53(d)(4)(ii) and
(d)(5)).
    In the following paragraphs, we discuss a comment on these proposed
revisions. After considering this comment, we are finalizing Sec.
314.53(d)(4)(ii) with revisions to maintain the CDER Central Document
Room as the official repository for submission of Form FDA 3542 and we
are finalizing Sec.  314.53(d)(4)(i) and (ii) to clarify that Forms FDA
3542a and 3542 can be submitted electronically. We also are finalizing
Sec.  314.53(d)(4)(i) and (ii) with an editorial correction to the
title of Forms FDA 3542a and 3542, and we are making the same
correction in Sec.  314.53(f)(2)(ii) through (iv).
    (Comment 19) One comment requests confirmation that NDA holders may
submit Form FDA 3542 to the OGD Document Room through the Electronic
Submissions Gateway (ESG). The comment also recommends that FDA clarify
that Form FDA 3542a must be submitted to the NDA via CDER's Central
Document Room.
    (Response 19) FDA is revising Sec.  314.53(d) to expressly provide
that Form FDA 3542 can be submitted in an electronic format submission
that complies with Sec.  314.50(l)(5), which permits submission through
the ESG. This revision and the corresponding revision to Sec.
314.53(d)(5) are intended to clarify how submission dates are
determined for Form FDA 3542, given the implications of untimely filing
of patent information on the patent certification obligations of
505(b)(2) and ANDA applicants that rely upon the listed drug (see
Sec. Sec.  314.50(i)(4) and 314.94(a)(12)(vi)). Beginning in May 2017,
Form FDA 3542 and other submissions under section 505(b), (i), and (j)
of the FD&C Act must be submitted in the electronic format specified by
FDA (see section 745A(a) of the FD&C Act (21 U.S.C. 379k-1(a)) and
guidance for industry entitled ``Providing Regulatory Submissions in
Electronic Form--Certain Human Pharmaceutical Product Applications and
Related Submissions Using the eCTD Specifications'' (May 2015),
available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm).
Accordingly, we only have specified the method of submission where it
is important to describe how receipt dates or submission dates are
determined for a particular type of submission.
    Based on the transition to electronic submission of Form FDA 3542
and related changes in FDA's administrative processes, we are not
finalizing our proposal to change the official repository for
submission of Form FDA 3542. Thus, Form FDA 3542 must continue to be
submitted to the NDA via the CDER Central Document Room or the ESG. The
CDER Central Document Room and the ESG promptly direct submissions of
Form FDA 3542 to the Orange Book staff for listing in the Orange Book.
To ensure that patents and patent information are listed in the Orange
Book only after Form FDA 3542 has been officially received by FDA, the
Orange Book staff intends to rely only on submissions of Form FDA 3542
that are received from the Central Document Room and disregard any
duplicate copies or courtesy copies of Form FDA 3542 that are submitted
through other channels. We are revising Sec.  314.53(d)(4)(ii) to
emphasize that Form FDA 3542 should not be submitted to the Orange Book
staff.
    V.B.2.d. Submission date of patent information (Sec.
314.53(d)(5)). We proposed to revise Sec.  314.53(d)(5) to establish
that the submission date of patent information provided by an NDA
holder after approval of an application is the earlier of the date on
which Form FDA 3542 is date-stamped by the OGD Document Room or
officially received electronically by FDA through the ESG (i.e., at the
completion of electronic transmission). We proposed that patent
information sent to another location at FDA would not be considered
received by FDA for purposes of Sec.  314.53(d)(3) on timely filing and
a 505(b)(2) or ANDA applicant's patent certification obligations
pursuant to Sec.  314.50(i)(4) and (6) or Sec.  314.94(a)(12)(vi) and
(viii), respectively, unless it is sent to the official repository
identified in the regulation. In the following paragraphs, we discuss
two comments on this provision. After considering these comments, we
are finalizing Sec.  314.53(d)(5) with revisions unrelated to the
comments to conform to the changes made to Sec.  314.53(d)(4)(ii).
    (Comment 20) One comment suggests that FDA provide a list of
untimely filed patent information to facilitate evaluation of patent
certification obligations by 505(b)(2) and ANDA applicants. Another
comment recommends that FDA include in the Orange Book the date on
which the patent information was submitted to FDA.
    (Response 20) FDA agrees that modifying the Orange Book to list the
date on which patent information was submitted to FDA as described in
Sec.  314.53(d)(5) would enable applicants to determine whether a
patent is late-listed as to a pending 505(b)(2) application or ANDA and
avoid the need for applicants to contact the Orange Book staff for this
information. FDA intends to list the date of submission of patents and
patent information in the Orange Book on a prospective basis beginning
as soon as practicable after the effective date of this rule. This
addition to the Orange Book does not require any modification to the
regulations. FDA does not intend to separately publish a list of
untimely filed patent information.
V.B.3. Public Disclosure of Patent Information (Sec.  314.53(e))
    We proposed technical corrections to Sec.  314.53(e) to delete the
reference to monthly supplements to the Orange Book and clarify that
copies of the ``submitted patent information'' (rather than copies of
the ``file'') may be requested from FDA's Freedom of Information Staff.
We also proposed to expressly state that the submitted patent
information, and requests for delisting patents, will be subject to
public disclosure (see proposed Sec.  314.53(e)). In the preamble to
the proposed rule, we explained that FDA may elect to proactively post
on FDA's Web site a copy of the submitted patent information (Form FDA
3542) for listed patents in advance of a request under the Freedom of
Information Act (FOIA) based on our anticipation of requests for this
information. In the following paragraphs, we discuss a comment on the
potential for proactive posting of Form FDA 3542 on FDA's Web site.
After considering this comment, we are making an editorial correction
to clarify the information that may be subject to public disclosure.
    (Comment 21) One comment urges FDA not to proactively post Form FDA
3542 on the FDA Web site based on concerns that the patent information
could be misused or lead to misinterpretation of the scope of relevant
patent rights in litigation or commercial contexts.
    (Response 21) FDA is not persuaded by the comment, given that Form
FDA 3542 must contain the verification required by Sec.
314.53(c)(2)(ii)(R) and may be subject to disclosure under FOIA and
applicable disclosure regulations. Moreover, FDA has advised
prospective 505(b)(2) and ANDA applicants that the use code and other
information provided on Form FDA 3542 is not meant to substitute for
the applicant's review of the patent. However, at this time, FDA does
not intend to proactively post Form FDA 3542 for patent information
submitted for listing in the Orange Book because there is an adequate
mechanism to obtain a Form FDA 3542 on an individual basis through a
FOIA request. We are revising Sec.  314.53(e) to clarify that the
submitted

patent information and requests to remove a patent or patent
information from the list may be subject to public disclosure.
V.B.4. Correction or Change of Patent Information (Sec.  314.53(f))
    V.B.4.a. Requests by persons other than the NDA holder (Sec.
314.53(f)(1)). We proposed to revise Sec.  314.53(f) to clarify and
improve the mechanism for challenging the accuracy or relevance of
patent information submitted to the Agency under Sec.  314.53 and
listed in the Orange Book (see proposed Sec.  314.53(f)(1)). First, we
proposed to establish a 30-day timeframe in which the NDA holder would
be required to respond to FDA's request to confirm the correctness or
omission of patent information to facilitate timely resolution of the
patent listing dispute. Second, we proposed enhanced procedures to
govern challenges to the accuracy or relevance of an NDA holder's
submission of method-of-use patent information so that the Agency has
additional information to implement section 505(b)(2)(B) and
(j)(2)(A)(viii) of the FD&C Act in cases where the accuracy or
relevance of the use code is disputed (see proposed Sec.
314.53(f)(1)).
    For a patent listing dispute regarding method-of-use patent
information, we proposed to ask the NDA holder to confirm the
correctness of its description of the approved indication or method of
use that has been included as the ``use code'' in the Orange Book, and
provide information on the specific approved use claimed by the patent
that would enable the Agency to make a determination in accordance with
section 505(b)(2)(B) or (j)(2)(A)(viii) of the FD&C Act (see proposed
Sec.  314.53(f)(1)). We proposed that if the NDA holder confirms the
accuracy of its submitted patent information in response to FDA's
request, fails to timely respond to the request, or submits a revision
to the use code that does not provide adequate clarity for FDA to
determine whether the scope of a proposed labeling carve-out would be
appropriate based on the NDA holder's use code and approved labeling,
FDA would review a proposed labeling carve-out(s) for the 505(b)(2)
application or ANDA with deference to the 505(b)(2) or ANDA applicant's
interpretation of the scope of the patent. In such a case, we explained
that FDA would consider the use code and labeling information submitted
by the NDA holder on Form FDA 3542, the history of labeling changes
related to approval of an indication(s) for the drug product, the
505(b)(2) or ANDA applicant's interpretation of the scope of the
patent, the need for consistent labeling among products approved under
section 505(j) of the FD&C Act, and the requirements of Sec. Sec.
314.94(a)(8)(iv) and 314.127(a)(7), as appropriate.
    Two comments support FDA's proposed revisions to the patent listing
dispute procedure. In the following paragraphs, we discuss several
other comments on this proposal. After considering these comments, we
are revising Sec.  314.53(f)(1) to describe the rules that will apply
to patent listing disputes involving drug substance, drug product, and
method-of-use claims. We also are revising Sec.  314.53(c)(2)(ii)(R) to
expressly state that the requirement to verify the accuracy and
completeness of the submission of patent information applies to a
response to a patent listing dispute under Sec.  314.53(f)(1). We
intend to take a stepwise approach and evaluate whether FDA's revisions
to the regulations on submission of method-of-use patent information
(see Sec.  314.53(b)(1) and (c)(2)) and patent listing dispute
procedures adequately address the problem of overbroad and ambiguous
use codes before we establish a process to review a proposed labeling
carve-out with deference to the 505(b)(2) and/or ANDA applicant(s)'
interpretation of the scope of the patent. Therefore, at this time, we
are not finalizing our proposal to review a proposed labeling carve-out
with deference to the applicant(s)' interpretation of the scope of the
patent in certain circumstances. We will continue to consider whether
there is a need to finalize this proposal in the future.
    (Comment 22) Three comments indicate that there are inconsistencies
between the text of proposed Sec.  314.53(f) and the process described
in the corresponding preamble, and request that FDA clarify the
circumstances in which the Agency proposes to review a proposed
labeling carve-out for a 505(b)(2) application or ANDA with deference
to the 505(b)(2) or ANDA applicant's interpretation of the scope of the
patent. Several comments contend that it is inappropriate to defer to
the 505(b)(2) or ANDA applicant's interpretation of the scope of the
patent where the NDA holder has confirmed the accuracy of the use code.
One comment asserts that this approach will encourage 505(b)(2) and
ANDA applicants to routinely dispute method-of-use patent information
in an attempt to receive deference on a narrow interpretation of the
method-of-use patent and submit a statement under section 505(b)(2)(B)
or (j)(2)(A)(viii) of the FD&C Act instead of a patent certification.
One comment also contends that the Agency's standard for determining
that an NDA holder's revision to the use code ``does not provide
adequate clarity'' or determining that there is ``insufficient
information'' to evaluate a proposed labeling carve-out is
impermissibly vague.
    (Response 22) FDA has made multiple changes to address the issue of
overbroad and ambiguous use codes, including revisions to the
regulations on submission of patent information and revisions to the
patent listing dispute procedures (see sections V.B.1.c and V.B.2.b).
We initially intend to evaluate whether these revisions to the
regulations adequately address the problem of overbroad and ambiguous
use codes. If these revisions to our regulations do not adequately
address the problem, we will further consider whether to finalize the
proposal to review a proposed labeling carve-out for a 505(b)(2)
application or ANDA with deference to the 505(b)(2) and/or ANDA
applicant(s)' interpretation of the scope of the patent. If FDA decides
to finalize the proposal, FDA would clarify the process and the
circumstances in which such deference may be given.
    We are revising the regulation to provide a more detailed
description of the procedure for patent listing disputes directed to
the accuracy or relevance of submitted patent information regarding an
approved method of using the drug product (see Sec.  314.53(f)(1) and
(f)(1)(i)(B); see also Sec.  314.53(f)(1)(i)(A) (describing patent
listing dispute procedures directed to drug substance or drug product
claims)). We also are revising Sec.  314.53(c)(2)(ii)(R) to expressly
state that the requirement that an NDA holder verify the accuracy and
completeness of the submission of patent information applies to a
response to a request under Sec.  314.53(f)(1). This regulatory
approach is intended to provide the Agency with additional information
to facilitate implementation of section 505(b)(2)(B) and
(j)(2)(A)(viii) of the FD&C Act (see section 701(a) of the FD&C Act).
    For all patent listing disputes, we are requiring that the patent
listing dispute communication contain a statement of dispute that
describes the specific grounds for disagreement regarding the accuracy
or relevance of patent information for FDA to send to the applicable
NDA holder. If a person disputes the accuracy or relevance of submitted
patent information regarding an approved method of using the drug
product, this statement of dispute must be only a narrative description
(no more than 250 words) of the person's

interpretation of the scope of the patent with respect to the method of
use.
    FDA intends to forward the statement of dispute (without review or
redaction) to the applicable NDA holder using the electronic mail
(email) address or facsimile (fax) number provided by the NDA holder on
the most recent Form FDA 356h submitted to the NDA. Therefore, the
person submitting the patent listing dispute communication should
clearly identify the statement of dispute that he or she intends for
FDA to send to the applicable NDA holder, and only include information
for which the person consents to disclosure.
     For patent listing disputes directed to drug substance or
drug product claims, the NDA holder must confirm the correctness of the
patent information and include the signed verification required by
Sec.  314.53(c)(2)(ii)(R) or withdraw or amend the patent information
in accordance with Sec.  314.53(f)(2) within 30 days of the date on
which the Agency sends the statement of dispute. Although proposed
Sec.  314.53(f)(1) would have permitted disputes over the omission of
patent information, it is unnecessary for FDA to request the NDA holder
to confirm the omission of patent information for a listed patent
because we no longer require an NDA holder to identify whether a patent
claims both the drug substance and the drug product (see Sec.
314.53(c)(2)(ii)(T)). Accordingly, we are making a conforming amendment
to remove the phrase ``or omission of patent information'' from Sec.
314.53(f)(1)(i)(A). Unless the NDA holder withdraws or amends its
patent information in response to the patent listing dispute, the
Agency will not change the patent information in the Orange Book (see
Sec.  314.53(f)(1)(i)(A)).
     For patent listing disputes directed to method-of-use
claims, the NDA holder must confirm the correctness of the NDA holder's
description of the approved method of use claimed by the patent that
has been included as the ``use code'' in the Orange Book or withdraw or
amend the patent information in accordance with Sec.  314.53(f)(2). In
either case, the NDA holder must provide a narrative description (no
more than 250 words) of the NDA holder's interpretation of the scope of
the patent that explains why the existing or amended ``use code''
describes only the specific approved method of use claimed by the
patent for which a claim of patent infringement could reasonably be
asserted if a person not licensed by the owner of the patent engaged in
the manufacture, use, or sale of the drug product. The NDA holder must
also include the signed verification required by Sec.
314.53(c)(2)(ii)(R) and submit its response within 30 days of the date
on which the Agency sends the statement of dispute (see Sec.
314.53(f)(1)(i)(B)). Any response from the NDA holder that is submitted
after 30 days will be considered untimely. The narrative description
must only contain information for which the NDA holder consents to
disclosure because FDA will send the text of the statement to the
person who submitted the patent listing dispute without review or
redaction to further assist the person (generally a 505(b)(2) or ANDA
applicant, a prospective applicant, or its representative) in
determining whether a use for which an applicant may seek approval is a
protected use.
    We are revising the regulation to clarify that if the NDA holder
timely responds to the patent listing dispute with a confirmation of
the correctness of the patent information, the narrative description
required by Sec.  314.53(f)(1)(i)(B), and the signed verification
required by Sec.  314.53(c)(2)(ii)(R), the Agency will not change the
patent information in the Orange Book (see Sec.
314.53(f)(1)(i)(B)(1)). We are also revising the regulation to more
clearly state that if the NDA holder timely responds to FDA's request
with revised patent information, the narrative description required by
Sec.  314.53(f)(1)(i)(B), and the signed verification required by Sec.
314.53(c)(2)(ii)(R), FDA will update the Orange Book to reflect the
revised patent information (see Sec.  314.53(f)(1)(i)(B)(2) and
Response 26). This approach provides additional clarity, and
establishes a mechanism for a person (including a 505(b)(2) or ANDA
applicant) to request that an NDA holder confirm compliance with the
updated requirements for submission of patent information described in
Sec.  314.53(b) and (c).
    A 505(b)(2) application or ANDA must contain an appropriate
certification or statement for each listed patent, including the
disputed patent, during and after the patent listing dispute (see Sec.
314.53(f)(1)(ii)). A disputed method-of-use patent may continue to be
the subject of a paragraph IV certification. We do not believe that an
ongoing patent listing dispute process will have an impact on the
timing of approval of a 505(b)(2) application or ANDA that is otherwise
eligible for approval and relies on the listed drug for which the
disputed patent is listed in the Orange Book. FDA may consider the
narrative description from the NDA holder required by Sec.
314.53(f)(1)(i)(B), as appropriate, to assist FDA in exercising its
scientific judgment to implement section 505(b)(2)(B) and
(j)(2)(A)(viii) of the FD&C Act.
    To advise prospective and pending 505(b)(2) or ANDA applicants of a
patent listing dispute involving a method-of-use patent, FDA will
promptly post information about the patent listing dispute on a Web
page linked to the Orange Book. FDA intends to provide information such
as the relevant drug product, NDA number, NDA holder, U.S. Patent
Number, relevant use code(s), and whether the NDA holder has timely
responded to the patent listing dispute (see Sec.  314.53(f)(1)(iii)).
    (Comment 23) Three comments recommend that FDA withdraw or revise
the proposal to review, in certain circumstances, a proposed labeling
carve-out for a 505(b)(2) application or ANDA with deference to the
505(b)(2) or ANDA applicant's interpretation of the scope of the
patent. One comment contends that there is no basis for FDA's proposed
approach because the statutory scheme contemplates that disputes over
the scope of a method-of-use patent will be resolved by Federal courts
in patent infringement litigation, especially given that the MMA
established a counterclaim procedure in which a 505(b)(2) or ANDA
applicant may seek an order requiring the NDA holder to correct or
delete the submitted patent information. Another comment maintains that
it would be legally inappropriate for FDA to defer to the 505(b)(2) or
ANDA applicant's view of the scope of a patent that the applicant does
not own, especially if the NDA holder has confirmed the accuracy of the
use code. Two comments suggest that when patent listing disputes arise,
FDA should seek clarification or correction of patent information
through other means.
    (Response 23) We believe that FDA has the authority to establish a
regulation describing the limited circumstances in which the Agency
would defer to the 505(b)(2) or ANDA applicant's interpretation of the
scope of a patent that it does not own. However, in light of the
incremental approach that we are taking to this issue, we are not
finalizing this aspect of our proposal at this time. We will continue
to consider whether there is a need to finalize this proposal in the
future.
    The statutory provisions that permit a 505(b)(2) or ANDA applicant
to submit a statement that a listed patent does not claim a use for
which the applicant is seeking approval complement the patent
certification requirements (see section 505(b)(2)(A) and (B) and
(j)(2)(A)(vii)

and (viii) of the FD&C Act). FDA's revised regulations are intended to
preserve FDA's ministerial role in listing patents (see 59 FR 50338 at
50349 and 68 FR 36676 at 36683 and 36687) and to also address ambiguous
or overbroad use codes that could be a barrier to approval of a
505(b)(2) application or ANDA for uses that are not claimed by the
listed patent (see Sec.  314.53(b)(1), (c)(2)(ii)(P)(3), and (f)(1)).
If an NDA holder provides a timely response to a patent listing dispute
and a 505(b)(2) or ANDA applicant disagrees with the NDA holder's
response to the patent listing dispute (or disagrees with the use
code), the 505(b)(2) or ANDA applicant may submit a paragraph IV
certification to challenge the method-of-use patent and assert a
counterclaim in the context of an infringement action or pursue a
declaratory judgment action, as appropriate, to obtain patent certainty
(see section 505(c)(3)(D)(i) and (ii) and (j)(5)(C)(i) and (ii) of the
FD&C Act).
    We disagree, however, that the counterclaim procedure in section
505(c)(3)(D)(ii) and (j)(5)(C)(ii) of the FD&C Act obviates the need
for an enhanced patent listing dispute procedure. Nothing in the FD&C
Act precludes FDA from developing a procedure for patent listing
disputes in light of our broad authority to issue regulations for the
efficient enforcement of the FD&C Act. As the U.S. Supreme Court
observed in Caraco Pharm. Labs., ``the counterclaim cannot restore the
smooth working of a statutory scheme thrown off kilter by an overly
broad use code. At best, it permits the generic manufacturer to do what
the scheme contemplates it should do--file an ANDA with a section viii
statement--but only after expensive and time-consuming litigation. A
fix is in order, but it must come from Congress or FDA'' (132 S.Ct.
1670 at 1689).
    Finally, we note that comments recommending that FDA seek
clarification or correction of patent information through other means
do not describe an alternative to the approach we proposed. We believe
that the modifications that we have made to the patent listing dispute
procedure, discussed in Response 22, and our stepwise approach to
evaluating whether FDA's revisions to this procedure and the
regulations on submission of method-of-use patent information address
the problem of overbroad and ambiguous use codes, adequately address
the comments received on our proposal.
    (Comment 24) Three comments assert that FDA's proposed deference to
the 505(b)(2) or ANDA applicant's interpretation of the scope of the
patent would be inconsistent with the Agency's longstanding ministerial
role in patent-related matters. These comments suggest that FDA lacks
the expertise to assess the adequacy of use codes and determine whether
deference to the 505(b)(2) or ANDA applicant's interpretation of the
scope of the patent is justified. A fourth comment suggests that FDA
provide an administrative appeals process and Administrative Law Judge
review where FDA reviews a proposed labeling carve-out for a 505(b)(2)
application or ANDA with deference to the 505(b)(2) or ANDA applicant's
interpretation of the scope of the patent. This comment also suggests
that FDA avoid a ``mere ministerial approach.''
    (Response 24) As noted in Response 23, we are not finalizing this
proposal at this time. Accordingly, we do not need to address comments
regarding specific aspects of implementation of this proposal in this
final rule.
    (Comment 25) One comment recommends that FDA require an NDA holder
to respond to a request to confirm the accuracy or relevance of patent
information in 15 days, rather than 30 days. The comment maintains that
a 15-day timeframe is consistent with the regulatory timeframe to make
corrections to an incomplete or otherwise inadequate submission of
patent information (see Sec.  314.53(c)(2)(ii)).
    (Response 25) We decline to modify the regulation as requested. We
believe that a period of 30 days from the date on which FDA sends the
statement of dispute to the NDA holder provides an appropriate
opportunity for the NDA holder to consider the statement of dispute and
submit a response that addresses the requirements of Sec.
314.53(f)(1)(i).
    (Comment 26) Two comments recommend that FDA clarify that an NDA
holder's amendment to the use code in response to a patent listing
dispute will not be considered untimely filed patent information under
Sec. Sec.  314.50(i)(4) and 314.94(a)(12)(vi). One comment expresses
concern that whether and how an NDA holder responds to a method-of-use
patent listing dispute may affect the availability of a 30-month stay
should the NDA holder subsequently file a patent infringement action in
response to notice of a paragraph IV certification to the patent.
    (Response 26) We agree that an NDA holder's amendment to its use
code or related information on Form FDA 3542 in response to a patent
listing dispute should not be considered untimely filed patent
information if it is submitted within 30 days of FDA's request under
Sec.  314.53(f)(1)(i)(B) and contains the information required under
Sec.  314.53(f)(1)(i)(B)(1) or (2) (see Sec. Sec.  314.50(i)(4)(i) and
314.94(a)(12)(vi)(A) (describing untimely filing of patent information
``except as provided in Sec.  314.53(f)(1)'')). We note, however, that
if an NDA holder responds to the patent listing dispute with an
amendment to its use code more than 30 days after the date on which FDA
sends the statement of dispute to the NDA holder, FDA will consider the
amendment to be untimely filing of patent information because the
submission does not comply with the requirements of Sec.  314.53(f)(1).
    The patent listing dispute procedure would not have an impact on
the availability of a 30-month stay if other statutory and regulatory
criteria are met (see section 505(c)(3)(C) and (j)(5)(B)(iii) of the
FD&C Act and Sec.  314.107).
    V.B.4.b. Requests by NDA holder (Sec.  314.53(f)(2)). We proposed
to expressly require that if an NDA holder determines that a patent or
patent claim (e.g., a method-of-use claim) no longer meets the
statutory requirements for listing, the NDA holder must promptly notify
FDA to withdraw the patent or patent information and request that the
patent or patent information be removed from the list (see proposed
Sec.  314.53(f)(2)(i) and section 505(b)(1) and (c)(2) of the FD&C
Act). If an NDA holder is required by court order to amend patent
information or withdraw a patent from the list, we proposed to require
the NDA holder to submit a copy of the court order to the Orange Book
Staff within 14 calendar days of the date on which the order was
entered. We also proposed to codify our current practice of removing a
patent or patent information from the Orange Book when the NDA holder
has informed us that the patent no longer meets the statutory
requirements for listing if there is no first applicant eligible for
180-day exclusivity or upon the expiration of the 180-day exclusivity
period (see proposed Sec.  314.53(f)(2)(i)). In addition, we proposed
that if the term of the patent is extended under the patent term
restoration provisions of 35 U.S.C. 156, the NDA holder must submit a
correction to the patent expiration date on Form FDA 3542 within 30
calendar days of receipt of a certificate of extension or documentation
of an extension of the term of the patent (see proposed Sec.
314.53(f)(2)(ii) and 35 U.S.C. 156(e)(1) and (2)).
    We proposed to require that corrections or changes to previously
submitted patent information must be submitted on Form FDA 3542a or
3542,

as appropriate (see proposed Sec.  314.53(f)(2)(iii)). However, we
proposed to clarify that an NDA holder's withdrawal of a patent and
request to remove a patent from the list is not required to be
submitted on Form FDA 3542, but the request must specify the patent
number, the application number, and each product(s) approved in the
application to which the request applies (see proposed Sec.
314.53(f)(2)(iv)).
    In the following paragraphs, we discuss two comments on these
proposed provisions. After considering these comments, we are making
clarifying revisions to the description of the required amendment or
supplement and the address to which the amendment or supplement must be
submitted, and technical amendments described in sections V.B.2.c and
V.P.3 We are also revising proposed Sec.  314.53(f)(2)(i) to more
precisely describe our practice of removing a patent or patent
information from the list in response to an NDA holder's request if
there is no first applicant eligible for 180-day exclusivity based on a
paragraph IV certification to that patent or after the 180-day
exclusivity period of a first applicant based on that patent has
expired or has been extinguished.
    (Comment 27) Two comments request that FDA clarify the implications
of failing to timely amend patent information or withdraw a patent. One
of the comments requests that FDA clarify the meaning of ``promptly
notify FDA'' in proposed Sec.  314.53(f)(2)(i), and explain whether the
timeframe may differ based on the circumstances (e.g., delay withdrawal
of an original patent held invalid until the reissued patent has
issued). The other comment suggests that if the NDA holder fails to
timely notify FDA of a patent term extension or of a court order to
amend patent information or withdraw a patent from the list, the patent
should be considered untimely filed.
    (Response 27) FDA is establishing regulatory timeframes for
withdrawal or amendment of patent information and withdrawal of a
patent to promote the NDA holder's timely compliance with obligations
under the FD&C Act and applicable regulations. If the NDA holder
determines that a patent or patent claim no longer meets the statutory
requirements for listing, the NDA holder must ``promptly notify FDA''
to withdraw the patent or patent information or amend the patent
information to ensure that pending 505(b)(2) applications or ANDAs that
contain a patent certification to the amended or withdrawn patent or
patent information are not inappropriately delayed if they are
otherwise eligible for approval. An NDA holder's withdrawal or
amendment of patent information or withdrawal of the patent within 14
days of the date on which the NDA holder determines that the patent or
patent claim no longer meets the requirements for listing under section
505(b)(1) or (c)(2) of the FD&C Act would be considered ``prompt.'' If
a court enters a final decision from which no appeal has been or can be
taken that a patent is invalid, the NDA holder must promptly notify FDA
to withdraw the patent and request that the patent be removed from the
list irrespective of whether the NDA holder or patent owner is
separately requesting a reissue of the patent.
    We decline to modify the regulation to consider a patent untimely
filed if the NDA holder fails to notify FDA of a court order to amend
or withdraw patent information within 14 days because a court can
enforce a failure to comply with its order. We also decline to modify
the regulation to consider a patent untimely filed if the NDA holder
fails to notify FDA of a patent term extension within 30 days because
NDA holders have adequate incentive to inform FDA of any patent term
extension. We require NDA holders to submit on Form FDA 3542 a
correction to the expiration date of the listed patent if the term is
extended under 35 U.S.C. 156(e) to ensure that prospective 505(b)(2)
and ANDA applicants have timely notice of changes to the asserted
patent coverage for a listed drug.
    (Comment 28) One comment recommends that FDA clarify where an NDA
holder should send a voluntary request to remove patent information
from the list.
    (Response 28) We agree. We are revising Sec.  314.53(f)(2)(iv) to
clarify that the NDA holder must submit an amendment to its NDA to the
same addresses described in Sec.  314.53(d)(4)(ii) to promptly notify
FDA to withdraw a patent and request that FDA remove a patent from the
list. We are also revising Sec.  314.53(f)(2)(i) and (iii) to clarify
that an NDA holder must submit a copy of a court order to amend patent
information or withdraw a patent from the list in an amendment to its
NDA that bears the identification described in Sec.  314.53(d)(6)
(``Time Sensitive Patent Information''). In addition, we are changing
the address for submission of the amendment from the Orange Book Staff
to the CDER Central Document Room, consistent with Sec.
314.53(d)(4)(ii).

V.C. Patent Certification (Sec. Sec.  314.50(i) and 314.94(a)(12))

V.C.1. Method-of-Use Patents (Sec. Sec.  314.50(i)(1)(iii) and
314.94(a)(12)(iii))
    We proposed to revise Sec. Sec.  314.50(i)(1)(iii) and
314.94(a)(12)(iii) to clarify that a 505(b)(2) or ANDA applicant that
is not seeking approval for a condition of use other than an indication
(e.g., a dosing regimen) that is covered by a method-of-use patent for
the listed drug(s) relied upon or RLD, respectively, may submit a
statement under section 505(b)(2)(B) or 505(j)(2)(A)(viii) of the FD&C
Act, instead of a patent certification with respect to any such method-
of-use claims.
    We received no comments regarding this proposed revision. We are
finalizing proposed Sec. Sec.  314.50(i)(1)(iii) and 314.94(a)(12)(iii)
with technical amendments to reflect the claim-based approach to patent
certification requirements for patents that include a method-of-use
claim (i.e., a 505(b)(2) or ANDA applicant may submit a statement with
respect to one or more method-of-use claims and a paragraph IV
certification with respect to the remaining patent claims). As revised,
a statement under section 505(b)(2)(B) or 505(j)(2)(A)(viii) of the
FD&C Act may be submitted if the applicant is not seeking approval for
``an'' indication or other condition of use claimed by a method-of-use
patent rather than ``any'' indications or other conditions of use
claimed by the method-of-use patent (see Sec. Sec.  314.50(i)(1)(iii)
and 314.94(a)(12)(iii)).
    We also are making technical amendments throughout part 314 to
clarify that a 505(b)(2) or ANDA applicant may submit an appropriate
patent certification or statement (see, e.g., Sec. Sec.
314.50(i)(1)(i)(A) through (C), (i)(5), (i)(6), (i)(6)(ii),
(i)(6)(iii)(A)(1) and (2); 314.53(d)(3); and 314.94(a)(12)(i)(A) and
(B), (a)(12)(vii) and (viii), (a)(12)(viii)(B), and
(a)(12)(viii)(C)(1)(i) and (ii)).
V.C.2. Method-of-Manufacturing Patents (Deletion of Sec. Sec.
314.50(i)(2) and 314.94(a)(12)(iv))
    We proposed to remove Sec. Sec.  314.50(i)(2) and
314.94(a)(12)(iv), which provide that an applicant is not required to
make a certification with respect to any patent that claims only a
method of manufacturing the drug product (method-of-manufacturing
patent or process patent) for which the applicant is seeking approval.
We proposed this deletion for clarity and consistency with the
regulation that

prohibits an NDA holder from submitting information on a patent that
only claims a method of manufacturing the drug product (see Sec.
314.53(b)).
    In the following paragraphs, we discuss a comment on this proposed
deletion. After considering this comment, we are removing (and
reserving) Sec. Sec.  314.50(i)(2) and 314.94(a)(12)(iv).
    (Comment 29) One comment recommends that FDA permit the listing of
process patents that claim production of the active pharmaceutical
ingredient in the approved drug product (e.g., synthesis process or
impurity reduction process).
    (Response 29) We decline to adopt the suggestion provided in the
comment. The FD&C Act requires an NDA applicant or holder to submit
information on any patent that claims the drug or that claims a method
of using such drug and with respect to which a claim of patent
infringement could reasonably be asserted if a person not licensed by
the owner engaged in the manufacture, use, or sale of the drug (see
section 505(b)(1) and (c)(2) of the FD&C Act). A method-of-
manufacturing patent or process patent does not meet the statutory
requirement for listing because it does not claim an approved drug or
an approved method of using the drug. We note, however, that a product-
by-process patent is eligible for listing in the Orange Book because
the invention claimed by the patent is, for example, the novel drug
product and not the process used to make the product (see 68 FR 36676
at 36679 to 36680).
V.C.3. Licensing Agreement (Sec. Sec.  314.50(i)(3) and
314.94(a)(12)(v))
    We proposed to revise Sec.  314.50(i)(3) regarding licensing
agreements to remove the references to an ``immediate effective date''
and clarify that the patent owner with whom the applicant has a
licensing agreement may consent to approval of the 505(b)(2)
application (if otherwise justified) as of a specific date. We
explained that this proposed revision did not alter the current
requirements for a 505(b)(2) (or ANDA) applicant to submit a paragraph
IV certification to a patent that claims the listed drug relied upon
even though the applicant has a licensing agreement with the patent
owner (see proposed Sec. Sec.  314.50(i)(3) and 314.94(a)(12)(v)). We
further explained that an applicant that has a licensing agreement with
the patent owner would still be required to send notice of the
paragraph IV certification to the NDA holder and each patent owner.
    In the following paragraphs, we discuss a comment on this proposed
revision. After considering this comment, we are making a clarifying
revision and editorial corrections to Sec.  314.50(i)(3) and conforming
revisions to Sec.  314.94(a)(12)(v).
    (Comment 30) One comment requests that FDA revise Sec.
314.50(i)(3) to apply to an ``agreement'' between a 505(b)(2) applicant
and the patent owner(s), rather than restrict the provision to a
``licensing agreement.'' The comment maintains that other forms of
agreement (e.g., a covenant not to sue) should not be treated
differently for purposes of determining the earliest date agreed upon
by the applicant and relevant patent owner(s) for approving an
application. The comment also recommends that FDA amend Sec.
314.94(a)(12)(v) to expressly describe consent to approval as of a
specific date because the provision also should apply to ANDAs.
    (Response 30) We decline to modify Sec.  314.50(i)(3) to broadly
refer to an agreement between a 505(b)(2) applicant and the patent
owner. Licensing agreements are described in section 505(b)(1) and
(c)(2) of the FD&C Act, which refer to a patent with respect to which a
claim of patent infringement could reasonably be asserted if a person
not licensed by the owner engaged in the manufacture, use, or sale of
the drug. It accords with the statute for a 505(b)(2) applicant to
submit a paragraph IV certification based on a licensing agreement with
the patent owner, and for the patent owner to consent to approval of
the 505(b)(2) application as of a specific date (if the 505(b)(2)
application is otherwise eligible for approval). However, it is unclear
whether other types of agreements (e.g., a covenant not to sue) would
necessarily be consistent with a paragraph IV certification that the
patent is invalid, unenforceable, or will not be infringed by the
manufacture, use, or sale of the proposed product for which the
505(b)(2) application (or ANDA) is submitted. The FD&C Act does not
contemplate FDA enforcement of private agreements between a 505(b)(2)
(or ANDA) applicant and a patent owner that are unrelated to the
statutory and regulatory requirements for approval.
    As a practical matter, it is unnecessary to broaden this provision
to describe other circumstances in which a patent owner may consent to
approval as of a specific date. If a 505(b)(2) applicant submits a
paragraph IV certification and the patent owner provides a covenant not
to sue, then the patent owner would not initiate patent infringement
litigation within the 45-day period and there would be no 30-month stay
of approval. If a 505(b)(2) applicant changes a previously submitted
certification or statement to a paragraph IV certification, the patent
owner and NDA holder for the listed drug relied upon may waive their
opportunity to file a patent infringement action within the 45-day
period (see Sec.  314.107(f)(3)).
    We agree that the regulations should expressly provide that if an
ANDA applicant has a licensing agreement with a patent owner, the
patent owner may consent to approval of the ANDA as of a specific date
(if the ANDA is otherwise eligible for approval). We are revising Sec.
314.94(a)(12)(v) to describe the requirements for a written statement
from the patent owner that has a licensing agreement with the applicant
and consents to approval of the ANDA as of a specific date. Agreements
between an ANDA applicant and a brand name drug company that must be
filed with the Assistant Attorney General and the FTC are described in
section 1112 of the MMA.
    We also are revising Sec. Sec.  314.50(i)(3) and 314.94(a)(12)(v)
to clarify that the 505(b)(2) application or ANDA will be approved
based on consent to approval as of a specific date only if the
505(b)(2) application or ANDA is ``otherwise eligible for approval''
rather than ``otherwise justified.''

V.D. Notice of Paragraph IV Certification (Sec. Sec.  314.52 and
314.95)

V.D.1. Timing of Notice
    V.D.1.a. Date before which notice may not be given. We proposed to
revise our regulations to clearly delineate the two limitations on the
timeframe within which notice of a paragraph IV certification to a
listed patent must be provided to the NDA holder and each patent owner:
The date before which notice must not be given and, as discussed in
section V.D.1.b, the date by which notice must be given.
    We proposed to codify our longstanding policy that notice of a
paragraph IV certification may not be sent by a 505(b)(2) or ANDA
applicant unless and until we have notified the applicant that its
application has been filed or received, as appropriate (see proposed
Sec. Sec.  314.52(b)(1) and 314.95(b)(1)). We proposed that any notice
sent by a 505(b)(2) or ANDA applicant before the receipt of an
acknowledgment letter or paragraph IV acknowledgment letter is invalid,
and thus does not trigger either the 45-day period in which the NDA
holder and each patent owner may initiate a patent

infringement action and obtain a 30-month stay or the beginning of any
related 30-month period. We proposed that an applicant that prematurely
sends notice of a paragraph IV certification would be required to
resend notice within the required timeframe after the 505(b)(2)
application or ANDA has been filed or received, respectively, to
satisfy the notice requirement of the FD&C Act and, in the case of a
first applicant, to qualify for 180-day exclusivity (see proposed
Sec. Sec.  314.52(b)(2) and 314.95(b)(2)).
    We proposed to clarify that if a 505(b)(2) or ANDA applicant
submits an amendment containing a paragraph IV certification before the
filing or receipt of the 505(b)(2) application or ANDA, respectively,
the applicant would be required to wait until it has received an
acknowledgment letter or a paragraph IV acknowledgment letter before
sending notice of its paragraph IV certification to the NDA holder and
each patent owner (see proposed Sec. Sec.  314.52(b) and (d)(2) and
314.95(b) and (d)(2)).
    With respect to patents that are listed in the Orange Book after
submission of an ANDA, we proposed that any notice of paragraph IV
certification would be invalid and would not be considered to comply
with the notice requirement of the FD&C Act if it is sent before the
first working day after the day the patent is listed in the Orange Book
(see proposed Sec. Sec.  314.94(a)(12)(viii)(C)(1)(ii) and
314.95(b)(2)). We proposed that the term ``working day'' would have the
meaning provided in 21 CFR 1.377 (``any day from Monday through Friday,
excluding Federal holidays''). We explained that this proposal is
intended to discourage ANDA applicants from submitting a paragraph IV
certification and sending notice to the NDA holder and each patent
owner every day during the 30-day period after issuance of a patent
that could be listed for the RLD in an effort to qualify as a first
applicant eligible for 180-day exclusivity if such patent ultimately is
listed for the RLD in the Orange Book. We also noted that this proposed
requirement would ensure that all ANDA applicants (irrespective of time
zone) have a reasonable opportunity to be first to certify to a newly
listed patent.
    In the following paragraphs, we discuss several comments on our
proposed regulations regarding the date before which notice of
paragraph IV certification must not be given. After considering these
comments, we are revising Sec.  314.52(b)(2) to provide that a
505(b)(2) applicant must send notice of a paragraph IV certification on
or after the date of filing of the 505(b)(2) application described in
Sec.  314.101(a)(2) or (3), as applicable, rather than on or after the
date it receives a paragraph IV acknowledgment letter. We are revising
proposed Sec.  314.95(b)(2) to delete the reference to an
``acknowledgment letter'' because an ANDA applicant will now receive a
``paragraph IV acknowledgment letter'' if it amends its ANDA to add a
paragraph IV certification before the ANDA is received (see section
V.A.1).
    (Comment 31) One comment asserts that the statutory terms
``submits'' and ``files'' in section 505(j)(2)(B)(ii)(I) and (II) of
the FD&C Act, respectively, indicate that an ANDA applicant may send
notice of a paragraph IV certification at the time of submission of an
amendment to an ANDA containing a paragraph IV certification, even if
the ANDA has not yet been ``filed'' (i.e., ``received'' under Sec.
314.101(b)). The comment suggests that ANDA applicants that submit an
amendment containing the first paragraph IV certification to a patent
listed for the RLD are concerned that they may risk eligibility for
180-day exclusivity if they do not send notice at the time of
submission of the amendment, even though the ANDA has not been received
under Sec.  314.101(b). The comment proposes that FDA allow ANDA
applicants to ``change'' rather than ``amend'' their patent
certification in an amendment prior to filing, and consider the date of
the ``change'' for purposes of determining eligibility for 180-day
exclusivity.
    (Response 31) We disagree with the comment's interpretation of
section 505(j)(2)(B)(ii)(II) of the FD&C Act, and decline to adopt the
comment's proposed revision to the regulations governing submission of
a paragraph IV certification prior to receipt of the ANDA.
    As a preliminary matter, we note that the requirement that an ANDA
applicant must wait until its ANDA has been received before sending
notice of a paragraph IV certification ensures that the NDA holder and
patent owner do not needlessly expend resources to initiate litigation
with respect to an ANDA that is incomplete and therefore may not be
reviewed by the Agency (see ``Abbreviated New Drug Application
Regulations,'' 54 FR 28872 at 28887, July 10, 1989; see also 59 FR
50338 at 50349 to 50350). This reflects the Agency's view that Congress
did not intend for incomplete ANDA submissions to have the potential to
trigger legal action by an NDA holder or patent owner (see 54 FR 28872
at 28887; see also Allergan, Inc. v. Actavis, Inc., 2014 WL 7336692 at
*12 (E.D. Tex. 2014) (finding that the act of infringement created by
35 U.S.C. 271(e)(2) requires that the ANDA has been received by FDA,
not merely transmitted to FDA). Accordingly, our existing regulations
require that an ANDA applicant's notice of a paragraph IV certification
must include a statement that FDA has received the ANDA (see Sec.
314.95(c)(1)).
    The requirement that notice of a paragraph IV certification only be
sent after FDA has received the ANDA was ratified by the MMA, which
established a 20-day period for sending notice of a paragraph IV
certification that runs from the date of the postmark on the notice
with which FDA informs the applicant that the ANDA has been filed
(i.e., received under Sec.  314.101(b)) (see section
505(j)(2)(B)(ii)(I) of the FD&C Act and section V.D.1.b). The MMA also
requires that an ANDA applicant send notice of a paragraph IV
certification submitted in an amendment or supplement to the ANDA at
the time of submission of the amendment or supplement, regardless of
whether the applicant already has given notice with respect to another
paragraph IV certification contained in the ANDA or in an amendment or
supplement to the ANDA (see section 505(j)(2)(B)(ii)(II) of the FD&C
Act). Consistent with the framework established by section
505(j)(2)(B)(ii) of the FD&C Act, FDA interprets section
505(j)(2)(B)(ii)(II) of the FD&C Act to apply only to an amendment to
the ANDA that is submitted after the Agency has received the ANDA (see
SB Pharmco Puerto Rico, Inc. v. Mutual Pharmaceutical Co., 552 F. Supp.
2d 500, 510 (E.D. Pa.), appeal dismissed, 2008 U.S. App. LEXIS 27672
(Fed. Cir. 2008) (upholding FDA's interpretation of section
505(j)(2)(B)(ii)(II) of the FD&C Act and finding that notice of a
paragraph IV certification sent at the time of submission of an
amendment to an ANDA that had not yet been received ``was not valid or
timely''). Thus, we disagree with the comment's suggestion that an ANDA
applicant can submit an amendment containing a paragraph IV
certification before the ANDA is received and immediately send notice
of the paragraph IV certification. If an ANDA applicant submits an
amendment containing a paragraph IV certification before it has
received a paragraph IV acknowledgment letter advising that the ANDA
has been received for substantive review, the applicant is required to
send notice of its paragraph IV certification within 20 days after the
date of the postmark on the paragraph IV acknowledgment letter.
    Based on the Agency's interpretation of the statute, it is
unnecessary to use the terminology suggested in the

comment to describe an amendment that contains a paragraph IV
certification to a newly listed patent or that changes a previously
submitted patent certification or statement to a paragraph IV
certification and is submitted before receipt of the ANDA.
    The relevant date for determining eligibility for 180-day
exclusivity based upon submission of a paragraph IV certification
contained in an amendment is the date of submission of the amendment.
We are revising Sec.  314.95(d)(2) to clarify that if an ANDA
applicant's notice of paragraph IV certification is timely provided in
accordance with Sec.  314.95(b)(2) and the applicant has not submitted
a previous paragraph IV certification, FDA will base its determination
of whether the applicant is a first applicant on the date of submission
of the amendment containing the paragraph IV certification.
    (Comment 32) One comment accepts FDA's ``settled administrative
practice'' that a 505(b)(2) or ANDA applicant may not send notice of
paragraph IV certification until the application is accepted for
review, but contends that FDA may not condition a 505(b)(2) applicant's
ability to send notice on its prior receipt of a paragraph IV
acknowledgment letter that would be sent up to 14 days after the
505(b)(2) application is accepted for review (filed). The comment
maintains that the benefits of this approach have not been shown to
outweigh the costs of a potential 2-week delay in approval of a
505(b)(2) application, and that the proposal is inconsistent with the
statute. Another comment recommends that FDA send a paragraph IV
acknowledgment letter to a 505(b)(2) applicant via email on the date on
which the 505(b)(2) application is filed to eliminate the disparity
between the dates on which paragraph IV acknowledgment letters are sent
to 505(b)(2) and ANDA applicants. A third comment requests that FDA
clarify when an ANDA applicant can send notice if the paragraph IV
acknowledgment letter is not received on day 60.
    (Response 32) We agree that there should not be a delay of
approximately 2 weeks between the date on which a 505(b)(2) application
is filed and the date on or after which a 505(b)(2) applicant must send
notice of a paragraph IV certification to the NDA holder and each
patent owner. We are revising proposed Sec.  314.52(b)(1) and (2) to
provide that a 505(b)(2) applicant must send notice of a paragraph IV
certification on or after the date of filing of the 505(b)(2)
application described in Sec.  314.101(a)(2) or (3), as applicable,
rather than on or after the date it receives a paragraph IV
acknowledgment letter, and we are making conforming revisions to Sec.
314.52(d)(1) and (2). This revised approach ensures that notice of a
paragraph IV certification will not be sent before the Agency has filed
the relevant 505(b)(2) application, and avoids a delay of up to 2 weeks
in the potential initiation of patent infringement litigation by an NDA
holder or patent owner and any corresponding 30-month stay of approval
of the 505(b)(2) application.
    FDA determines whether a 505(b)(2) application may be filed within
60 days after FDA is in receipt of the 505(b)(2) application (see Sec.
314.101(a)(1)). If the 505(b)(2) applicant does not receive a refusal
to file letter on or before day 60, the 505(b)(2) application is deemed
filed. If FDA refuses to file the 505(b)(2) application and the
505(b)(2) application is filed over protest or resubmitted, then the
date of filing described in Sec.  314.101(a)(3) applies. We are
requiring that a 505(b)(2) applicant send notice of a paragraph IV
certification on or after the date of filing of the 505(b)(2)
application, but not later than 20 days after the date of the postmark
on the paragraph IV acknowledgment letter (see Sec.  314.52(b)(1)). The
``paragraph IV acknowledgment letter'' for a 505(b)(2) application is
the filing communication that generally is sent to the 505(b)(2)
applicant not later than 14 calendar days after the 60-day filing date
(sometimes referred to as the ``74 day letter'') (see section V.A.1).
The ``date of the postmark'' for a paragraph IV acknowledgment letter
for a 505(b)(2) application is considered to be four calendar days
after the date on which the letter is signed by the signatory authority
(generally the Division Director or designee in the OND review
division). Accordingly, this revision to our regulations implements the
statutory requirement that notice be sent within 20 days of the
postmark on the filing communication while preserving the principle
that notice must not be sent before a 505(b)(2) application is filed.
    We are maintaining the requirement that an ANDA applicant must send
notice of a paragraph IV certification on or after the date it receives
a paragraph IV acknowledgment letter because FDA intends to
electronically transmit the letter to the ANDA applicant on the date on
which the ANDA is received under Sec.  314.101(b). Accordingly, in
contrast to the interval of up to 14 days for 505(b)(2) applications,
there is no interval between the date on which the ANDA is received
under Sec.  314.101(b) and the date on which an ANDA applicant receives
a paragraph IV acknowledgment letter (see section V.A.6). An ANDA
applicant can send notice of a paragraph IV certification submitted in
an original ANDA or submitted in an amendment to an ANDA that has not
yet been received on or after the date the ANDA applicant receives a
paragraph IV acknowledgment letter.
    (Comment 33) One comment asserts that the proposed requirement that
a paragraph IV certification must not be submitted earlier than the
first working day after the day the patent or patent claim is listed in
the Orange Book would conflict with the statute and prevent ANDA
applicants from submitting a paragraph IV certification to a newly
listed patent at the first lawful opportunity. Another comment
maintains that the proposed requirement for submission of a paragraph
IV certification to a newly listed patent may result in multiple ANDA
applicants becoming eligible for 180-day exclusivity and thus would
dilute the value of 180-day exclusivity.
    (Response 33) We believe that our approach to patent certification
requirements for newly listed patents is consistent with the statute
and provides a reasonable opportunity for ANDA applicants to compete to
have the first substantially complete ANDA that contains a paragraph IV
certification to a listed patent for the RLD.
    The requirement that an ANDA applicant must not submit a paragraph
IV certification earlier than the first working day after the day the
patent or patent claim is listed in the Orange Book reflects FDA's
determination that selecting the first working day after the day on
which the patent information is published creates a level playing field
for all ANDA applicants (see Sec. Sec.  314.94(a)(12)(viii)(C)(1)(ii)
and 314.95(b)(2)). One court has determined, in the absence of a
regulation to the contrary, that ``reality matters'' if a patent has
been submitted to FDA, and an ANDA applicant can submit a paragraph IV
certification even if the patent is not yet listed in the Orange Book
(see Teva Pharms., USA, Inc. v. Leavitt, 548 F.3d 103, 105 (D.C. Cir.
2008)). However, FDA has determined that permitting serial submissions
of amendments and multiple notices of paragraph IV certifications is
overly burdensome to FDA and NDA holders. Such a practice makes it
difficult to determine which paragraph IV certification and notice of
paragraph IV certification is valid. Our decision to

level the playing field for paragraph IV certifications in this manner
is consistent with our authority to establish rules for the efficient
enforcement of the FD&C Act (see section 701(a) of the FD&C Act).
    We are not persuaded by the comment's assertion that leveling the
playing field for ANDA applicants will dilute the value of 180-day
exclusivity. For example, FDA continues to receive multiple ANDAs on
the day that 4 years of a 5-year exclusivity period under section
505(j)(5)(F)(ii) of the FD&C Act has expired (the first day that ANDAs
containing a paragraph IV certification are permitted to be submitted)
even though many of these ANDAs will likely share eligibility for 180-
day exclusivity.
    (Comment 34) One comment supports the proposed requirement that a
paragraph IV certification must not be submitted earlier than the first
working day after the day the patent or patent claim is listed in the
Orange Book, but recommends that FDA establish a time after which
patent information listed in the Orange Book will be deemed to have
been published the next day. Another comment suggests that FDA
instantaneously notify ANDA applicants when a patent is listed for the
RLD after ANDA submission to provide an equal opportunity for timely
submission of an appropriate patent certification or statement to the
pending ANDA and, if applicable, notice of paragraph IV certification.
    (Response 34) We decline to adopt the suggestions provided in the
comments. FDA generally posts daily electronic updates to the Orange
Book in the afternoon (Eastern Standard Time); however, we are not
establishing a specific time by which FDA will update the Orange Book
to preserve flexibility in the event of technical difficulties.
Applicants will have an equal opportunity for timely submission of an
appropriate patent certification or statement for a newly listed patent
or patent claim because FDA will make this information publicly
available through the Orange Book. Although we decline to undertake the
burden of notifying individual ANDA applicants when a patent or patent
claim for the RLD is newly listed in the Orange Book, we are committed
to facilitating public access to the Orange Book through efficient
means (see, e.g., the ``Orange Book Express'' mobile application
launched on November 9, 2015).
    V.D.1.b. Date by which notice must be given. We proposed to
establish a regulation that would implement section 505(b)(3)(B) and
(j)(2)(B)(ii) of the FD&C Act by providing that an applicant must send
notice of a paragraph IV certification contained in a 505(b)(2)
application or ANDA not later than 20 days after the date of the
``postmark'' on the acknowledgment letter or paragraph IV
acknowledgment letter (see proposed Sec. Sec.  314.52(b)(1) and
314.95(b)(1) and section 505(b)(3)(B)(i) and (j)(2)(B)(ii)(I) of the
FD&C Act). We proposed a definition of the term ``postmark'' and, as
applied to paragraph IV acknowledgment letters for 505(b)(2)
applications, an alternate proposed interpretation of the term
``postmark'' to reflect current practice regarding the mailing of
filing communications (see section V.A.1). We also proposed to specify
the method of calculating the 20-day period for providing notice of a
paragraph IV certification (see proposed Sec. Sec.  314.52(b)(1) and
314.95(b)(1)).
    We proposed that an applicant must send notice of a paragraph IV
certification contained in an amendment to a 505(b)(2) application or
ANDA that has been filed or received for substantive review,
respectively, or in a supplement to an approved 505(b)(2) application
or ANDA at the same time that the amendment or supplement is submitted
to FDA (see proposed Sec. Sec.  314.52(d)(1) and 314.95(d)(1) and
section 505(b)(3)(B)(ii) and (j)(2)(B)(ii)(II) of the FD&C Act). We
proposed that notice of a paragraph IV certification in an amendment or
supplement must be provided regardless of whether the applicant has
already given notice with respect to another paragraph IV certification
contained in the 505(b)(2) application or ANDA or in an amendment or
supplement to the 505(b)(2) application or ANDA (see proposed
Sec. Sec.  314.52(d)(1) and 314.95(d)(1) and section 505(b)(3)(B)(ii)
and (j)(2)(B)(ii)(II) of the FD&C Act).
    We proposed to require an applicant that submits an amendment or
supplement to a 505(b)(2) application or ANDA that seeks approval for a
different strength of the drug product and contains a paragraph IV
certification adhere to the timing requirements for notice in
Sec. Sec.  314.52(d)(1) or (2) and 314.95(d)(1) or (2), respectively,
based on whether the 505(b)(2) application has been filed or the ANDA
has been received (see proposed Sec. Sec.  314.52(d)(3) and
314.95(d)(3)).
    We did not receive any other comments on proposed Sec. Sec.
314.52(b)(1), (d)(1) and (2), and 314.95(b)(1), (d)(1) and (2). We are
finalizing proposed Sec.  314.52(b)(1) and (2) and (d)(1) and (2) with
the revisions discussed in Response 32. We are finalizing proposed
Sec.  314.95(b)(1) and (d)(2) with clarifying revisions to consistently
refer to ``a paragraph IV acknowledgment letter'' because these
provisions refer to an ANDA that contains a paragraph IV certification
before the ANDA is received and thus FDA will send the ANDA applicant a
paragraph IV acknowledgment letter. We also are making the clarifying
revision to proposed Sec.  314.95(d)(2) discussed in Response 31. We
are finalizing proposed Sec.  314.95(d)(1) with a clarifying revision
to add the phrase ``or an acknowledgment letter'' because an applicant
may amend or supplement its ANDA to include a paragraph IV
certification irrespective of whether the ANDA contained a paragraph IV
certification at the time of receipt. We also are making the technical
amendment to Sec.  314.95(d)(1) described in section V.P.1.
V.D.2. Contents of Notice
    We proposed that a 505(b)(2) or ANDA applicant's notice of a
paragraph IV certification must include, among other things: (1) A
statement that data from any required bioavailability or bioequivalence
studies have been submitted; (2) a statement that the applicant has
received an acknowledgment letter or a paragraph IV acknowledgment
letter for its 505(b)(2) application or ANDA; (3) the patent number and
expiration date of each patent listed in the Orange Book that is the
subject of the paragraph IV certification; and (4) an offer of
confidential access, if the applicant alleges that the patent will not
be infringed and may later decide to file a civil action for
declaratory judgment in accordance with section 505(c)(3)(D) and
(j)(5)(C) of the FD&C Act) (see proposed Sec. Sec.  314.52(c) and
314.95(c)). We also proposed to require the 505(b)(2) or ANDA applicant
to cite section 505(b)(3)(D) and (j)(2)(B)(iv) of the FD&C Act,
respectively, as amended by the MMA, in the notice of paragraph IV
certification (see proposed Sec. Sec.  314.52(c) and 314.95(c)). In the
proposed rule, we explained that the Agency assesses neither the
adequacy of the contents of a 505(b)(2) or ANDA applicant's notice of
paragraph IV certification nor the applicant's stated basis for
certifying that a listed patent is invalid, unenforceable, or will not
be infringed by its proposed drug product.
    In the following paragraphs, we discuss two comments on the
proposed requirements for the content of a notice of paragraph IV
certification. After considering these comments, we are not finalizing
proposed Sec.  314.52(c)(3) and we are making conforming editorial
changes to the numbering of subsequent paragraphs in Sec.  314.52(c).
We are

revising proposed Sec.  314.95(c)(3) to omit the reference to an
``acknowledgment letter'' and require that the ANDA applicant include a
statement that the applicant has received the paragraph IV
acknowledgment letter for the ANDA. We are making a grammatical
correction to the introductory text of Sec. Sec.  314.52(c) and
314.95(c) to provide that the notice must include, but is not limited
to, the information described in Sec. Sec.  314.52(c)(1) through (8)
and 314.95(c)(1) through (9). We are finalizing the remaining
provisions of proposed Sec. Sec.  314.52(c) and 314.95(c) without
change, except for a revision to proposed Sec. Sec.  314.52(c)(8) and
314.95(c)(8) to clarify that an offer of confidential access must be
provided by an applicant that seeks to preserve the option to file a
civil action for declaratory judgment in accordance with section
505(c)(3)(D) or (j)(5)(C) of the FD&C Act.
    (Comment 35) One comment asserts that FDA lacks authority to
require a 505(b)(2) or ANDA applicant to include, in any notice of
paragraph IV certification, a statement that the applicant has received
an acknowledgment letter or a paragraph IV acknowledgment letter
because section 505(b)(3)(D) and (j)(2)(B)(iv) of the FD&C Act does not
expressly require such a statement.
    (Response 35) We disagree. FDA has the authority to establish
regulations regarding the contents of notice of a paragraph IV
certification to support the efficient enforcement of the FD&C Act (see
section 701(a) of the FD&C Act). The FD&C Act requires that a notice of
paragraph IV certification must state that the 505(b)(2) application or
ANDA containing the certification ``has been submitted'' (see section
505(b)(3)(D)(i) and (j)(2)(B)(iv)(I) of the FD&C Act). As discussed in
Response 31, it is the Agency's longstanding policy that notice of a
paragraph IV certification may not be sent unless and until we have
notified the applicant that its 505(b)(2) application has been filed or
its ANDA has been received because premature notice could result in
lawsuits over applications that FDA refuses to file or receive and thus
no longer are pending. Accordingly, our existing regulations require
that a 505(b)(2) or ANDA applicant's notice of a paragraph IV
certification must include a statement that FDA has filed the NDA (in
the case of a 505(b)(2) application) or has received the ANDA (see
Sec. Sec.  314.52(c)(1) and 314.95(c)(1)). To help ensure that notices
of paragraph IV certifications are not sent prematurely, we also are
requiring that an ANDA applicant's notice of paragraph IV certification
include a statement that the applicant has received the paragraph IV
acknowledgment letter for the ANDA (see Sec.  314.95(c)(3)). We are
revising proposed Sec.  314.95(c)(3) to delete the reference to an
``acknowledgment letter'' because an ANDA applicant will now receive a
``paragraph IV acknowledgment letter'' if the ANDA contains a paragraph
IV certification at any time before the ANDA is received (see section
V.A.1).
    With respect to a 505(b)(2) application, we are maintaining the
requirement that a 505(b)(2) applicant's notice of a paragraph IV
certification must include a statement that FDA has filed the NDA (see
Sec.  314.52(c)(1)). However, we are not requiring the 505(b)(2)
applicant to include a statement that it has received a paragraph IV
acknowledgment letter because we are revising our regulations to
provide that a 505(b)(2) applicant must send notice of a paragraph IV
certification on or after the date of filing of the 505(b)(2)
application described in Sec.  314.101(a)(2) or (3), as applicable,
rather than on or after the date the applicant receives a paragraph IV
acknowledgment letter (see Sec.  314.52(b)(1) and Response 32).
    (Comment 36) One comment requests that FDA revise the regulations
to enable any recipient of notice of paragraph IV certification to
request that FDA confirm the adequacy of notice with respect to
statutory and regulatory requirements (other than the factual and legal
basis for the paragraph IV certification). This comment recommends that
FDA provide that inadequate notice is invalid and does not trigger the
45-day period described in section 505(c)(3)(C) or (j)(5)(B)(iii) of
the FD&C Act. Another comment recommends that FDA provide an additional
time period in which a 505(b)(2) or ANDA applicant can correct a
deficient notice of paragraph IV certification that would extend the
time for a patent holder under its duties or obligations.
    (Response 36) We decline to revise the regulations to provide for a
ministerial review of notice of a paragraph IV certification to
evaluate compliance with the statutory and regulatory requirements. A
505(b)(2) or ANDA applicant is required to submit an amendment to its
505(b)(2) application or ANDA certifying, among other things, that the
notice of paragraph IV certification met the content requirements under
Sec. Sec.  314.52(c) or 314.95(c), respectively (see Sec. Sec.
314.52(b)(3) or 314.95(b)(3)). The regulations also provide that a copy
of the notice of paragraph IV certification does not need to be
submitted to FDA (see Sec. Sec.  314.52(b)(3) or 314.95(b)(3)). Given
the clarifying revisions to the regulations to enhance compliance with
the requirements for notice of a paragraph IV certification and the
administrative burden that would be associated with a ministerial
review of a notice of paragraph IV certification, we do not believe
that such review is warranted. The second comment does not clearly
describe the requested action or provide adequate support for any
proposed change. We note, however, that an applicant may amend its
505(b)(2) application or ANDA with a written statement that a later
date should be used as the first day of the 45-day period provided in
section 505(c)(3)(C) or (j)(5)(B)(iii) of the FD&C Act (see Sec. Sec.
314.52(f) and 314.95(f)).
V.D.3. Documentation of Timely Sending and Receipt of Notice
    V.D.3.a. Acceptable methods of sending notice of paragraph IV
certification. We proposed to expand the list of acceptable delivery
methods that 505(b)(2) and ANDA applicants may use to send notice of
paragraph IV certification to the NDA holder and each patent owner by
permitting a 505(b)(2) or ANDA applicant to use a ``designated delivery
service'' (see proposed Sec. Sec.  314.52(a) and 314.95(a)). We
proposed to define a ``designated delivery service'' to mean a delivery
service provided by a trade or business that FDA determines: (1) Is
available to the general public throughout the United States; (2)
records electronically to its database, kept in the regular course of
its business, or marks on the cover in which any item referred to in
this section is to be delivered, the date on which the item was given
to the trade or business for delivery; and (3) provides overnight or 2-
day delivery service throughout the United States (see Sec. Sec.
314.52(g)(1) and 314.95(g)(1)). We proposed to periodically issue
guidance describing designated delivery services that meet the
regulatory criteria (see proposed Sec. Sec.  314.52(g)(2) and
314.95(g)(2)). We also proposed to clarify that a 505(b)(2) or ANDA
applicant may send notice of paragraph IV certification by an
alternative method (i.e., a method other than registered or certified
mail, return receipt requested, or a designated delivery service) only
if FDA has agreed in advance that the method will produce an acceptable
form of documentation (see proposed Sec. Sec.  314.52(a)(4) and (e) and
314.95(a)(4) and (e)).
    In the following paragraphs, we discuss a comment on these proposed
provisions. After considering this comment, we are finalizing proposed

Sec. Sec.  314.52(a) and (g)(1) and 314.95(a) and (g)(1) without
change, except for a technical amendment to add ``505(b)(2)'' before
``applicant'' in Sec.  314.52(a) for clarity. We are revising
Sec. Sec.  314.52(g)(2) and 314.95(g)(2) to clarify that FDA may
periodically issue guidance regarding designated delivery services.
    (Comment 37) One comment requests that FDA clarify whether a
505(b)(2) or ANDA applicant may use a delivery service that appears to
satisfy the criteria in Sec. Sec.  314.52(g)(1) and 314.95(g)(1) even
if the delivery service has not been identified by FDA in periodic
guidance.
    (Response 37) At this time, FDA does not intend to identify
specific designated delivery services in guidance. A 505(b)(2) or ANDA
applicant that sends notice of a paragraph IV certification may use a
delivery service that satisfies the regulatory criteria in Sec. Sec.
314.52(g)(1) or 314.95(g)(1), as applicable, without FDA's prior
approval. For purposes of the definition of ``designated delivery
service,'' FDA is clarifying that ``United States'' means the 50
States, the District of Columbia, and the Commonwealth of Puerto Rico,
but not the Territories. This approach acknowledges that some delivery
services may not routinely provide overnight or 2-day delivery services
to each of the Territories of the United States. If a 505(b)(2) or ANDA
applicant is required to send notice of a paragraph IV certification to
an NDA holder or patent owner (or its representative) that resides in a
Territory of the United States or outside the United States, the
applicant should ensure that the designated delivery service provides
service to the area or request permission to use an alternate method of
delivery.
    We are revising Sec. Sec.  314.52(g)(2) and 314.95(g)(2) to clarify
that FDA may periodically issue guidance regarding designated delivery
services. We note that a 505(b)(2) or ANDA applicant may send notice of
a paragraph IV certification by an alternate method that does not meet
the criteria in Sec. Sec.  314.52(g)(1) or 314.95(g)(1) only if the
applicant has obtained FDA's agreement in advance (see Sec. Sec.
314.52(a)(4) and 314.95(a)(4)).
    V.D.3.b. Amendment documenting timely sending and confirmation of
receipt of notice of paragraph IV certification. We proposed to revise
Sec. Sec.  314.52(e) and 314.95(e) to clarify the requirements for
submission of an amendment to a 505(b)(2) application or ANDA,
respectively, containing documentation of timely sending of notice of
paragraph IV certification and confirmation of receipt of same by the
NDA holder and each patent owner.
    We proposed that an applicant must amend its 505(b)(2) application
or ANDA at the time that it provides notice of a paragraph IV
certification with a statement certifying that notice has been provided
to the NDA holder and each patent owner as required by Sec. Sec.
314.52(a) and 314.95(a) and met the content requirements described in
Sec. Sec.  314.52(c) and 314.95(c) (see proposed Sec. Sec.
314.52(b)(3) and 314.95(b)(3)). We also proposed to clarify that a copy
of the notice of paragraph IV certification itself does not need to be
submitted to FDA in the amendment (see proposed Sec. Sec.  314.52(b)(3)
and 314.95(b)(3)).
    We proposed that an applicant must amend its 505(b)(2) application
or ANDA with documentation that the notice of paragraph IV
certification was sent on a date that complies with the timeframe
required by Sec.  314.52(b) or (d) or Sec.  314.95(b) or (d), as
applicable (see proposed Sec. Sec.  314.52(e) and 314.95(e) and section
505(b)(3)(B) and (j)(2)(B)(ii) of the FD&C Act). For administrative
efficiency, we proposed that a 505(b)(2) or ANDA applicant can submit a
single amendment that contains documentation of timely sending of the
notice(s) of paragraph IV certification and receipt of the notice(s) by
each person provided the notice. We proposed that the amendment must be
submitted within 30 days after the last date on which notice was
received by a person described in Sec.  314.52(a) or Sec.  314.95(a),
respectively (see proposed Sec. Sec.  314.52(e) and 314.95(e)). We also
proposed to clarify the types of documentation of timely sending and
receipt of notice of paragraph IV certification that can satisfy the
regulatory requirements (see proposed Sec. Sec.  314.52(e) and
314.95(e)).
    In addition, we proposed to require that ANDA applicants include in
their amendment a dated printout of the Orange Book entry for the RLD
that includes the patent that is the subject of the notice of paragraph
IV certification. This proposed requirement would ensure that a
paragraph IV certification that may qualify an ANDA applicant for 180-
day exclusivity is submitted only for a listed patent and is not sent
before the first working day after the day the patent is listed in the
Orange Book (see proposed Sec. Sec.  314.95(b)(2) and
314.94(a)(12)(viii)(C)(1)(ii)).
    We did not receive any comments on these proposed revisions.
However, for administrative efficiency, the Agency has revised
Sec. Sec.  314.52(b)(3) and 314.95(b)(3) to remove the requirement for
a 505(b)(2) or ANDA applicant to submit an amendment at the time it
sends notice of paragraph IV certification. Instead, the 505(b)(2) or
ANDA applicant may submit a single amendment that contains the
statements required by Sec. Sec.  314.52(b)(3) and 314.95(b)(3) and
documentation of timely sending and receipt of notice of paragraph IV
certification if the amendment contains all of the information required
by Sec. Sec.  314.52(b)(3) and (e) and 314.95(b)(3) and (e) and is
submitted within 30 days of the date on which the last notice was
received.

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

    We proposed to revise the introductory text of Sec.
314.94(a)(12)(viii) to remove the provision that restricts an ANDA
applicant from changing a paragraph IV certification to a paragraph III
certification in certain circumstances. We also proposed to revise
Sec. Sec.  314.50(i)(6) and 314.94(a)(12)(viii) to require that a
505(b)(2) or ANDA applicant submit an amended patent certification as
an amendment to its pending application (including a supplemental
505(b)(2) application or supplemental ANDA) and not by letter. We
received no comments, and we are finalizing these proposed revisions to
Sec. Sec.  314.50(i)(6) and 314.94(a)(12)(viii) without change, except
for the technical amendments described in sections V.P.2 and V.P.6.
V.E.1. Amended Patent Certifications After a Finding of Infringement
    We proposed to amend Sec. Sec.  314.50(i)(6)(i) and
314.94(a)(12)(viii)(A) to reflect changes to the FD&C Act made by the
MMA that clarify the requirements for a 505(b)(2) or ANDA applicant to
amend its paragraph IV certification after a judicial finding of patent
infringement (see section 505(c)(3)(C)(ii)(II) and
(j)(5)(B)(iii)(II)(bb) of the FD&C Act). We proposed to require that a
505(b)(2) and ANDA applicant submit an amendment to change its
paragraph IV certification to a paragraph III certification or, if
appropriate, to a statement under section 505(b)(2)(B) or
(j)(2)(A)(viii) of the FD&C Act if a court enters a final decision from
which no appeal has been or can be taken that the patent at issue is
valid and has been infringed (see proposed Sec. Sec.  314.50(i)(6)(i)
and 314.94(a)(12)(viii)(A)). We proposed to apply this requirement
irrespective of whether the patent infringement action was brought
within 45 days of receipt of the notice of paragraph IV certification
because a 505(b)(2) or ANDA applicant can no longer lawfully maintain a
paragraph IV certification after the final court decision.

    We also proposed to require a 505(b)(2) or ANDA applicant to submit
an amendment to change its paragraph IV certification to a paragraph
III certification or, if appropriate, to a statement under section
505(b)(2)(B) or (j)(2)(A)(viii) of the FD&C Act if a court signs a
settlement order, or consent decree in the action that includes a
finding that the patent is infringed, unless the final decision,
settlement order or consent decree also finds the patent to be invalid
(see proposed Sec. Sec.  314.50(i)(6)(i) and 314.94(a)(12)(viii)(A)).
We noted, however, that if a settlement is reached without a finding of
patent infringement or invalidity, then a paragraph IV certification
may continue to be appropriate.
    We received no comments, and we are finalizing these proposed
revisions to Sec. Sec.  314.50(i)(6)(i) and 314.94(a)(12)(viii)(A)
without change, except for a technical amendment to clarify that a
settlement order or consent decree must be signed and entered by the
court as required by section 505(c)(3)(C) and (j)(5)(B)(iii) of the
FD&C Act and the additional technical amendments described in sections
V.P.2 and V.P.6.
V.E.2. Amended Certifications After Request by the NDA Holder To Remove
a Patent or Patent Information From the List
    We proposed to revise Sec. Sec.  314.50(i)(6)(ii) and
314.94(a)(12)(viii)(B) to clarify the circumstances and timeframe in
which a 505(b)(2) or ANDA applicant must submit an amended patent
certification to its 505(b)(2) application or ANDA after an NDA holder
has requested removal of a patent or patent information from the list
(patent delisting). These proposed revisions also describe our practice
regarding patent delisting as it relates to the eligibility of one or
more first applicants for 180-day exclusivity.
    We received one comment supporting our proposal that if an NDA
holder has requested removal of a patent or patent information from the
list and one or more first applicants are eligible for 180-day
exclusivity, FDA will not remove the patent or patent information from
the list until we have determined that no first applicant is eligible
for 180-day exclusivity or the 180-day exclusivity is extinguished (see
proposed Sec. Sec.  314.50(i)(6)(ii) and 314.94(a)(12)(viii)(B)). We
are finalizing proposed Sec. Sec.  314.50(i)(6)(ii) and
314.94(a)(12)(viii)(B) with revisions to consistently refer to a
request to remove a patent or patent information from the Orange Book
and to clarify that the patent or patent information will remain listed
until any 180-day exclusivity based on that patent has expired or has
been extinguished. We also are making the technical amendments
described in sections V.P.1, V.P.3, and V.P.6 and the revision to Sec.
314.94(a)(12)(viii)(B) described in section V.E.3.
V.E.3. Amended Certifications Upon Patent Reissuance
    We proposed to revise our regulations to describe a 505(b)(2) and
ANDA applicant's patent certification obligations with respect to a
reissued patent. Our approach reflected our consideration of the
original patent and the reissued patent as a ``single bundle of patent
rights,'' albeit patent rights that may have changed with reissuance,
for purposes of administering the patent certification requirements of
the FD&C Act and any 30-month stay of approval or 180-day exclusivity
that relates to a paragraph IV certification to the original patent
(see section V.B.1.e).
    We proposed to require that a 505(b)(2) or ANDA applicant provide
an appropriate patent certification or statement with respect to a
reissued patent, unless the NDA holder did not timely file patent
information with FDA on either the original patent or the reissued
patent. We also proposed that the patent information listed for the
reissued patent would be treated as though it had been submitted under
505(b)(1) or 505(c)(2) of the FD&C Act at the time of listing of the
original patent for purposes of determining the availability of a 30-
month stay if other criteria were met (see section 505(c)(3)(C) and
(j)(5)(B)(iii) of the FD&C Act).
    For a first applicant eligible for 180-day exclusivity based on a
paragraph IV certification to an original patent that is subsequently
reissued, we proposed that if the applicant opined that the reissued
patent also is invalid, unenforceable, or will not be infringed, the
applicant must submit a paragraph IV certification to the reissued
patent within 30 days of the date on which the reissued patent is
listed in the Orange Book to lawfully maintain its paragraph IV
certification for purposes of eligibility for 180-day exclusivity (see
proposed Sec.  314.94(a)(12)(viii)(B)). Otherwise, we proposed that we
would consider the first applicant to have amended or withdrawn its
paragraph IV certification to the original patent on which it qualified
for 180-day exclusivity under section 505(j)(5)(D)(i)(III) of the FD&C
Act. We indicated that if a first applicant who qualifies as such based
on a paragraph IV certification to the original patent forfeits 180-day
exclusivity, another applicant would not be eligible for 180-day
exclusivity based on a paragraph IV certification to the reissued
patent (see section 505(j)(5)(D)(iii)(II) of the FD&C Act).
    In the following paragraphs, we discuss a comment on this proposal
(see section V.B.1.e for a discussion of comments regarding submission
of additional information on reissued patents). After considering this
comment, we are not finalizing this proposal.
    (Comment 38) One comment objects to FDA's proposal that a first
applicant eligible for 180-day exclusivity based on a paragraph IV
certification to a patent that has been reissued must submit a
paragraph IV certification to the reissued patent within 30 days of
listing to have lawfully maintained its paragraph IV certification for
purposes of 180-day exclusivity. The comment asserts that failure to
comply with this proposed requirement does not provide an adequate
basis for FDA to extinguish a first applicant's eligibility for 180-day
exclusivity. In the alternative, the comment requests that FDA
expressly state that the requirement only will be applied
prospectively. The comment also recommends that an amended patent
certification only be required if the original certification becomes
inaccurate.
    (Response 38) As discussed in Response 17, FDA has determined that
the ``single bundle of patent rights'' approach reflected in its
proposed regulations on reissued patents is no longer appropriate based
on the recent decision in Mylan Pharms., Inc. v. FDA (594 Fed. Appx.
791). Accordingly, the Agency is not finalizing the proposed revision
to Sec.  314.94(a)(12)(viii)(B) regarding reissued patents because we
now consider reissued patents as separate and distinct from the
original patent for purposes of administering the patent certification
requirements of the FD&C Act and any 30-month stay of approval or 180-
day exclusivity. This determination that the ``single bundle of patent
rights'' approach is no longer appropriate means that FDA assesses
whether a reissued patent is timely filed based solely on whether the
NDA holder has submitted the required patent information within 30 days
of reissuance (provided that the patent is reissued after the date of
approval of the NDA) or otherwise meets the requirements for timely
filing of patent information (see Sec. Sec.  314.50(i)(4) and
314.94(a)(12)(vi)). Similarly, the date on which patent information on
the reissued patent (and not the original patent) is submitted to FDA
determines

whether a paragraph IV certification to the reissued patent could give
rise to a 30-month stay if other criteria are met (see section
505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act). This also means that
FDA evaluates eligibility for 180-day exclusivity based on whether the
criteria are met for an original patent (irrespective of whether it
subsequently is reissued) or for a reissued patent. It is unnecessary
to address the comment requesting that FDA prospectively apply the
proposed revision to Sec.  314.94(a)(12)(viii)(B) because we are not
finalizing this proposed change.
    With respect to the comment regarding an ``amended'' patent
certification, we note that an appropriate patent certification or
statement is required for timely filed patent information submitted by
an NDA holder for the listed drug relied upon or RLD, including timely
filed patent information on a reissued patent (see Sec. Sec.
314.50(i)(4) and 314.94(a)(12)(vi), and sections V.B.2.b and V.E.4; see
also Sec. Sec.  314.60(f) and 314.96(d) and section V.F).
V.E.4. Other Amended Certifications
    We proposed to expressly require a 505(b)(2) or ANDA applicant to
submit an appropriate patent certification or statement if, after
submission of the 505(b)(2) application or ANDA, a new patent is issued
by the USPTO that claims the listed drug or RLD or that claims an
approved use for such drug, except as provided in Sec. Sec.
314.50(i)(4) and 314.94(a)(12)(vi) (see proposed Sec. Sec.
314.50(i)(6)(iii)(A)(2) and 314.94(a)(12)(viii)(C)(1)(ii)). We also
explained our longstanding position that if an applicant that
previously submitted a paragraph III certification, a paragraph IV
certification, or a statement under section 505(b)(2)(B) or
(j)(2)(A)(viii) of the FD&C Act fails to amend its patent certification
to a paragraph II certification upon patent expiration, the Agency will
consider the 505(b)(2) or ANDA applicant to have constructively changed
its patent certification to a paragraph II certification. We proposed
that a patent certification or statement by an ANDA applicant must not
be submitted earlier than the first working day after the day the
patent is published in the Orange Book (see proposed Sec.
314.94(a)(12)(viii)(C)(1)(ii); see also proposed Sec.  314.95(b)(2) and
section V.D.1.a). Finally, we proposed to revise our regulations to
clarify that an applicant is not required to submit a supplement solely
to change a submitted patent certification after approval of the
application (see proposed Sec. Sec.  314.50(i)(6)(iii)(B) and
314.94(a)(12)(viii)(C)(2)).
    In section V.D.1.a, we discuss comments on proposed Sec.
314.94(a)(12)(viii)(C)(1)(ii) (see Responses 33 and 34). We received no
other comments and are finalizing these provisions without change,
except for the technical amendments described in section V.P.4.

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

V.F.1. Types of Amendments for Which Patent Certification Is Required
    We proposed to add Sec. Sec.  314.60(f) and 314.96(d) to clarify
and augment the patent certification requirements for amendments
described in Sec. Sec.  314.50(i)(6)(iii) and 314.94(a)(12)(viii)(C).
In these provisions, we proposed to require that an applicant must
submit patent certifications described in Sec. Sec.  314.50(i) or
314.94(a)(12) if approval is sought for any of the following types of
amendments to a 505(b)(2) application or ANDA: (1) To add a new
indication or other condition of use; (2) to add a new strength; (3) to
make other than minor changes in the product formulation; or (4) to
change the physical form or crystalline structure of the active
ingredient of the drug product.
    We explained that this proposed requirement would not apply to
minor changes in product formulation that FDA would regard as resulting
in essentially the same product (see proposed Sec. Sec.  314.60(f)(3)
and 314.96(d)(3)). We proposed that a new patent certification would
not be required if the new formulation in the amendment is
qualitatively (Q1) the same as the previous formulation (i.e., contains
all of the same inactive ingredients) and quantitatively (Q2)
essentially the same (i.e., each inactive ingredient differs by no more
than plus or minus 5 percent from the previous formulation). If an
applicant submits an amendment to a 505(b)(2) application or ANDA for
any of the categories of changes described in these provisions and does
not submit a new patent certification, we proposed that the applicant
would be required to verify that the proposed change described in the
amendment is not the type of change for which a new patent
certification or statement is required (e.g., the proposed formulation
change meets the criteria for a ``minor'' formulation change).
    In the following paragraphs, we discuss several comments on this
proposal. After considering these comments, we are finalizing
Sec. Sec.  314.60(f) and 314.96(d) with revisions to clarify that the
specified types of amendments are required to contain an appropriate
patent certification (or recertification) or statement and to describe
the required verification.
    (Comment 39) Three comments recommend that an amended patent
certification should not be required if the 505(b)(2) or ANDA applicant
determines that the change described in its amendment does not
materially affect the factual and legal basis for a previous paragraph
IV certification or materially affect the product in a manner that
could be protected by a listed patent. These comments express concern
that requiring a patent certification for the types of amendments
described in Sec. Sec.  314.60(f) and 314.96(d) could give rise to a
second 30-month stay of approval, contrary to the intent of the MMA.
Two other comments opine that the proposal is under-inclusive, and
recommend that FDA require a new patent certification in all
circumstances in which an amendment may alter the proposed product's
relationship to a listed patent and require that the applicant provide
the basis for a claim of noninfringement. These comments recommend
requiring a new patent certification (and corresponding opportunity for
resolution of potential patent infringement claims before approval) if
approval is sought for any of the following types of changes: Any
change in product formulation; a change in the physical form, particle
size, grade, purity, or crystalline structure of the active ingredient;
or a change to a proposed drug-delivery device.
    (Response 39) We acknowledge comments suggesting that the patent
certification requirements for amendments to a 505(b)(2) application or
ANDA may be considered either under-inclusive or over-inclusive.
However, we believe that our approach strikes an appropriate balance by
protecting the patent rights of NDA holders without unnecessarily
delaying approval of 505(b)(2) applications and ANDAs. A 505(b)(2) or
ANDA applicant is required to amend its patent certification if, at any
time before approval, the applicant learns that the previously
submitted patent certification is no longer accurate with respect to
the pending application or supplement, as amended (see Sec. Sec.
314.50(i)(6)(iii) and 314.94(a)(12)(viii)(C)). An applicant that
submits a 505(b)(2) application or ANDA containing a paragraph IV
certification to a listed patent must

reevaluate whether the patent certification continues to be accurate
after a change to the proposed product submitted in an amendment to the
505(b)(2) application or ANDA. To address concerns that the factual and
legal basis of the applicant's opinion that a patent will not be
infringed may have changed, we are requiring an applicant to submit an
appropriate patent certification (or recertification, for a previously
submitted paragraph IV certification) or statement, for the following
types of amendments to a 505(b)(2) application or ANDA: (1) To add a
new indication or other condition of use; (2) to add a new strength;
(3) to make other than minor changes in the product formulation; or (4)
to change the physical form or crystalline structure of the active
ingredient of the drug product (see Sec. Sec.  314.60(f)(1) and
314.96(d)(1) and Response 42). These patent certification requirements
are intended to facilitate ongoing compliance with section 505(b)(2)(A)
and (j)(2)(A)(vii) of the FD&C Act. We do not agree that the need for
an appropriate patent certification (or recertification) or statement
for the types of amendments described in Sec. Sec.  314.60(f) and
314.96(d) should be left entirely to the applicant's discretion because
applicants may be uncertain when it is necessary. To implement the
proposed verification by the 505(b)(2) or ANDA applicant described in
the proposed rule (see 80 FR 6802 at 6823), we are adding Sec. Sec.
314.60(f)(2) and 314.96(d)(2) to require that if the amendment to the
505(b)(2) application or ANDA does not contain a patent certification
or statement, the applicant must verify that the proposed change
described in the amendment is not one of the types of amendments
described in Sec. Sec.  314.60(f)(1)(i) through (iv) and
314.96(d)(1)(i) through (iv).
    We also do not agree that it is necessary to expressly require an
appropriate patent certification (or recertification) with the broader
range of changes to a proposed product described in the comments. We
previously have explained that ``[g]iven the range of changes that may
be the subject of a [chemistry, manufacturing, and controls] amendment,
such a requirement would impose a significant burden without clearly
enhancing compliance with the statutory patent certification
requirements. Through our proposal to require a new patent
certification and, with respect to a paragraph IV certification, a new
notice of paragraph IV certification to be sent at the same time that
certain types of amendments are submitted to FDA, we are upholding the
legislative balance of the Hatch-Waxman Amendments that facilitates the
availability of generic drug products while protecting innovator
intellectual property rights'' (see Letter from Janet Woodcock, M.D.,
Director, CDER, to John B. Dubeck and Frederick A. Stearns, dated
February 6, 2015, regarding Docket No. FDA-2003-P-0519, available at
http://www.regulations.gov).
    We recognize that a 30-month stay of approval may result from
initiation of a patent infringement action in response to a second
notice of paragraph IV certification that is provided with an amendment
to a 505(b)(2) application or ANDA. This scenario may occur if the
patent at issue in the infringement action was listed before the date
of submission of the original 505(b)(2) application or ANDA and, for
example, the infringement action was warranted by the change proposed
in the amendment (see, e.g., Letter from Janet Woodcock, M.D.,
Director, CDER, to Gerald F. Masoudi, dated October 19, 2010, regarding
Docket No. FDA-2010-P-0223, available at http://www.regulations.gov
(concluding that a new 30-month stay of approval stems from a timely
lawsuit based on the second notice of paragraph IV certification
submitted in connection with an amendment to the ANDA for reformulated
doxercalciferol injection); Letter from Janet Woodcock, M.D., Director,
CDER, to Christina M. Markus, dated June 7, 2011, regarding Docket No.
FDA-2011-P-0127, available at http://www.regulations.gov (confirming
that a second 30-month stay of approval stems from a timely lawsuit
based on the second notice of paragraph IV certification submitted in
connection with an amendment to the ANDA for desflurane liquid)).
    (Comment 40) One comment recommends that an amendment to a
505(b)(2) application or ANDA to add a new indication or other
condition of use should only require submission of a patent
certification to a patent that claims the new use and for which a
patent certification previously was not made.
    (Response 40) We agree that if an applicant amends its 505(b)(2)
application or ANDA only to add a new indication or other condition of
use, the applicant need only certify to listed patents that have been
identified as claiming an approved use and relate to the change
described in the amendment (provided that the 505(b)(2) application or
ANDA contained an appropriate patent certification or statement to any
other listed patent(s) prior to submission of the amendment). This
approach preserves the NDA holder's intellectual property rights
without requiring the 505(b)(2) or ANDA applicant to submit a
duplicative certification to a listed patent(s) that has not been
identified by the NDA holder as claiming a method of use and would not
be implicated by the amendment (compare proposed Sec.  314.70(i)(2)).
This approach also is consistent with existing patent certification
requirements under Sec. Sec.  314.50(i)(6)(iii) and
314.94(a)(12)(viii)(C). If any other changes described in paragraphs
(ii) through (iv) of Sec. Sec.  314.60(f)(1) or 314.96(d)(1) are
proposed in the amendment, the applicant would be required to address
all timely filed listed patents for the listed drug relied upon or RLD
with an appropriate patent certification (or recertification) or
statement.
    An ANDA applicant would be expected to submit an amendment to add a
new indication or other condition of use if the applicant previously
submitted a statement described in section 505(j)(2)(A)(viii) of the
FD&C Act and now seeks approval for the use or if the RLD was approved
for a new indication or other condition of use after the ANDA was
submitted (see section 505(j)(2)(A)(v) of the FD&C Act and Sec.
314.94(a)(8)(iv)). Most requests for approval of a different indication
or condition of use by a 505(b)(2) applicant should not be made as an
amendment to the 505(b)(2) application (see Sec.  314.60(b)(6) and
guidance for industry entitled ``Submitting Separate Marketing
Applications and Clinical Data for Purposes of Assessing User Fees''
(December 2004) at 4 to 5, available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm).
Accordingly, we expect that there would be limited circumstances in
which this provision would apply to a 505(b)(2) application (e.g.,
indication changed from prescription status to OTC use).
V.F.2. Types of Supplements for Which Patent Certification Is Required
    We proposed to add Sec. Sec.  314.70(i) and 314.97(c), and make
conforming revisions to Sec. Sec.  314.50(i)(6)(iii)(B) and
314.94(a)(12)(viii)(C)(2), to clarify the patent certification
requirements for a 505(b)(2) or ANDA supplement. In these provisions,
we proposed to require patent certifications described in Sec.
314.50(i) or Sec.  314.94(a)(12), if the applicant requests approval to
add a new indication or other condition of use or to add a new strength
in a 505(b)(2) or ANDA supplement (see proposed Sec. Sec.  314.70(i)
and 314.97(c)).

    For a 505(b)(2) supplement that seeks approval for a new indication
or other condition of use, the 505(b)(2) applicant currently is
required to submit an appropriate patent certification or statement for
each timely filed patent that claims the listed drug(s) relied upon or
a method of using such drug(s) for which the applicant is seeking
approval (see section 505(b)(2) of the FD&C Act). We proposed to reduce
these patent certification requirements by providing that a 505(b)(2)
supplement that only seeks approval to add a new indication or other
condition of use is required to contain an appropriate patent
certification or statement described in Sec.  314.50(i) only for
patents that are identified as claiming an approved use (see proposed
Sec.  314.70(i)(2)).
    We did not propose to require a patent certification with a
supplement to change the formulation or to change the physical form or
crystalline structure of the active ingredient of a product approved in
a 505(b)(2) application or ANDA. We explained that it would not be
necessary for FDA to require patent certifications under these
circumstances because the NDA holder for a listed drug and any patent
owner can monitor postapproval changes in the formulation or active
ingredient of a marketed drug product and address any patent-related
concerns without the involvement of FDA.
    In the following paragraphs, we discuss two comments on proposed
Sec. Sec.  314.70(i) and 314.97(c). We are continuing to consider these
comments, and thus we are not finalizing proposed Sec. Sec.  314.70(i)
and 314.97(c) (or the references to these provisions in proposed
Sec. Sec.  314.50(i)(6)(iii)(B) and 314.94(a)(12)(viii)(C)(2)),
respectively, at this time. Accordingly, FDA will maintain its current
practice of regulating directly from the statute and general patent
certification regulations in requiring an appropriate patent
certification or statement with a 505(b)(2) or ANDA supplement.
    (Comment 41) Two comments disagree with FDA's proposal to not
expressly require a new patent certification with a 505(b)(2) or ANDA
supplement in each of the circumstances in which a new patent
certification (or recertification) is required for amendments to a
505(b)(2) application or ANDA. One comment maintains that the Agency's
approach is inconsistent with the statute, which clearly describes
patent certification requirements for 505(b)(2) and ANDA supplements.
This comment also expresses concern that a 505(b)(2) or ANDA applicant
could circumvent the patent certification requirements by seeking
approval of a noninfringing product that the applicant does not intend
to market followed by a supplement for a modified form of the active
ingredient or a different formulation of the drug product that the
applicant intends to market. Both comments contend that monitoring of
postapproval changes by an NDA holder or patent owner is not a
replacement for notice from the 505(b)(2) or ANDA applicant of a
paragraph IV certification and the opportunity to litigate any
potential infringement claims prior to approval of the change requested
in the supplement.
    (Response 41) We are continuing to evaluate these comments,
including whether our regulations should expressly require a new patent
certification with a broader range of changes submitted in supplemental
applications than described in the proposed rule. Accordingly, we are
declining to finalize proposed Sec. Sec.  314.70(i) and 314.97(c) at
this time. We will continue to implement the requirement for an
appropriate patent certification or statement with a 505(b)(2) or ANDA
supplement directly from the statute and our general regulations on
patent certifications (see Sec. Sec.  314.50(i)(6)(iii) and
314.94(a)(12)(viii)(C) (requiring a 505(b)(2) or ANDA applicant to
amend its patent certification if, at any time before approval, the
applicant learns that the previously submitted patent certification is
no longer accurate with respect to the pending application or
supplement)).
V.F.3. Requirements for Notice of Paragraph IV Certifications and
Implications for 180-Day Exclusivity
    We proposed that notice to the NDA holder and each patent owner
would be required for all paragraph IV certifications, irrespective of
whether the 505(b)(2) or ANDA applicant previously provided notice of
paragraph IV certification to the same patent or to another patent
claiming the listed drug relied upon or RLD (see section 505(b)(3)(B)
and (j)(2)(B)(ii) of the FD&C Act and proposed Sec. Sec.  314.52(d)(1)
and 314.95(d)(1)). We proposed that a first applicant that submits an
amendment to its pending ANDA or a supplement would be considered to
have lawfully maintained a paragraph IV certification to the patent
upon which eligibility for 180-day exclusivity was based if the
amendment is accompanied by another paragraph IV certification to the
patent and notice of paragraph IV certification is sent in accordance
with proposed Sec.  314.95(d).
    In the following paragraphs, we discuss two comments on this topic.
After considering these comments, we are revising proposed Sec.
314.96(d) regarding amendments to an ANDA to clarify that a paragraph
IV certification to a patent or patent claim for which an ANDA
applicant previously submitted a paragraph IV certification is a
``recertification'' rather than an ``amendment'' of the paragraph IV
certification. We are making conforming revisions to Sec.  314.60(f).
We are finalizing Sec.  314.52(d)(1) with the changes described in
Response 32, and we are finalizing Sec.  314.95(d)(1) with the changes
described in section V.D.1.b and the technical amendments described in
section V.P.1.
    (Comment 42) One comment expresses concern that a first applicant
could inadvertently forfeit its eligibility for 180-day exclusivity if,
pursuant to proposed Sec.  314.96(d), the first applicant submits a new
paragraph IV certification to the patent that qualified the applicant
for 180-day exclusivity (see section 505(j)(5)(D)(i)(III) of the FD&C
Act). The comment suggests that FDA require an ANDA applicant to
provide a new notice of its paragraph IV certification to the NDA
holder and each patent owner instead of submitting a new patent
certification to the Agency. Another comment recommends that FDA not
require an ANDA applicant to submit a new patent certification with an
amendment to the ANDA if a patent infringement action already has been
filed against the applicant with respect to the ANDA.
    (Response 42) FDA interprets the statute to mean that a first
applicant ``lawfully maintains'' a paragraph IV certification to the
patent or patent claim upon which eligibility for 180-day exclusivity
is based if any subsequent amendment to the ANDA that requires a patent
certification contains a paragraph IV certification to the qualifying
patent or patent claim and notice of the paragraph IV certification is
sent in accordance with Sec.  314.95(d). This interpretation is
supported by our longstanding requirement that an ANDA applicant must
amend a submitted certification if, at any time before approval of the
ANDA, the applicant learns that the submitted certification is no
longer accurate (see Sec.  314.94(a)(12)(viii)(C)(1)(i)). A subsequent
paragraph IV certification to the qualifying patent or patent claim is
not an ``amendment'' of the previously submitted paragraph IV
certification under section 505(j)(5)(D)(i)(III) of the FD&C Act
because the type of certification remains the same; rather, it is a
reaffirmation of the patent challenge

notwithstanding the amendment to the ANDA. Therefore, we are using the
term ``recertification'' to describe this scenario (see Sec.
314.96(d)(1); see also Sec.  314.60(f)(1)).
    We decline to adopt the comment's proposal to require a new notice
of paragraph IV certification--but not a new patent certification--with
an amendment to the ANDA. Notice of a paragraph IV certification is
inextricably linked to the submission of a corresponding paragraph IV
certification. The statute expressly requires that an applicant that
submits a paragraph IV certification in an amendment to the ANDA
provide the required notice at the time of submission of the amendment
regardless of whether the applicant has already given notice with
respect to another such certification contained in the application (see
section 505(j)(2)(B)(ii)(II) of the FD&C Act). Notice of a new
paragraph IV certification submitted with an amendment to the ANDA must
be updated to correspond to the proposed product as changed by the
amendment. However, we believe that the concern described in the
comment is addressed by our explanation that a paragraph IV
certification to a patent or patent claim for which an ANDA applicant
previously submitted a paragraph IV certification is a
``recertification'' rather than an ``amendment'' of the paragraph IV
certification and by the corresponding changes to Sec.  314.96(d)(1).
    We also do not agree with the suggestion that a new notice of
paragraph IV certification should not be required if the NDA holder or
owner of the relevant patent(s) already is litigating claims of patent
infringement against the ANDA applicant. As previously discussed, the
statute requires an ANDA applicant to provide notice with all paragraph
IV certifications (see section 505(j)(2)(B)(ii)(II) of the FD&C Act).
Moreover, if the factual and legal bases for the paragraph IV
certification have changed, it would be particularly important to
timely provide this information to the NDA holder and each patent owner
to support the efficient use of judicial resources.

V.G. Amendments or Supplements to a 505(b)(2) Application for a
Different Drug and Amendments or Supplements to an ANDA That Reference
a Different Listed Drug (Sec. Sec.  314.60, 314.70, 314.96, and 314.97)

V.G.1. Amendments and Supplements to an ANDA (Sec. Sec.  314.96(c) and
314.97(b))
    We proposed to establish a regulation that would implement section
505(j)(2)(D)(i) of the FD&C Act by providing that an ANDA applicant may
not amend or supplement an ANDA to seek approval of a drug referring to
a listed drug that is different from the RLD identified in the ANDA
(see proposed Sec. Sec.  314.96(c) and 314.97(b)). For example, we
proposed that if at any time before approval of the ANDA, an NDA is
approved for a drug product that is pharmaceutically equivalent to the
proposed product in the pending ANDA and that NDA is designated as an
RLD, the applicant would not be permitted to amend its pending ANDA to
reference the new RLD (see proposed Sec.  314.96(c)). We proposed that
this restriction also would apply if one or more changes proposed in an
amendment or a supplement to an ANDA would result in the proposed
product being a pharmaceutical equivalent to a different listed drug
than the RLD identified in the ANDA. In these scenarios, we proposed
that the ANDA applicant would be required to submit a new ANDA to
identify the pharmaceutically equivalent product as the new RLD (see
proposed Sec. Sec.  314.96(c) and 314.97(b) and section 505(j)(2)(D)(i)
of the FD&C Act).
    In the proposed rule, we confirmed that different strengths of an
approved drug product continue to be regarded as different listed
drugs. However, to implement section 505(j)(2)(D)(ii) of the FD&C Act,
we proposed to codify our practice that permits an applicant to amend
or supplement an ANDA to seek approval of a different strength of the
drug (see proposed Sec. Sec.  314.96(c) and 314.97(b)).
    We received no comments on proposed Sec.  314.97(b) regarding
supplements. In the following paragraphs, we discuss three comments on
proposed Sec.  314.96(c) regarding amendments. After considering these
comments, we are finalizing proposed Sec. Sec.  314.96(c) and 314.97(b)
without change.
    (Comment 43) One comment requests that FDA modify the proposed
regulation to require that if, at any time before submission (rather
than any time before approval) of the ANDA, an NDA is approved for a
drug product that is pharmaceutically equivalent to the proposed
product and that NDA is designated as an RLD, the ANDA applicant would
be required to submit an ANDA that identifies the pharmaceutically
equivalent product as the RLD. The comment suggests that this proposed
revision (and a similar proposal discussed in comment 49) would
harmonize FDA's proposed requirements for ANDAs and 505(b)(2)
applications by imposing limitations up until the time of ANDA
submission rather than approval. Another comment expresses concern that
requiring an ANDA applicant to submit a new ANDA that identifies the
pharmaceutically equivalent product as the RLD may unnecessarily
require additional data and delay ANDA approval, although the comment
acknowledges that this may be appropriate and efficient in some
circumstances.
    (Response 43) We decline to adopt the suggested modification to
proposed Sec.  314.96(c). Under existing practice, FDA will refuse to
receive an ANDA that does not cite an appropriate RLD or rely on an
approved suitability petition as its basis for ANDA submission (see
Sec.  314.94(a)(3)). In addition, there are circumstances in which an
ANDA that has been received, but not approved, may be required to
submit a new ANDA that identifies a pharmaceutically equivalent product
as the RLD. This may occur, for example: (1) If a pharmaceutically
equivalent product is approved after an ANDA is submitted pursuant to
an approved suitability petition (petitioned ANDA) or (2) if changes
are proposed in an amendment or a supplement to the ANDA such that the
proposed product is pharmaceutically equivalent to a different listed
drug than the RLD identified in the original ANDA (modified ANDA).
Before enactment of the MMA, FDA required an applicant to amend its
ANDA in these scenarios to cite the pharmaceutically equivalent product
as its RLD. However, the MMA prohibits an ANDA applicant from amending
its ANDA to change the RLD (see section 505(j)(2)(D)(i) of the FD&C
Act). Accordingly, for the applicant to obtain approval of the proposed
product under section 505(j) of the FD&C Act in these scenarios, we
require the applicant to submit a new ANDA that identifies the
pharmaceutically equivalent product as its RLD and complies with
applicable statutory and regulatory requirements.
    We require an ANDA applicant to identify as its RLD a
pharmaceutically equivalent product approved any time before approval,
rather than submission, of the ANDA, because a generic drug product
must demonstrate, among other things, that it is bioequivalent to the

RLD to obtain approval (see section 505(j)(2)(A)(iv) of the FD&C Act
and Sec.  314.127(a)(6)(i)). We disagree that an ANDA applicant should
only be required to identify a pharmaceutically equivalent product as
its RLD until submission of the ANDA, because this approach would not
ensure that an ANDA applicant cites an appropriate RLD in the context
of a petitioned ANDA or modified ANDA unless the RLD was approved
before submission of the ANDA. Such an approach would foster a
potentially confusing proliferation of pharmaceutically equivalent drug
products that have not demonstrated therapeutic equivalence to the RLD.
The additional data and time that may be needed for an ANDA applicant
to identify a pharmaceutically equivalent drug product as the RLD is
warranted by the need for a clear determination of therapeutic
equivalence. The modification requested in the comment would ``diminish
the utility and accuracy of FDA's therapeutic equivalence
determinations and potentially allow ANDA applicants to circumvent
otherwise applicable patent and exclusivity rights accorded the NDA
holder for the pharmaceutically equivalent RLD'' (see Letter from Janet
Woodcock, M.D., Director, CDER, to Mark S. Aikman, Pharm.D., Osmotica
Pharmaceutical Corp., dated November 25, 2008, regarding Docket No.
FDA-2008-P-0329, at 11-12, available at http://www.regulations.gov)
(Venlafaxine ER CP Response).
    Unlike an ANDA that relies on a single RLD, a 505(b)(2) application
may rely for approval on one or more listed drugs and is not required
to demonstrate bioequivalence or pharmaceutical equivalence to a listed
drug on which it relies for approval. Although the Agency requires a
505(b)(2) applicant to rely upon a drug product approved in an NDA that
is pharmaceutically equivalent to the proposed product, the basis and
timeframe for this requirement for 505(b)(2) applications differs from
that of ANDAs.
    (Comment 44) One comment recommends that FDA permit an ANDA
applicant to amend its ANDA if FDA changes the RLD or the ANDA
applicant petitions to change the RLD.
    (Response 44) The comment is unclear because the Agency's
designation of an additional RLD or selection of a new reference
standard generally would not require an ANDA applicant to change its
RLD. The RLD is the listed drug identified by FDA as the drug product
upon which an applicant relies in seeking approval of its ANDA (see