> David S. Machlowitz Medco Health Solutions, Inc.

SVP, General Counsel & Secretary 100 Parsons Pond Drive

> Franklin Lakes, NJ 07417

![](media/image1.png) tel 201-269-5200

fax 201-269-1005

[david_machlowitz@medco.com](mailto:david_snow@medco.com)

April 3, 2007

Division of Dockets Management

Food and Drug Administration

Room 1061 (HFA-305)

5630 Fishers Lane

Rockville, MD 20852

> **Re: Docket No. 2007N-0123 - Amlodipine Abbreviated New Drug
> Application Approvals**

Dear Sir or Madam:

Medco Health Solutions, Inc. ("Medco"), a leading pharmacy benefit
manager with the nation's largest mail order pharmacy operations,
submits these comments in response to the Food and Drug Administration's
("FDA's") solicitation of views concerning the Agency's ability to
approve Abbreviated New Drug Applications ("ANDAs") for amlodipine
besylate tablets.[^1] Medco's interest in the issues presented in this
case stems from the company's business objective of ensuring that
Americans have access to affordable, high quality prescription drugs.

As explained below in Medco's response to each of the five sets of FDA's
questions, the Agency should grant final approval to tentatively
approved ANDAs for amlodipine besylate, because neither (1) the
now-expired 180-day exclusivity period applicable to Mylan's ANDA
#76-418, nor (2) Pfizer's pediatric exclusivity applicable to United
States Patent No. 4,879,303 ("the '303 patent") listed in the Orange
Book as covering NORVASC (amlodipine besylate) 2.5mg, 5mg, and 10mg
Tablets, provides a legal basis to delay further generic competition.

**1. What date controls FDA's giving effect to the decision in [Pfizer
Inc. v. Apotex*,* Inc.]{.underline}, No. 2006-1261 (Fed. Cir. March 22,
2007) ("[Apotex]{.underline} decision") holding that \[the '303 patent\]
is invalid? Can FDA treat the '303 patent as invalid as of March 22,
2007, or must FDA await the issuance of the mandate? Is the answer the
same for all purposes, that is, for determining the applicability of
pediatric exclusivity, the triggering of 180-day exclusivity, and the
eligibility of other ANDA applicants for final approval?**

March 22, 2007 is the date that controls FDA's giving effect to the
[Apotex]{.underline} decision; and as of that date, FDA should treat the
'303 patent as invalid for purposes of triggering the start of Mylan's
180-day exclusivity period, the eligibility of other generic applicants
with tentative approvals for final approval, and for determining the
inapplicability of Pfizer's pediatric exclusivity.[^2] FDA need
[not]{.underline} await the issuance of a mandate from the Federal
Circuit.

Section 505(j)(5)(B)(iii)(II)(aa) (2006) of the FDC Act states, in
pertinent part, that an ANDA with a paragraph IV patent certification
(and the sponsor of which was sued by the NDA holder/patent owner for
patent infringement within 45 days of receiving notice of that
certification, and if the district court decides before the end of the
30-month stay that the patent has been infringed and the judgment is
appealed) "shall be made effective [on the date on which the court of
appeals decides]{.underline} that the patent is invalid or not infringed
. . . ." FDC Act § 505(j)(5)(B)(iii)(II)(aa)(AA) (2006) (emphasis
added).[^3] Thus, Congress clearly intended "the date on which the court
of appeals decides" to be the controlling date for purposes of giving
effect to a decision that a patent is invalid or not infringed, and not
the date of the issuance of a court of appeals mandate.

Indeed, this interpretation is supported by other provisions in FDC Act
§ 505(j)(5)(B)(iii) (2006). For example, one provision states that "if
the judgment of the district court is not appealed or is affirmed, the
approval shall be made effective [on the date specified by the district
court in a court order under \[35 U.S.C. § 271(e)(4)(A)\]]{.underline}."
[Id.]{.underline} § 505(j)(5)(B)(iii)(II)(bb) (2006) (emphasis added).
Other provisions state that ANDA approval "shall be made effective [on
the date on which the \[district\] court enters judgment]{.underline}
reflecting the decision; or [the date of a settlement order or consent
decree]{.underline} signed and entered by the \[district\] court stating
that the patent . . . is invalid or not infringed." [Id.]{.underline}
§ 505(j)(5)(B)(iii)(I)(aa)-(bb) (2006) (emphasis added). If Congress
intended the date of the issuance of a mandate to be controlling, as
opposed to "the date on which the court of appeals decides," then it
would have identified this date with particularity as it did in other
FDC Act § 505(j)(5)(B)(iii) (2006) provisions. But it did not. Thus, the
date that controls FDA's giving effect to the [Apotex]{.underline}
decision, and the date Congress intended, is March 22, 2007.

FDA's guidance document, "Court Decisions, ANDA Approvals, and 180-Day
Exclusivity Under the Hatch-Waxman Amendments to the Federal Food, Drug,
and Cosmetic Act" (Mar. 2000) (hereinafter "Court Decisions Guidance"),
states, in relevant part, that "\[i\]f the district court finds the
patent is infringed, but that decision is reversed on appeal, the Agency
may approve the ANDA on the date the district court issues a judgment
that the patent is invalid, unenforceable, or not infringed [pursuant to
a mandate issued by the court of appeals]{.underline}."
[Id.]{.underline} at 4 (emphasis added). FDA issued this guidance
document prior to the enactment of the MMA and in the wake of the
decisions in [TorPharm Inc., v. Shalala]{.underline}, No. 97-1925, 1997
WL 33472411 (D.D.C. Sep. 15, 1997), [appeal withdrawn and
remanded]{.underline}, 1998 WL 135491 (D.C. Cir. Feb. 5, 1998), and
[Mylan Pharma., Inc. v. Shalala]{.underline}, 81 F. Supp. 2d 30 (D.D.C.
2000), in which the plaintiffs successfully challenged the Agency's
interpretation of the definition of the term "court decision" in the FDC
Act provisions (pre-MMA) governing the timing of ANDA approvals and the
triggering of 180-day exclusivity.

As a result of the decisions cited above, FDA also withdrew the Agency's
regulations at 21 C.F.R. §§ 314.107(e)(1) and (2)(i)-(iii), promulgated
in 1994, concerning court decisions for purposes of establishing the
effective date of ANDA approval. [See]{.underline} FDA, Interim Rule,
Court Decisions, ANDA Approvals, and 180-Day Exclusivity, 65 Fed. Reg.
43,233, 43,235 (July 13, 2000). Section 314.107(e)(2)(iii) stated that
"\[i\]f the district court enters a decision that the patent is
infringed, and the decision is appealed, the date on which the district
court enters a judgment that the patent is invalid, unenforceable, or
not infringed [pursuant to a mandate issued by a court of
appeals]{.underline}" will be deemed to be the date of the final
decision of the court. 21 C.F.R. § 314.107(e)(2)(iii) (1999) (emphasis
added). Although § 314.107(e)(2)(iii) was removed from FDA's
regulations, the Court Decisions Guidance states that the Agency will
continue to apply "the same process as described in . . .
§ 314.107(e)(2)(iii)." Court Decisions Guidance at 4 n. 9; [see
also]{.underline} 65 Fed. Reg. at 43,234.[^4] However, FDA's "mandate
policy" described in the Court Decisions Guidance, even if it was an
appropriate interpretation in March 2000 (an issue that is questionable
given the clear "date of the court decision" statutory language),
applies only to the pre-MMA version of FDC Act § 505(j)(5)(B)(iii) and
is not a valid interpretation of the current version of FDC Act
§ 505(j)(5)(B)(iii) (2006), which applies in this case.[^5]

FDA's "mandate policy" described in the Court Decisions Guidance would
not withstand scrutiny under [Chevron, U.S.A., Inc. v. National
Resources Defense Council]{.underline}, 467 U.S. 837 (1984) in the
post-MMA context. FDA's power to interpret the FDC Act is "not the power
to make law. Rather, it is the power to adopt regulations \[and
policies\] to carry into effect the will of Congress as expressed by the
statute." [Ernst & Ernst v. Hochfelder]{.underline}, 425 U.S. 185,
213-14 (1976) (citation and internal quotation omitted). Under
[Chevron]{.underline}, FDA is entitled to "deference," but only if the
statute is unclear or ambiguous; "\[i\]f the intent of Congress is
clear, that is the end of the matter; for the court, as well as the
agency, must give effect to the unambiguously expressed intent of the
Congress." [Chevron]{.underline} at 842-43. FDA's pre-MMA "mandate
policy" is contrary to the clear language of FDC Act
§ 505(j)(5)(B)(iii)(II)(aa)(AA) (2006). Congress unambiguously stated
that ANDA approval "shall be made effective [on the date on which the
court of appeals decides]{.underline} that the patent is invalid or not
infringed . . . ." In this case, that date is March 22, 2007.[^6] This
reading is supported by other provisions in FDC Act § 505(j)(5)(B)(iii)
(2006) that specifically identify the dates on which ANDA approval
becomes effective. Had Congress intended to link ANDA approval with the
issuance of a court of appeals mandate, it would have done so.

March 22, 2007 is also the date that controls FDA's giving effect to
Mylan's 180-day exclusivity period and for determining the
inapplicability of Pfizer's pediatric exclusivity. FDC Act
§ 505(j)(5)(B)(iv) states that 180-day exclusivity may be triggered by
"the [date of a decision of a court]{.underline} . . . holding the
patent which is the subject of the \[paragraph IV\] certification to be
invalid or not infringed." FDC Act § 505(j)(5)(B)(iv)(II) (emphasis
added).[^7] The date of such a "decision of a court" is "[the date on
which the court of appeals decides]{.underline} that the patent is
invalid or not infringed," in this case, March 22, 2007.
[Id.]{.underline} § 505(j)(5)(B)(iii)(II)(aa)(AA) (2006) (emphasis
added). These two provisions must be read consistently.[^8] As such,
because the date in this case under FDC Act
§ 505(j)(5)(B)(iii)(II)(aa)(AA) (2006) is March 22, 2007, the date
triggering Mylan's 180-day exclusivity under FDC Act
§ 505(j)(5)(B)(iv)(II) must also be March 22, 2007.

Although not as explicit as the statutory provisions controlling ANDA
approval and the triggering of 180-day exclusivity, the provisions for
determining the applicability of Pfizer's pediatric exclusivity must
also be read to identify March 22, 2007 as the controlling date in this
case. FDC Act § 505A(c)(2)(B) (2006) states:

> if the drug is the subject of a listed patent for which a \[paragraph
> IV\] certification has been submitted . . . , and in the patent
> infringement litigation resulting from the certification [the court
> determines]{.underline} that the patent is valid and would be
> infringed, the period during which an application may not be approved
> under section 505(c)(3) or section 505(j)(5)(B) shall be extended by a
> period of six months after the date the patent expires (including any
> patent extensions).

FDC Act § 505A(c)(2)(B) (2006) (emphasis added).

The "court \[that\] determines that the patent is valid and would be
infringed" is the same court referred to in FDC Act
§§ 505(j)(5)(B)(iii)(II)(aa)(AA) (2006) and 505(j)(5)(B)(iv)(II). In
this case, the Federal Circuit decided that the '303 patent is invalid.
Thus, Pfizer is not entitled to pediatric exclusivity with respect to
that patent ─pediatric exclusivity does not apply to an invalid patent.
As such, March 22, 2007 is also the date for purposes of determining the
applicability (or inapplicability as the case is) of Pfizer's pediatric
exclusivity.

**2. If FDA must await the issuance of the mandate, does pediatric
exclusivity bar approval of all unapproved ANDAs in the meantime?**

If FDA must await the issuance of the Federal Circuit's mandate (which
Medco does not believe is the case), then Pfizer's pediatric exclusivity
applicable to the '303 patent would prevent the Agency from fully
approving tentatively approved ANDAs containing a paragraph III or
paragraph IV certification to that patent. [See]{.underline} FDC Act §§
505A(c)(2)(A)(ii), (B) (2006).  However, once the Federal Circuit's
mandate is issued declaring the '303 patent invalid, FDA should treat
the patent as "delisted" as a matter of law as of the date of the court
of appeals decision on March 22, 2007, and any paragraph III or IV
certifications to that patent as changed to a certification that there
are no relevant patents. [See]{.underline} 21 C.F.R.
§ 314.94(a)(12)(ii).

**3. If and when the [Apotex]{.underline} decision is implemented, what
is the effect of the decision that the '303 patent is invalid on the
obligation of an ANDA applicant to change its certification? Must Pfizer
delist its patent, so that certifications can be withdrawn? Or can FDA
treat an invalid patent as delisted as a matter of law, and presume the
withdrawal of the certifications? Or must the ANDA applicants file
paragraph II certifications stating that the '303 patent has expired?**

The Federal Circuit's March 22, 2007 decision that the '303 patent is
invalid should not require the applicant of a tentatively approved ANDA
to amend its patent certification to a paragraph II, or cause FDA to
consider a paragraph IV certification to be effectively changed to a
paragraph II to which Pfizer's pediatric exclusivity attaches.[^9]
Instead, FDA should treat the '303 patent as "delisted" from the Orange
Book as a matter of law, either effectively change ─*nunc pro tunc*─ any
paragraph III or IV patent certifications to the '303 patent to a
certification that there are no relevant patents or accept such a change
submitted by an ANDA applicant pursuant to 21 C.F.R.
§ 314.94(a)(12)(viii)(C), and fully approve any tentatively approved
ANDAs previously containing a paragraph III or IV certification to the
'303 patent. Indeed, FDA can take these actions because the '303 patent
is invalid and has expired and, as discussed below in response to
question set #5, Mylan's 180-day exclusivity has expired.

FDA's regulation at 21 C.F.R. § 314.94(a)(12)(viii)(B) governs the
"delisting" of invalid patents from the Orange Book, and states, in
relevant part:

> If a patent is removed from the \[Orange Book\], any applicant with a
> pending application (including a tentatively approved application with
> a delayed effective date) who has made a certification with respect to
> such patent shall amend its certification. The applicant shall certify
> under \[21 C.F.R. § 314.94(a)(12)(ii)\] that no patents described in
> \[21 C.F.R. § 314.94(a)(12)(i)\] claim the drug or, if other relevant
> patents claim the drug, shall amend the certification to refer only to
> those relevant patents. . . . A patent that is the subject of a
> lawsuit under \[21 C.F.R. § 314.107(c)\] shall not be removed from the
> \[Orange Book\] until FDA determines either that no delay in effective
> dates of approval is required under that section as a result of the
> lawsuit, that the patent has expired, or that any such period of delay
> in effective dates of approval is ended.

FDA explained this provision in the 1994 preamble to the Agency's final
ANDA regulations:

> An applicant may change its certification at any time. Although there
> is no need for the agency to pronounce such changes in certification
> nunc pro tunc \[(now for then)\], the agency agrees that the
> protection offered by 180-day exclusivity should not be undermined by
> changes from paragraph IV certification or by the filing of original
> certifications other than paragraph IV certifications. . . . To ensure
> that this does not occur, the agency has required that a patent remain
> \[in the Orange Book\] after being declared invalid or unenforceable
> [until the end of any applicable 180-day exclusivity
> period]{.underline}. This means that a patent is deemed to be relevant
> under § 314.94(a)(12)(ii) [until the end of the term of the patent or
> applicable 180-day exclusivity period, whichever occurs
> first]{.underline}. Thus, where there is a patent that has been
> challenged by a paragraph IV applicant, a subsequent applicant will
> not be able to file a certification that there is no relevant patent
> or seek an immediately effective approval [until either the patent or
> the 180-day exclusivity period expires]{.underline}. The agency has
> amended § 314.94(a)(12)(viii)(B) and made a similar change to §
> 314.50(i)(6)(ii) to reflect this position.

FDA, Final Rule, ANDA Regulations; Patent and Exclusivity Provisions, 59
Fed. Reg. 50,338, 50,348 (Oct. 3, 1994) (emphasis added).[^10]

In this case, the '303 patent has been ruled invalid (and therefore,
there is no pediatric exclusivity with respect to the patent) and
Mylan's 180-day exclusivity has expired. The appropriate certification
when there are no relevant patents is a certification under 21 C.F.R.
§ 314.94(a)(12)(ii). Pediatric exclusivity does not attach to such a
certification. [See]{.underline} FDC Act § 505A(c)(2).[^11] In the
absence of any existing and applicable patents or exclusivities, FDA
must fully approve tentatively approved ANDAs.

**4. If and when the [Apotex]{.underline} decision is implemented and
the patent is treated as invalid, does pediatric exclusivity attach to
the '303 patent with respect to any unapproved ANDAs? Does it matter
whether the ANDA applicant filed a paragraph III or IV certification
before patent expiration?**

The [Apotex]{.underline} decision, which invalidated the '303 patent
effective as of March 22, 2007, and which provides FDA with a basis to
treat the '303 patent as "delisted" from the Orange Book, means that
Pfizer's pediatric exclusivity should not attach to any tentatively
approved ANDA containing a paragraph III or IV certification to the '303
patent, because such certifications have effectively changed (or via an
ANDA amendment) to a certification that there are no relevant patents.

FDC Act §§ 505A(c)(2)(A) and (B) (2006) extend the period during which
FDA cannot approve an ANDA (or a 505(b)(2) application) that includes a
paragraph II or paragraph III patent certification, or a paragraph IV
patent certification that concerns a patent that a court has determined
is valid and would be infringed by the manufacture, use, or sale of a
product that is the subject of an ANDA (or 505(b)(2) application).
[See]{.underline} FDC Act § 505A(c)(2) (2006). Because the '303 patent
is invalid as of March 22, 2007 and has otherwise expired (and
furthermore, because there is no blocking period of 180-day
exclusivity), FDA may "delist" the patent from the Orange Book, and
Pfizer's pediatric exclusivity is inapplicable.

**5. Does 180-day exclusivity triggered before a patent expires continue
to bar approvals of other ANDAs after the patent expires, even if other
ANDA applicants change their certifications to paragraph II or withdraw
their certifications altogether?**

Mylan's period of 180-day exclusivity expired on March 25, 2007 when the
'303 patent expired. As such, FDA should fully approve all tentatively
approved ANDAs previously containing either a paragraph III or IV
certification to the '303 patent (and that now effectively contain a
certification that there are no relevant patents). Interpreting the FDC
Act to prevent the full approval of pending, tentatively approved ANDAs
until 180-days after Mylan's exclusivity was triggered (or until
September 22, 2007) is not in the interest of the public, is contrary to
Congress' intent in creating the 180-day exclusivity period, and is
contrary to long-standing FDA policy.

FDC Act § 505(j)(5)(B)(iv) states, in relevant part, that "\[i\]f the
application contains a \[paragraph IV certification\] . . . and is for a
drug for which a previous application has been submitted under this
subsection \[containing\] such a certification, the application [shall
be made effective not earlier than \[180\] days after]{.underline}" the
earlier of (1) the first commercial marketing of the approved generic
drug product, or (2) a court decision finding that the patent on which
180-day exclusivity based to be invalid and/or not infringed.
[See]{.underline} FDC Act §§ 505(j)(5)(B)(iv)(I)-(II) (emphasis added).

Congress' intent in adding this provision was to reward applicants for
designing around and challenging relevant patents on brand name drugs.
When there is no longer a relevant patent, however, the broader
objective of the Hatch-Waxman Act ─to "make available more low costs
generic drugs"─ is controlling. H.R. Rep. No. 857, 98th Cong. 1st Sess.,
pt. 1, at 14 (1984), [reprinted in]{.underline} 1984 U.S.C.C.A.N.
2647.[^12] FDA's interpretation of FDC Act § 505(j)(5)(B)(iv) with
respect to the approval of subsequent ANDA applicants when a patent on
which 180-day exclusivity is based expires must, and does, take into
account this broader Congressional objective.

FDA's regulations at 21 C.F.R. § 314.94 interpret FDC Act §
505(j)(5)(B)(iv) to mean that 180-day exclusivity is tied to patent
expiry ─regardless of whether an ANDA applicant is eligible for 180-day
exclusivity or whether that period has been triggered:

> If a patent is removed from the \[Orange Book\], any applicant with a
> pending application (including a tentatively approved application with
> a delayed effective date) who has made a certification with respect to
> such patent shall amend its certification. The applicant shall certify
> under \[21 C.F.R. § 314.94(a)(12)(ii)\] that no patents described in
> \[21 C.F.R. § 314.94(a)(12)(i)\] claim the drug or, if other relevant
> patents claim the drug, shall amend the certification to refer only to
> those relevant patents. . . . A patent that is the subject of a
> lawsuit under \[21 C.F.R. § 314.107(c)\] shall not be removed from the
> \[Orange Book\] until FDA determines either that no delay in effective
> dates of approval is required under that section as a result of the
> lawsuit, [that the patent has expired]{.underline}, or that any such
> period of delay in effective dates of approval is ended.

21 C.F.R. § 314.94(a)(12)(viii)(B) (emphasis added).[^13]

FDA explained this provision in the 1994 preamble to the Agency's final
ANDA regulations:

> To ensure that \[the protection offered by 180-day exclusivity is not
> undermined by changes from paragraph IV certification or by the filing
> of original certifications other than paragraph IV certifications\],
> the agency has required that a patent remain on the list after being
> declared invalid or unenforceable until the end of any
> [applicable]{.underline} 180-day exclusivity period. This means that a
> patent is deemed to be relevant under § 314.94(a)(12)(ii) [until the
> end of the term of the patent or applicable 180-day exclusivity
> period, whichever occurs first]{.underline}. Thus, where there is a
> patent that has been challenged by a paragraph IV applicant, a
> subsequent applicant will not be able to file a certification that
> there is no relevant patent or seek an immediately effective approval
> [until either the patent or the 180-day exclusivity period
> expires]{.underline}.

59 Fed. Reg. at 50,348 (emphasis added).

FDA reiterated this position in the preamble to the Agency's 1999
proposed rule on triggering 180-day exclusivity:

> The agency is clarifying that once the patent for which the first
> applicant filed a paragraph IV certification expires, the first
> applicant is no longer eligible for exclusivity. When the first
> applicant is no longer eligible for exclusivity, FDA may approve all
> otherwise eligible ANDA's. FDA regulations at \[21 C.F.R.
> § 314.94(a)(12)(viii)\] [currently provide that exclusivity cannot
> extend beyond the term of the patent]{.underline}.

64 Fed. Reg. at 42,877.[^14]

FDA, the courts, and Congress have also, on several occasions, expressed
their views that 180-day exclusivity cannot extend beyond the date of
expiration of the patent for which a paragraph IV certification has been
made (and on which 180-day exclusivity is based):

-   FDA Response, Docket No. 1999P-1271, at 4 (Aug. 2, 1999) ("Because
    \[180-day\] exclusivity cannot extend beyond the expiration of a
    patent, Pharmachemie lost its eligibility for exclusivity when the
    \[patent\] expired before either of the events described in \[FDC
    Act § \] 505(j)(5)(B)(iv)(I) and (II) occurred."); [see
    also]{.underline} FDA Letter re: ANDA 75-347 (omeprazole) (Nov.
    17, 2001) at 2 (discussing FDA's August 2, 1999 decision);

-   [Dr. Reddy's Labs., Inc. v. Thompson]{.underline}, 302 F. Supp. 2d
    340, 351 (D.N.J. 2003) (approving FDA's interpretation of FDC Act
    § 505(j)(5)(B)(iv) that upon patent expiration a paragraph IV
    certification in a tentatively approved ANDA converts to a paragraph
    III and 180-day exclusivity is lost);

-   [Ranbaxy Labs. Ltd v. Leavitt]{.underline}, Case No. 06-5154, at 11
    (note) (D.C. Cir., Nov. 14, 2006) ("We need not address the question
    of patent expiration in this case. We note, however, . . . the text
    and structure of the \[FDC Act\] suggest a distinction between
    expiration and delisting such that [the first generic applicant may
    no longer retain exclusivity when the patent has
    expired]{.underline}.") (emphasis added); and

-   In December 2003, Congress passed the MMA, which amended the FDC Act
    to add certain provisions that cause a "first applicant" submitting
    an ANDA with a paragraph IV patent certification to forfeit 180-day
    exclusivity. [See]{.underline} FDC Act § 505(j)(5)(D)(i) (2006). One
    such provision states that exclusivity is forfeited if "\[a\]ll of
    the patents as to which the applicant submitted a certification
    qualifying it for the 180-day exclusivity period have expired."
    [Id.]{.underline} § 505(j)(5)(D)(i)(VI). Although Congress did not
    make this provision retroactive to pre-MMA cases, such as the
    current case involving amlodipine, FDA can carry out Congress'
    intent in creating FDC Act § 505(j)(5)(D)(i)(VI) in this case by
    considering Mylan's 180-day period to have expired on March 25, 2007
    when the '303 patient expired.

Not only is FDA's view that 180-day exclusivity is tied to patent expiry
(both in the cases of tentatively approved and fully approved ANDAs) a
long-standing policy, but it is a reasonable interpretation of the
ambiguous language of FDC Act § 505(j)(5)(B)(iv) that should survive
[Chevron]{.underline} scrutiny.

Under [Chevron]{.underline}, a court must uphold an agency
interpretation if "the intent of Congress is clear" as to the "precise
question at issue" and the agency's interpretation follows that intent.
467 U.S. at 842. [Chevron]{.underline} also directs courts to defer to
agency interpretations when Congress' intent is unclear and the agency's
interpretation "is based on a permissible construction of the statute."
[Id.]{.underline} at 843. Importantly, "\[i\]f the agency's reading
fills a gap or defines a term in a reasonable way in light of the
Legislature's design," a court must "give that reading controlling
weight, even if it is not the answer 'the court would have reached if
the question initially had arisen in judicial proceeding.'" [Regions
Hosp. v. Shalala]{.underline}, 522 U.S. 448, 457 (1998) ([quoting
Chevron]{.underline}, 467 U.S. at 843 n. 11); [see also]{.underline}
[Whitman v. Am. Trucking Assns., Inc.]{.underline}, 531 U.S. 457 (2001).

One example of this principle is [Young v. Community Nutrition
Inst.]{.underline}, 476 U.S. 974 (1986). In that case, the Court upheld
FDA's interpretation of FDC Act § 406 (concerning tolerances for
poisonous ingredients in food). While the Court acknowledged that the
interpretation adopted by the court of appeals (and the Community
Nutrition Institute) "may seem to some to be the more natural
interpretation," the Court noted that "the phrasing of \[FDC Act § 406\]
admits of either respondents' or petitioner's reading of the statute,"
and therefore sustained FDA's interpretation. [Id.]{.underline} at 980.
[Young]{.underline} demonstrates that a reviewing court would have to
uphold FDA's interpretation of FDC Act § 505(j)(5)(B)(iv) unless the
statutory provision is incapable of being read to permit the expiry of
180-day exclusivity upon patent expiration. Because FDA's interpretation
of FDC Act § 505(j)(5)(B)(iv) that 180-day exclusivity ends upon patent
expiry is consistent with both the language of the statute and with the
goal of Congress to get affordable generic drugs onto the market, FDA's
current sensible interpretation is permissible.

\###

In sum, neither Mylan's expired 180-day exclusivity, nor Pfizer's
inapplicable pediatric exclusivity with respect to the '303 patent
provide a legal basis to delay further generic competition. FDA should
immediately (or as soon as permitted to by a court) grant final approval
to all tentatively approved ANDAs for amlodipine besylate tablets.

> Respectfully Submitted,

![](media/image2.png){width="2.375in" height="0.47638888888888886in"}

> David S. Machlowitz
>
> Senior Vice President,
>
> General Counsel & Secretary

cc: Gary J. Buehler

> Director, Office of Generic Drugs

[^1]: Medco is also submitting a copy of the company's views to the FDA
    dockets established pursuant to the submission of three citizen
    petitions concerning amlodipine exclusivity issues, Docket Nos.
    2007P-0110 and 2007P-0111 (submitted by Pfizer Inc. ("Pfizer")), and
    2007P-0116 (submitted by Mylan Pharmaceuticals Inc. ("Mylan")).

[^2]: FDA approved ANDA #76-418 on October 3, 2005 after Mylan notified
    the Agency that no action for patent infringement was brought by the
    NDA/patent holder. ANDA #76-418 was submitted to FDA prior to the
    enactment of Title XI of the Medicare Prescription Drug,
    Improvement, and Modernization Act of 2003 ("MMA"), Pub. L. No.
    108-173, 117 Stat. 2066 (Dec. 8, 2003). As such, the triggering of
    Mylan's 180-day exclusivity is governed by the pre-MMA version of §
    505(j)(5)(B)(iv)(I)-(II) of the Federal Food, Drug, and Cosmetic Act
    ("FDC Act"). The approval of amlodipine ANDAs is governed by the
    post-MMA version of FDC Act § 505(j)(5)(B)(iii). All post-MMA FDC
    Act references in this letter are identified with a "2006" notation.
    It is noteworthy that if this were a post-MMA case involving the
    triggering of 180-day exclusivity, Mylan would almost certainly have
    forfeited its exclusivity. Mylan began commercial marketing on March
    23, 2007, which is the latest possible date on which Mylan's 180-day
    exclusivity was triggered. Mylan's 180-day exclusivity expired,
    however, on March 25, 2007 when the '303 patent expired.

[^3]: Pfizer argues that FDC Act § 505(j)(5)(B)(iii)(II)(aa)(AA) (2006)
    does not apply in this case, because "the 30-month stay of Apotex's
    ANDA expired on January 7, 2006 --prior to the district court
    decision on January 29, 2006." Pfizer Comments, Docket No.
    2007N-0123, at 3 (Mar. 25, 2007). Pfizer later argues that if FDC
    Act § 505(j)(5)(B)(iii)(II)(aa)(AA) (2006) applies "it does not
    authorize FDA to approve Apotex's ANDA based on the non-final ruling
    of the Federal Circuit issued on March 22\[, 2007\]."
    [Id.]{.underline} Because FDA did not (and could not) make the
    approval of Apotex's ANDA "effective upon the expiration of the
    thirty-month period," FDC Act § 505(j)(5)(B)(iii)(II)(aa)(AA) (2006)
    must control in this case. It is the only applicable provision in
    FDC Act § 505(j)(5)(B)(iii) (2006).

[^4]: FDA's Court Decisions Guidance is but one example of the Agency's
    attempt to regulate directly from the FDC Act. FDA announced that
    the Agency would "regulate directly from the statute, and will make
    decisions on 180-day generic drug exclusivity on a case-by-case
    basis" in the wake of the decisions in [Mova Pharm. Corp. v.
    Shalala]{.underline}, 140 F.3d 1060 (D.C. Cir. 1998), and [Granutec,
    Inc. v. Shalala]{.underline}, 1998 U.S. App. LEXIS 6685 (4th Cir.
    1998) (unpublished opinion). FDA, Guidance or Industry, "180-Day
    Generic Drug Exclusivity Under the Hatch-Waxman Amendments to the
    Federal Food, Drug, and Cosmetic Act," (June 1998) at 4 (hereinafter
    "180-Day Guidance"); [see also]{.underline} FDA, Proposed Rule,
    180-Day Generic Drug Exclusivity for ANDAs, 64 Fed. Reg. 42,873,
    42,876 (Aug. 6, 1999) (withdrawn 67 Fed. Reg. 66,593 (Nov. 1, 2002)
    ("The removal of the successful defense requirement has resulted in
    a fragmented regulatory framework, forcing the agency to modify not
    only the regulatory language in certain parts but also . . . its
    interpretation of language that is to remain."). These cases and
    others ─[e.g.]{.underline}, [Mylan Pharma., Inc. v.
    Shalala]{.underline}, 81 F. Supp. 2d 30 (D.D.C. 2000) (invalidating
    FDA regulation defining "court decision")─ struck down other aspects
    of FDA's 1994 ANDA regulations because an actual conflict existed
    between the FDC Act and the Agency's implementing regulations.
    Similarly, FDA's "mandate policy" based on now-removed 21 C.F.R.
    § 314.107(e)(2)(iii) (1999) and the pre-MMA version of FDC Act
    § 505(j)(5)(B)(iii) conflicts with the clear and unambiguous text of
    the post-MMA FDC Act version applicable in this case and should not
    be followed.

[^5]: The MMA amended FDC Act § 505(j)(5)(B)(iii). The amendments to
    this provision apply to all ANDAs pending on or after December 8,
    2003. Prior to the MMA, FDC Act 505(j)(5)(B)(iii) stated, in
    relevant part, "if before the expiration of \[the 30-month stay\]
    the court decides that such patent is invalid or not infringed, the
    approval \[of an ANDA containing a paragraph IV certification\]
    shall be made effective [on the date of the court
    decision]{.underline}." FDC Act § 505(j)(5)(B)(iii)(I) (emphasis
    added). Even here, given the statutory language identifying a
    specific date, FDA's pre-MMA "mandate policy" is questionable. The
    post-MMA version of FDC Act § 505(j)(5)(B)(iii), however, removes
    any doubt given the surrounding provisions that specifically
    identify the dates on which ANDA approval becomes effective.

[^6]: Black's Law Dictionary defines the term "decision" to mean,
    generally, "\[a\] determination arrived at after consideration of
    facts, and, in legal context, law. A popular rather than technical
    or legal word; a comprehensive term having no fixed, legal meaning."
    Black's Law Dictionary, 6th Ed. at 407. Unless specifically defined,
    a court must presume that Congress intended the ordinary meaning of
    a term when it is used in a statute. [See]{.underline}
    [Chevron]{.underline} at 860. Thus, the use of the term "decision"
    in this case must mean the date on which the Federal Circuit ruled
    the '303 patent invalid.

[^7]: 180-day exclusivity may also be triggered on the date of "first
    commercial marketing." FDC Act § 505(j)(5)(B)(iv)(I). In this case,
    Mylan began commercially marketing on March 23, 2007, which is the
    latest possible date on which Mylan's 180-day exclusivity was
    triggered.

[^8]: [See e.g.]{.underline}, [National Pharm. Alliance v.
    Henney]{.underline}, 47 F. Supp. 2d 37, 39 (D.D.C. 1999) (upholding
    FDA's interpretation that pediatric exclusivity granted under FDC
    Act § 505A applies to all of a sponsor's approved drug products
    containing the studied "active moiety" rather than a specific drug
    product as "consistent with the overall structure of regulation of
    generic drugs, as set forth in the Hatch-Waxman Amendments, Pub. L.
    98-417, 98 Stat. 1585 (1984).").

[^9]: FDA has, in other cases, effectively converted a paragraph IV
    patent certification to a paragraph II to which pediatric
    exclusivity attaches and delays ANDA approval. [See
    e.g.]{.underline}, [Mylan Labs., Inc. v. Thompson]{.underline}, 389
    F.3d 1272 (D.C. Cir. 2004); [Ranbaxy Labs. Ltd. v. FDA]{.underline},
    307 F. Supp. 2d 15 (D.D.C. 2004), [aff'd]{.underline}, 307 Fed.
    Appx. 1 (D.C. Cir. 2004). However, these cases differ significantly
    from the current case in that there was no court decision on patent
    invalidity. As such, the rulings in these cases cannot serve as
    precedent for FDA to determine the applicability of Pfizer's
    pediatric exclusivity to ANDA applicants.

[^10]: [See also]{.underline} 21 C.F.R. § 314.50(i)(6)(ii) ("A patent
    that is the subject of a lawsuit under \[21 C.F.R. § 314.107(c)\]
    shall not be removed from the \[Orange Book\] until FDA determines
    either that no delay in effective dates of approval is required
    under that section as a result of the lawsuit, that the patent has
    expired, or that any such period of delay in effective dates of
    approval is ended."). While the '303 patent could remain listed in
    the Orange Book until the expiration of Mylan's 180-day exclusivity
    ([i.e.]{.underline}, March 25, 2007 ─the same date the '303 patent
    expired), because the Federal Circuit ruled that the '303 patent is
    invalid on March 22, 2007, Pfizer's pediatric exclusivity is
    inapplicable with respect to the '303 patent as of that date.

[^11]: FDA's authority to "delist" the '303 patent from the Orange Book
    in this case is not affected by the recent decision of the United
    States Court of Appeals for the District of Columbia in [Ranbaxy
    Labs. Ltd v. Leavitt]{.underline}, Case No. 06-5154 (D.C. Cir., Nov.
    14, 2006). That case concerned "whether the FDA may delist a patent
    upon the request of the NDA holder after a generic manufacturer has
    filed an ANDA containing a paragraph IV certification so that the
    effect of delisting is to deprive the applicant of a period of
    marketing exclusivity." [Id.]{.underline} at 10. Mylan's 180-day
    exclusivity has already been triggered and run ([i.e.]{.underline},
    as of March 25, 2007 when the '303 patent expired). Indeed, the
    court specifically stated that "\[w\]e need not address the question
    of patent expiration in this case. We note, however, . . . the text
    and structure of the \[FDC Act\] suggest a distinction between
    expiration and delisting such that [the first generic applicant may
    no longer retain exclusivity when the patent has
    expired]{.underline}." [Id.]{.underline} at 11 (note) (emphasis
    added).

[^12]: [See also]{.underline} [Mead Johnson Pharm. Group v.
    Bowen]{.underline}, 838 F.2d 1332, 1333 (D.C. Cir. 1988) ("The
    purpose of \[the Hatch-Waxman Act is\] to increase competition in
    the drug industry by facilitating the approval of generic copies of
    drugs.").

[^13]: [See also]{.underline} 21 C.F.R. § 314.50(i)(6)(ii) ("A patent
    that is the subject of a lawsuit under \[21 C.F.R. §\] 314.107(c)
    shall not be removed from the \[Orange Book\] until FDA determines
    either that no delay in effective dates of approval is required
    under that section as a result of the lawsuit, [that the patent has
    expired, or that any such period of delay in effective dates of
    approval is ended]{.underline}.") (emphasis added). While the '303
    patent could remain listed in the Orange Book until the expiration
    of Mylan's 180-day exclusivity ([i.e.]{.underline}, March 25, 2007),
    Pfizer's pediatric exclusivity is inapplicable with respect to the
    '303 patent, because the Federal Circuit ruled that the '303 patent
    is invalid on March 22, 2007.

[^14]: FDA's proposal was intended to respond to some of the issues
    created as a result of the [Mova]{.underline} and
    [Granutec]{.underline} court decisions. Under one such proposal, FDA
    would "delay the effective date of approval of a subsequent ANDA
    [for up to 180 days]{.underline} from the date described in
    paragraph (c)(1) of this section only when the first applicant is
    eligible for 180-day exclusivity." 64 Fed. Reg. at 42,886 (proposed
    21 C.F.R. § 314.107(c)(2)). Thus, it has clearly been FDA's
    long-held position that 180-day exclusivity may not always extend
    for 180-days, and that the Agency may approve, under certain
    circumstances, subsequent ANDAs prior to the date that is 180-days
    after a first filer's ANDA approval.