Sanofi-Aventis U.S. LLC v. Food and Drug Administration ( 2010 )

UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF COLUMBIA
)
SANOFI-AVENTIS U.S. LLC, )
)
Plaintiff, )
)
v. )
)
FOOD AND DRUG ADMINISTRATION, ) Civil Action No. 10-1255 (EGS)
et al., )
)
Defendants, )
and )
)
SANDOZ INC., )
)
Intervenor-Defendant. )
)
MEMORANDUM OPINION
Pending before the Court is the motion for preliminary
injunction of Plaintiff Sanofi-Aventis U.S. LLC (“Sanofi”).
Plaintiff, manufacturer of the leading and widely prescribed
anticoagulant Lovenox, seeks an Order directing the Food and Drug
Administration (“FDA”) to withdraw its approval of an abbreviated
new drug application (“ANDA”) submitted by Sandoz Inc. (“Sandoz”)
for a generic version of Lovenox - enoxaparin sodium injection.
Upon consideration of the motion, the response, the reply and
surreply thereto, the amicus brief of AARP, the arguments made
during the hearing on August 17, 2010, the applicable law, the
administrative record, and for the following reasons, the Court
hereby DENIES plaintiff’s motion for a preliminary injunction.
I. BACKGROUND
A. Statutory Background
The Food, Drug, and Cosmetic Act (the “FDCA” or the “Act”)
provides that “[n]o person shall introduce or deliver for
introduction into interstate commerce any new drug” without first
obtaining FDA approval. 21 U.S.C. § 355(a). To obtain approval
of a “new drug” a pharmaceutical company must file either a new
drug application (“NDA”) or an abbreviated new drug application
(“ANDA”). See id.Under the FDCA, a company seeking to market a “pioneer” or
“innovator” drug must obtain FDA approval by filing an NDA
containing, among other things, “full reports of investigations
which have been made to show whether or not such drug is safe for
use and whether such drug is effective in use . . . a full list
of the articles used as components of such drug . . . [and] a
full description of the methods used in, and the facilities and
controls used for, the manufacture, processing, and packing of
such drug . . . .” Id. § 355(b)(1). After an NDA is approved,
this pioneer drug is referred to as the listed drug. 21 C.F.R.
§ 314.3(b).
Recognizing that the NDA process is costly and time-
consuming, and seeking “to make available more low cost generic
drugs,” Congress amended the FDCA in 1984 to permit a
manufacturer of a generic alternative to an RLD to seek FDA
2
approval by submitting an ANDA. Serono Labs., Inc. v. Shalala,
158 F.3d 1313, 1316 (D.C. Cir. 1998) (citing H.R. Rep. No. 98-
857, pt. 1 at 14 (1984)). The ANDA process shortens the time and
effort needed for new drug approval by, among other things,
allowing an ANDA applicant to rely on the FDA’s previous findings
of safety and effectiveness for the reference listed drug
(“RLD”).1 See generally 21 U.S.C. § 355(j). Therefore, instead
of submitting independent clinical studies in support of the
safety and effectiveness of its proposed generic drug, an ANDA
applicant must submit sufficient information to establish that
its proposed drug is “the same as” the RLD with respect to active
ingredient, dosage form, strength, route of administration, and
labeling, and that its product is bioequivalent to the listed
drug. See id. § 355(j)(2)(A); see also Astellas Pharma US, Inc.
v. FDA, 642 F. Supp. 2d 10, 13-14 (D.D.C. 2009) (“Rather than
requiring the applicant to make an independent showing that the
proposed generic is itself safe and effective, the amended
statute requires a showing that the proposed generic operates in
the same manner as the pioneer drug on which it is based – its
reference listed drug. Thus, the FDA’s approval of a new generic
drug relies on its prior determination that the RLD is safe and
effective.”). “The underlying premise of the ANDA approval
1
An RLD is “the listed drug identified by FDA as the drug
product upon which an applicant relies in seeking approval of its
abbreviated application.” 21 C.F.R. § 314.3(b).
3
requirements is that the generic drug product and the RLD can be
substituted for each other with the full expectation that they
will have the same clinical effect and safety profile.” AR 2879.
The FDA must approve an ANDA unless, among other things, the
ANDA sponsor has failed to make the statutorily-required showings
of sameness and bioequivalence, or if the methods used in, or the
facilities and controls used for, the manufacture, processing,
and packing of the drug are inadequate to assure and preserve its
identity, strength, quality, and purity. See 21 U.S.C.
§ 355(j)(4).
B. Factual & Procedural Background
On March 29, 1993, the FDA approved plaintiff’s NDA for
Lovenox. AR 2881. Lovenox is a widely prescribed anticoagulant
used to prevent or treat thromboembolic disease and deep vein
thrombosis, as well as to prevent complications associated with
angina and certain forms of heart attack. Pl.’s Mem. at 4; AR
2881-82. With its active ingredient enoxaparin sodium
(“enoxaparin”), Lovenox is part of a relatively new class of
anticoagulants known as low molecular weight heparins (“LMWHs”).
AR 2882. LMWHs such as enoxaparin are manufactured by
depolymerizing heparin sodium polysaccharide chains into
correspondingly shorter oligosaccharide chains. AR 2882.
On February 19, 2003, plaintiff submitted a citizen
petition to the FDA requesting that the FDA withhold approval of
4
any ANDA for a generic version of Lovenox “[u]ntil such time as
enoxaparin has been fully characterized . . . unless the
manufacturing process used to create the generic product is
determined to be equivalent to [Sanofi’s] manufacturing process
for enoxaparin, or the application is supported by proof of
equivalent safety and effectiveness demonstrated through clinical
trials.” AR 1.2 Plaintiff also requested that the FDA refrain
from approving any ANDA citing Lovenox as the RLD unless the
generic product contained a “1,6 anhydro ring structure” at
certain terminal ends of the oligosaccharide chains. AR 1. In
its petition, plaintiff argued that “[b]ecause enoxaparin is not
fully characterized, utilizing [Sanofi’s] process (or an
acceptable equivalent) is the only way to ensure that the generic
product will contain all of the pharmacologically active
components (both known and yet to be discovered) for enoxaparin.
Absent that, FDA cannot consider the generic to have the ‘same’
active ingredient as enoxaparin and must therefore require a
demonstration of equivalent safety and effectiveness through
clinical testing.” AR 4.
2
A drug is “characterized” by scientific analysis (or a
variety of analyses) to determine the physical and chemical
characteristics of the compound. Enoxaparin has not yet been
“fully characterized” because scientists have not been able to
identify all of the structures within the drug. See Pl.’s Mem.
at 9-10 (explaining that as much as 30% of enoxaparin cannot be
fully characterized by direct analysis given the limitations of
current analytical technology).
5
On August 26, 2005, while Sanofi’s citizen petition was
pending, Sandoz filed an ANDA with the FDA seeking approval for a
generic version of Lovenox. AR 4167. On November 5, 2007, the
FDA sent a letter to Sandoz informing the company that the agency
had determined that “the ANDA is not approvable because the
application does not adequately address the potential for
immunogenicity of the drug product.” AR 4167.3 The agency
offered, however, to meet with Sandoz “to address what additional
information should be provided to adequately address this
concern.” AR 4167.
In a follow-up letter dated December 4, 2007, the FDA
informed Sandoz that:
FDA is particularly concerned with product and
process derived impurities that may modify the
biological activity or enhance the immunogenicity
of your product. Understanding the potential for
your product to elicit an immune response is
critical, since [LMWHs] are associated with a
serious immune-driven adverse event, heparin
induced thrombocytopenia (“HIT”). Impurities can
interact with either the product or with the host
immune system in ways that alter outcome. Thus,
for products that have the potential for
immunologic adverse events and certainly for
products with known immunologic adverse events,
the contribution of impurities needs to be
carefully considered.
AR 4170. The letter then provided a list of items that Sandoz
needed to address as part of its ANDA, as well as a list of
3
Immunogenicity is the potential of a drug substance or
product to elicit an immune response, such as an allergic
reaction, when introduced to the body.
6
suggested approaches to address the agency’s concerns. AR 4171-
73. Following Sandoz’s submission of this additional
information, the FDA approved Sandoz’s ANDA for generic
enoxaparin on July 23, 2010. See AR 4440-41 (“We have completed
the review of this ANDA and have concluded that adequate
information has been presented to demonstrate that the drug is
safe and effective for use as recommended in the submitted
labeling. Accordingly, the ANDA is approved, effective on the
date of this letter. The Office of Generic Drugs has determined
that your Enoxaparin Sodium Injection . . . meets the standards
for approval (including those for active ingredient sameness and
bioequivalence) and, therefore, is therapeutically equivalent to
the [RLD], Lovenox Injection[.]”).
On the same date that the FDA approved Sandoz’s ANDA, the
agency denied Sanofi’s citizen petition with the exception of
approving its request regarding the 1,6 anhydro ring structure.
See AR 2878-922. In its denial, the FDA explained that “[w]e do
not find it necessary for an ANDA applicant seeking approval of
generic enoxaparin to submit the information you request.” AR
2879. While acknowledging that “the approval of ANDAs for
enoxaparin raises complicated scientific and regulatory issues,”
the agency explained that “[b]ased on our evaluation of all the
relevant data and other current relevant scientific information,
our experience and expertise, Agency precedent, and applicable
7
law, we find that enoxaparin has been adequately characterized
for the purposes of approving naturally sourced generic
enoxaparin; and we conclude that an ANDA applicant for enoxaparin
can demonstrate active ingredient sameness by meeting five
criteria, each of which captures different aspects of the active
ingredient’s ‘sameness.’” AR 2879-80.4 The agency also noted
that “[i]n addition to the issues raised in your petition, we
have also considered issues related to immunogenicity,”
explaining that “[i]t is important that ANDA applicants assess
the potential of the generic product to generate a greater immune
response as compared to the RLD, Lovenox.” AR 2881.
Three days after Sandoz’s ANDA was approved and Sanofi’s
citizen petition was largely denied, Sanofi filed suit in this
Court. Although Sanofi initially requested a temporary
restraining order (“TRO”), during a telephonic status hearing on
July 26, 2010, Sanofi agreed to consolidate its request for a TRO
with its request for a preliminary injunction. See Minute Order
dated July 26, 2010. On July 27, 2010, Sandoz sought leave to
intervene in this lawsuit as a defendant, and on July 28, 2010,
4
These five criteria address: (1) the physical and chemical
characteristics of enoxaparin; (2) the nature of the source
material and method used to break up the polysaccharide chains
into smaller fragments; (3) the nature and arrangement of
components that constitute enoxaparin; (4) certain laboratory
measurements of anticoagulant activity; and (5) certain aspects
of the drug’s effect in humans. AR 2880; see also infra Section
III.A.3 (providing further discussion of the five-part sameness
test).
8
the Court granted the unopposed request. The Court also granted
the unopposed motion of AARP to file an amicus brief in support
of defendants. Having received expedited briefing and heard oral
argument from each of the parties, Sanofi’s motion for a
preliminary injunction is now ripe for determination by the
Court.
II. LEGAL STANDARD FOR INTERIM INJUNCTIVE RELIEF
Preliminary injunctive relief is an “extraordinary remedy
never awarded as of right.” Winter v. NRDC, Inc., 129 S. Ct.
365, 376 (2008); Munaf v. Geren, 553 U.S. 674, 128 S. Ct. 2207,
2219 (2008) (“A preliminary injunction is an extraordinary and
drastic remedy[.]” (internal quotation marks omitted)). “A
plaintiff seeking a preliminary injunction must establish that he
is likely to succeed on the merits, that he is likely to suffer
irreparable harm in the absence of preliminary relief, that the
balance of equities tips in his favor, and that an injunction is
in the public interest.” Winter, 129 S. Ct. at 374.
These four factors have typically been evaluated on a
“sliding scale,” whereby if the movant makes an unusually strong
showing on one of the factors, then it does not necessarily have
to make as strong a showing on another factor. Davis v. Pension
Benefit Guar. Corp., 571 F.3d 1288, 1291-92 (D.C. Cir. 2009)
(citing Davenport v. Int’l Bhd. of Teamsters, 166 F.3d 356, 361
(D.C. Cir. 1999)). While it is unclear whether the “sliding
9
scale” is still controlling in light of the Supreme Court’s
decision in Winter, the Court need not decide this issue because
plaintiff’s request for a preliminary injunction fails even under
the less stringent “sliding scale” analysis of Davenport. See
id. (declining, given the facts of the case, to decide if Winter
created a “stricter standard” to obtain interim injunctive
relief).5
5
At least two judges in this Circuit have announced the
position that “[i]n light of the Supreme Court’s recent decisions
. . . the old sliding-scale approach to preliminary injunctions –
under which a very strong likelihood of success could make up for
a failure to show a likelihood of irreparable harm, or vice versa
– is no longer controlling, or even viable.” Davis, 571 F.3d at
1297 (Kavanaugh, J., concurring, joined by Henderson, J.,
concurring) (internal quotation marks omitted); see also id. (“It
appears that a party moving for a preliminary injunction must
meet four independent requirements. To be sure, the third
preliminary injunction factor requires a balancing of the
equities, but that’s an additional requirement, not a substitute
for the first two requirements. In other words, under the Supreme
Court’s precedents, a movant cannot obtain a preliminary
injunction without showing both a likelihood of success and a
likelihood of irreparable harm, among other things.”).
Notably, since Davis was decided, a circuit split has
emerged regarding the continued viability of the sliding-scale
approach. While the Fourth Circuit has rejected the approach as
invalid, see Real Truth About Obama, Inc. v. Fed. Election
Comm’n, 575 F.3d 342, 347 (4th Cir. 2009) (holding that the
circuit’s prior test, which permitted “flexible interplay” among
the elements, “may no longer be applied” after Winter), vacated
on other grounds, 130 S. Ct. 2371, 176 L. Ed. 2d 764 (2010), the
Second, Seventh, and Ninth Circuits have found that a “serious
questions” version of the sliding-scale test is permissible.
Under this modified sliding-scale approach, “‘[a] preliminary
injunction is appropriate when a plaintiff demonstrates . . .
10
III. ANALYSIS
Sanofi argues that it has satisfied all four criteria
necessary to obtain a preliminary injunction, while the FDA and
Sandoz argue that none of the criteria for provisional injunctive
relief have been met. The Court will begin by addressing
Sanofi’s likelihood of success on the merits.
A. Likelihood of Success on the Merits
Sanofi sets forth three reasons that it is likely to succeed
on the merits. Specifically, Sanofi argues that the FDA:
(1) exceeded its authority under 21 U.S.C. § 355(j)(2)(A) by
requiring Sandoz to submit additional studies “to demonstrate
safety and effectiveness” beyond what is permitted for ANDAs; (2)
departed from agency precedent by approving a generic version of
a drug derived from a complex biological starting material that
has not yet been fully characterized; and (3) approved generic
enoxaparin without sufficient evidence that it has the “same”
active ingredient as Lovenox, as required by § 355(j)(2)(A).
Pl.’s Mem. at 16. The Court will explore these arguments in
turn.
that serious questions going to the merits were raised and the
balance of hardships tips sharply in the plaintiff’s favor.’”
Alliance for the Wild Rockies v. Cottrell, — F.3d —, No. 09-
35756, 2010 U.S. App. LEXIS 15537, at *8-19 (9th Cir. July 28,
2010) (analyzing the circuit split surrounding the sliding-scale
approach after Winter).
11
1. FDA’s Request for Additional Studies by Sandoz
As discussed above, the FDA initially found that Sandoz’s
ANDA for generic enoxaparin was “not approvable” because the
application did not adequately address the potential for
immunogenicity of the drug product. AR 4167; see also AR 4170
(“FDA is particularly concerned with product and process derived
impurities that may modify the biological activity or enhance the
immunogenicity of your product.”). The FDA therefore required
Sandoz to submit three types of studies comparing the
immunogenicity of its product with Lovenox. See AR 4171-73 ((i)
explaining that “the presence of impurities may affect the
interaction of enoxaparin with PF4,” and requesting that Sandoz
“compare the ability of your product with that of the innovator
product to bind to and form complexes with chemokine PF4, and
characterize the size and charge of the resulting complexes”;
(ii) requesting studies to enable the FDA to “understand the
amount and nature of potential product contaminants relative to
those in the innovator product”; and (iii) requesting functional
studies to assess “any potential immunogenic properties of your
product as compared to the innovator product”); see also Fed.
Defs.’ Opp’n Br. at 20 (describing the additional immunogenicity
data submitted by Sandoz).
Sanofi argues that by requiring Sandoz to submit these
additional immunogenicity studies, the FDA violated
12
§ 355(j)(2)(A) of the FDCA, which prohibits the FDA from
requiring an ANDA applicant to submit information beyond that
which is specified in §§ 355(j)(2)(A)(i)-(viii). See 21 U.S.C.
§ 355(j)(2)(A) (“The Secretary may not require that an
abbreviated application contain information in addition to that
required by clauses (i) through (viii).”). The FDA counters that
the type of immunogenicity information that it requested falls
well within the agency’s authority to consider whether the
manufacturing methods, controls, and specifications of a
potential generic drug manufacturer are comparable to those of
the innovator drug. See, e.g., id. § 355(j)(2)(A)(vi),
§ 355(b)(1)(D) (requiring an ANDA applicant to submit “a full
description of the methods used in, and the facilities and
controls used for, the manufacture, processing, and packing of
[its proposed] drug” (quoting § 355(b)(1)(D))); 21 C.F.R.
§ 314.94(a)(9), § 314.50(d)(1) (requiring an ANDA applicant to
submit information regarding its “[c]hemistry, manufacturing, and
controls,” including “the specifications necessary to ensure the
identity, strength, quality, and purity of the drug substance
. . . [and] the drug product” (quoting § 314.50(d)(1))). For the
reasons discussed below, the Court finds that plaintiff is not
likely to establish that the FDA lacked the authority to request
13
data comparing the immunogenicity of Sandoz’s proposed generic
enoxaparin with the RLD, Lovenox, as part of Sandoz’s ANDA.6
As a threshold matter, the Court’s analysis of the FDA’s
interpretation of the FDCA is governed by Chevron U.S.A. Inc. v.
Natural Resources Defense Council, Inc., 467 U.S. 837 (1984).
Under Chevron, the Court must first determine “whether Congress
has directly spoken to the precise question at issue.” Id. at
842. Courts “use ‘traditional tools of statutory construction’
to determine whether Congress has unambiguously expressed its
intent,” Serono, 158 F.3d at 1320, including an examination of
6
While Sanofi repeatedly attempts to characterize the FDA’s
request for additional data on immunogenicity as impermissible
“safety testing,” the FDA explains that “[t]he additional data
sought from Sandoz in this case was limited solely to assuring
that Sandoz’s manufacturing process would not produce impurities
with potential immunogenic effects to any greater degree than
Lovenox itself.” Fed. Defs.’ Surreply at 3-4 n.1. The agency
further explains that: “Although information about a product’s
purity and its impact on immunogenicity is certainly relevant to
its safety, the impurity data that FDA considered was intended to
compare the respective impurities and potential immune responses
of Sandoz’s generic enoxaparin with Sanofi’s Lovenox. . . .
Contrary to Sanofi’s implication, FDA did not request or demand
anything approaching the type of large-scale clinical safety and
efficacy trials mandated for new drugs. Instead, the safety of
Sandoz’s enoxaparin, like any generic drug, was based upon the
agency’s prior finding that the innovator drug (in this case
Lovenox) was itself safe and effective.” Fed. Defs.’ Surreply at
3-4 n.1. Because this explanation appears consistent with the
administrative record submitted in this case, see, e.g., AR 4170-
74, the Court finds no reason to doubt the FDA’s explanation
regarding its request for additional information relating to
impurities.
14
the statute’s text, structure, purpose, and legislative history.
See Shays v. FEC, 414 F.3d 76, 105 (D.C. Cir. 2005). “If 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 Congress.” Chevron, 467 U.S.
at 842-43. If, however, “the statute is silent or ambiguous with
respect to the specific issue, the question for the court is
whether the agency’s answer is based on a permissible
construction of the statute.” Id. at 843. In making such an
assessment, “considerable weight” is generally accorded to “an
executive department’s construction of a statutory scheme it is
entrusted to administer[.]” Id. Indeed, “under Chevron, courts
are bound to uphold an agency interpretation as long as it is
reasonable – regardless whether there may be other reasonable, or
even more reasonable, views.” Serono, 158 F.3d at 1321.
Sanofi argues that this case should be resolved under
Chevron step one because § 355(j)(2)(A) “unambiguously prohibits
FDA from requiring an ANDA applicant to conduct basic safety
testing such as immunogenicity testing.” Pl.’s Reply Br. at 5.
While it is undoubtedly true that the FDA may not require an ANDA
applicant to submit information beyond what is specified in
§ 355(j)(2)(A)(i)-(viii), the FDA persuasively counters that “the
categories of required information are set forth in broad,
general terms that provide FDA with ample discretion to determine
15
what information it may assess to evaluate an ANDA.” Fed. Defs.’
Surreply at 4; see also Serono, 158 F.3d at 1324 (“[T]he clauses
[in § 355(j)(2)(A)(i)-(viii)] simply describe what the
‘information’ in an application must ‘show.’ They do not specify
the kinds of studies that can or cannot be used to satisfy the
requirement[s].”). This Court agrees.
The statute itself says nothing about the type of “full
description” an ANDA applicant must submit in order to satisfy
the FDA that the chemistry, manufacturing, and controls of the
generic drug producer are sufficient to ensure the purity of the
proposed drug product. See 21 U.S.C. § 355(j)(2)(A)(vi),
§ 355(b)(1)(D). It says only that the full description must
allow the FDA to determine that “the methods used in, or the
facilities and controls used for, the manufacture, processing,
and packing of the drug are [not] inadequate to assure and
preserve its identity, strength, quality, and purity[.]” 21
U.S.C. § 355(j)(4)(A). Accordingly, when reading
§§ 355(j)(2)(A)(vi) and 355(b)(1)(D)’s requirement that
applicants fully describe their manufacturing process, in
conjunction with § 355(j)(4)(A)’s requirement that the FDA assess
a drug’s “purity” in determining whether to approve an ANDA, the
Court cannot agree with plaintiff’s assertion that § 355(j)(2)(A)
unambiguously prohibits the FDA from requesting the submission of
16
data comparing the impurity profile of a proposed generic drug
with the RLD.
Turning to the second Chevron inquiry, the Court must
determine whether the FDA’s request for data comparing the
impurity profiles of Sandoz’s generic enoxaparin with Lovenox is
“based on a permissible construction of the statute.” Chevron,
467 U.S. at 843. As noted above, this Court must defer to the
FDA’s interpretation of the FDCA as long as it reasonable –
“regardless whether there may be other reasonable, or even more
reasonable, views.” Serono, 158 F.3d at 1321. Similarly, the
Court must defer to an agency’s reading of its own regulations
unless it is “plainly erroneous or inconsistent with the
regulation.” Id. at 1320 (internal quotation marks omitted).
Here, the FDA argues that its regulations “have long
construed the statutory requirement of a ‘full description’ of
manufacturing methods and controls, 21 U.S.C. § 355(b)(1)(D), and
the parallel provision in 21 U.S.C. § 355(j)(4)(A), to include,
among other things, detailed information related to the
assessment of impurities.” Fed. Defs.’ Surreply at 5; see, e.g.,
21 C.F.R. § 314.94(a)(9) (requiring the specifications necessary
to ensure the purity of the drug product, including, for example,
tests, analytical procedures, and acceptance criteria); 57 Fed.
Reg. at 17,959 (Apr. 28, 1992) (“As for possible impurities or
residues in the ANDA product, ANDA applicants would be required
17
to provide information on the drug substance and the drug product
as part of the chemistry, manufacturing, and controls section of
the application. This would include information on impurities
and residues. The ‘Guideline for Submitting Supporting
Documentation in Drug Applications for the Manufacture of Drug
Substances’ suggests that impurities ‘should not only be detected
and quantitated, but should also be identified and characterized
when this is possible with reasonable effort.’” (internal
citations omitted)).7 Despite Sanofi’s protestations to the
contrary, see Pl.’s Reply Br. at 8-12, the Court concludes that
the FDA’s construction of the FDCA as permitting the agency to
request information to assess whether impurities resulting from a
generic drug producer’s manufacturing processes and controls
would generate a greater immune response than the RLD is both
reasonable and consistent with its regulations. Moreover,
because the FDA’s determination of what is required to assess the
“purity” of a generic drug for purposes of the FDCA “rests on the
7
The federal defendants also submitted a guidance document
regarding the FDA’s evaluation of impurities with its surreply.
See Docket No. 22-1, Guidance for Industry, ANDAs: Impurities in
Drug Substances (June 2009). This guidance document discusses,
among other things, the “qualification of impurities,” which is
“the process of acquiring and evaluating data that establish the
biological safety of an individual impurity or a given impurity
profile at the level(s) being considered.” Id. at 4. The
guidance document indicates that “[w]hen appropriate, we
recommend that [ANDA] applicants provide a rationale for
establishing impurity acceptance criteria that includes safety
considerations,” id., and provides recommendations regarding
“methods for qualifying impurities.” Id. at 5.
18
‘agency’s evaluations of scientific data within its area of
expertise,’” it is “entitled to a ‘high level of deference’ from
this court.” Serono, 158 F.3d at 1320 (quoting A.L. Pharma, Inc.
v. Shalala, 62 F.3d 1484, 1490 (D.C. Cir. 1995)). Accordingly,
the Court concludes that Sanofi is unlikely to demonstrate that
the FDA exceeded its authority under the FDCA when it approved
Sandoz’s ANDA despite having required Sandoz to submit additional
information comparing the impurity profiles of its generic
enoxaparin with Lovenox.
2. FDA’s Approval of a Generic Drug that is Not Fully
Characterized
Next, Sanofi argues that the FDA departed from agency
precedent by approving a generic version of a drug derived from a
complex biological starting material that has not yet been fully
characterized. Specifically, Sanofi asserts that the FDA’s
approval of Sandoz’s ANDA “represents a significant departure
from well-established agency precedent regarding complex products
– like enoxaparin – that are not fully characterized,” and must
therefore be enjoined as an arbitrary and capricious decision
under the Administrative Procedure Act (the “APA”), 5 U.S.C.
§ 706(2)(A). Pl.’s Mem. at 24-25. In support of its argument,
plaintiff asserts that the FDA’s approval of generic enoxaparin
is inconsistent with its decisions for (i) hyaluronidase, (ii)
Omnitrope, and (iii) Premarin. See Pl.’s Mem. at 25-33. Sanofi
further argues that the FDA “fails to address that enoxaparin is
19
not fully characterized or to provide a substantive reason for
why it should be treated differently than other drugs that are
not fully characterized.” Pl.’s Mem. at 24.
The FDA responds that Sanofi’s reliance on these past
decisions is “misplaced,” explaining that the FDA “may and must
approve drugs by considering the individual characteristics of
the particular drug at issue.” Fed. Defs.’ Opp’n Br. at 31. The
FDA further responds that its decision to approve Sandoz’s ANDA
is “consistent with the general principles underlying past agency
decisions[.]” Fed. Defs.’ Opp’n Br. at 31; see also AR 2900-02
(explaining how the agency’s approach for determining the
“sameness” of enoxaparin is “consistent with [its] previous ANDA
approval decisions for other generic drug products containing
active ingredients that are heterogeneous polysaccharides,”
including heparin and hetastarch). For the reasons discussed
below, the Court finds the FDA’s explanations regarding its past
decisions persuasive and concludes that Sanofi is unlikely to
succeed on its claim that the FDA’s approval of generic
enoxaparin was arbitrary and capricious.
In reviewing Sanofi’s claims that the FDA violated the APA,
it is well established in this Circuit that the Court’s review is
“highly deferential.” Bloch v. Powell, 348 F.3d 1060, 1070 (D.C.
Cir. 2003). This is particularly true when, as here, the
agency’s decision is based on the evaluation of complex
20
scientific information within the agency’s technical expertise.
See Troy Corp. v. Browner, 120 F.3d 277, 283 (D.C. Cir. 1997)
(emphasizing that “considerable deference” must be shown because
courts “review scientific judgments of the agency not as the
chemist, biologist, or statistician that we are qualified neither
by training nor experience to be, but as a reviewing court
exercising our narrowly defined duty of holding agencies to
certain minimal standards of rationality” (internal quotation
marks omitted)). Therefore, when reviewing agency action under
the APA, the Court must only assess whether the challenged
decision was “arbitrary, capricious, an abuse of discretion, or
otherwise not in accordance with law.” 5 U.S.C. § 706(2)(A); see
also Motor Vehicle Mfrs. Ass’n v. State Farm Mut. Auto Ins. Co.,
463 U.S. 29, 43 (1983) (explaining that courts may only set aside
agency action under the APA if the agency “relied on factors
which Congress has not intended it to consider, entirely failed
to consider an important aspect of the problem, offered an
explanation for its decision that runs counter to the evidence
before the agency, or is so implausible that it could not be
ascribed to a difference in view or the product of agency
expertise”).   As long as the “agency’s reasons and policy choices
. . . conform to ‘certain minimal standards of rationality’ . . .
the [agency decision] is reasonable and must be upheld.” Small
21
Refiner Lead Phase-Down Task Force v. EPA, 705 F.2d 506, 520-21
(D.C. Cir. 1983) (citation omitted).
As discussed above, Sanofi argues that the FDA’s decision to
approve Sandoz’s ANDA for enoxaparin is inconsistent with its
past “precedent” regarding complex drugs that have not yet been
fully characterized. Pl.’s Mem. at 24-25. While it is
undoubtedly true that “an agency must treat similar cases in a
similar manner unless it can provide a legitimate reason for
failing to do so,” Bracco Diagnostics, Inc. v. Shalala, 963 F.
Supp. 20, 27 (D.D.C. 1997) (quoting Indep. Petroleum Ass’n of
America v. Babbitt, 92 F.3d 1248, 1258 (D.C. Cir. 1996)), this is
not a case in which the FDA treated drugs that were “identical in
all material respects” differently. Id.; see, e.g., AR at 2916-
17 (“While both enoxaparin and hyaluronidase are heterogeneous
mixtures of molecular entities, these two active ingredients are
derived from different origins and are composed of entirely
different molecular structures.”; “Enoxaparin consists of a
heterogenous mixture of oligosaccharides produced through
alkaline depolymerization of the benzyl ester of heparin derived
from porcine intestinal mucosa, whereas hyaluronidase is a
mixture of glycosylated protein isoforms (isoenzymes) that is
derived from either naturally sourced tissue – ovine tissue
(Vitrase) or bovine tissue (Amphadase, Hydase) – or through
recombinant means (Hylenex).”); AR at 2915-16 (explaining that
22
the active ingredients of Premarin and enoxaparin “are derived
from different origins and are composed of entirely different
molecular structures”; “Enoxaparin is a heterogenous mixture of
oligosaccharides produced through alkaline depolymerization of
the benzyl ester of heparin derived from porcine intestinal
mucosa, whereas Premarin’s conjugated estrogens are a mixture of
steroids derived from pregnant mare’s urine.”).8 Nor is this a
case in which the FDA “simply gloss[ed] over its earlier
decisions.” Pl.’s Mem. at 24. To the contrary, the FDA provided
“legitimate reason[s]” for deciding that enoxaparin should be
treated differently than the drugs cited by Sanofi. Bracco, 963
F. Supp. at 27; see AR 2900-02, 2914-18 (explaining why approval
of an ANDA for enoxaparin is consistent with FDA precedent).9
8
See also AR at 2914-15 (explaining that the active
ingredients of enoxaparin and Pergonal “have different origins
and are composed of entirely different molecular structures”;
“Enoxaparin is a heterogenous mixture of oligosaccharides
produced through alkaline depolymerization of the benzyl ester of
heparin derived from porcine intestinal mucosa, whereas
Pergonal’s menotropins are a mixture of protein isoforms of FSH
and LH derived from the urine of post-menopausal women.”).
9
See also Fed. Defs.’ Opp’n Br. at 31 (explaining that the
FDA denied an ANDA to manufacture generic hyaluronidase because
the active ingredient in hyaluronidase had “not yet been
sufficiently characterized to permit the Agency to conclude that
another hyaluronidase product has an identical active
ingredient”; “In this case, by contrast, FDA has confidence that
the active ingredient in Lovenox and in Sandoz’s enoxaparin
product has been adequately characterized to permit FDA to
conclude that Sandoz’s product has the same active ingredient.”
(citing AR 2918) (internal quotation marks omitted)); Fed. Defs.’
23
Having carefully reviewed the FDA’s denial of Sanofi’s
citizen petition and its explanations regarding its past
decisions, the Court is unpersuaded that the FDA failed to
“conform to ‘certain minimal standards of rationality’” in its
evaluation of enoxaparin. Small Refiner Lead Phase-Down Task
Force, 705 F.2d at 521. Therefore, given the deferential
standard of review that this Court must accord the FDA’s
scientific determinations, the Court finds it unlikely that
Sanofi will succeed in its argument that the FDA’s approval of
generic enoxaparin is inconsistent with its past precedent.
3. FDA’s Determination that Sandoz’s ANDA has the
Same Active Ingredient as Lovenox
Finally, Sanofi argues that it is likely to succeed on the
merits because the FDA approved generic enoxaparin without
Opp’n Br. at 32 (“Omnitrope, unlike enoxaparin, was never
determined to have the ‘same’ active ingredient as the innovator
[RLD], and in fact had acknowledged differences in certain
respects. Thus, it was not approvable as an ANDA under 21 U.S.C.
§ 355(j)(2)(A). By contrast, FDA has determined that Sandoz’s
enoxaparin has the ‘same’ active ingredient as the listed drug,
Lovenox, because it has been adequately characterized and has met
the five criteria.”); Fed. Defs.’ Opp’n Br. at 33-34 (“In its
Premarin decision, FDA determined that it would not accept an
ANDA for a synthetic (laboratory-synthesized) version of Premarin
because the RLD was not adequately characterized. FDA stated,
however, that it could approve generic copies of Premarin if they
originated from the same natural source material (pregnant mares’
urine) and were subject to similar manufacturing controls. FDA’s
enoxaparin decision is consistent with its decision for natural
sourced Premarin because generic enoxaparin is derived from the
equivalent source material and is manufactured using a well-
controlled process.” (internal citations omitted)).
24
sufficient evidence that Sandoz’s ANDA has the “same” active
ingredient as Lovenox as required by § 355(j)(2)(A). Sanofi
contends that in approving Sandoz’s ANDA, the FDA “ignored
voluminous scientific evidence demonstrating that until
enoxaparin is fully characterized, generic enoxaparin products
that do not use a manufacturing process that is equivalent to
[Sanofi’s] process will not be the same as Lovenox.” Pl.’s Mem.
at 33. It further asserts that the FDA failed to provide a
“rational explanation for its decision to disregard scientific
evidence that directly contradicts its administrative findings,”
and therefore is arbitrary and capricious. Pl.’s Mem. at 33-34.
The Court finds these arguments unavailing.
In its response to Sanofi’s citizen petition, the FDA
provided a detailed explanation regarding its determination that
an ANDA applicant for enoxaparin can demonstrate “active
ingredient sameness” by meeting five criteria, “each of which
captures different aspects of the active ingredient’s
‘sameness.’” AR 2879-80. In particular, the FDA found that an
ANDA applicant seeking approval for generic enoxaparin must
demonstrate: (1) equivalence of physicochemical properties, such
as molecular weight distribution and overall chemical
composition; (2) equivalence of heparin source material (i.e.,
heparin that is derived from porcine intestinal mucosa and that
meets USP monograph standards for Heparin Sodium USP) and mode of
25
depolymerization (i.e., cleavage by alkaline β-elimination of the
benzyl ester derivative of heparin); (3) equivalence in
disaccharide building blocks, fragment mapping, and sequence of
oligosaccharide species; (4) equivalence of in vitro biological
and biochemical assay results; and (5) equivalence of in vivo
pharmacodynamic profile based upon measurements of in vivo anti-
Xa and anti-IIa profiles. See AR 2888-900. The FDA also
provided an exhaustive response to the arguments raised in
Sanofi’s citizen petition, see generally AR 2904-21, including
Sanofi’s claim that the FDA should refrain from approving any
ANDAs citing Lovenox as the RLD unless, among other things, the
manufacturing process used to create the generic drug product was
deemed to be equivalent to Sanofi’s manufacturing process for
Lovenox. See AR 2905-13 (explaining why ANDA applicants for
enoxaparin do not need to demonstrate that they use the same
manufacturing process as Sanofi).
While Sanofi may not agree with the FDA’s determination that
an ANDA applicant for enoxaparin can demonstrate sameness by
satisfying the five-part test discussed above, the Court
concludes that the FDA’s definition of “sameness,” as applied to
enoxaparin products, is reasonable. AR 2888; see also Serono,
158 F.3d at 1320 (“The FDA’s determination of what is required to
establish ‘sameness’ for purposes of the Act rests on the
agency’s evaluations of scientific data within its area of
26
expertise, and hence is entitled to a ‘high level of deference’
from this court.” (internal quotation marks omitted)). It was
similarly reasonable for the FDA to conclude that an ANDA
applicant need not use the same manufacturing process as Sanofi
in light of its determination that “[a]n ANDA applicant would not
need to know [Sanofi’s] exact manufacturing process parameters
and conditions (e.g., depolymerization time, pH, and temperature)
to manufacture the same active ingredient as Lovenox’s
enoxaparin.” AR 2906. In sum, just because the FDA – after
seven years of careful consideration of Sanofi’s citizen petition
and five years of examination of Sandoz’s ANDA – reached a
conclusion at odds with the position advanced by Sanofi, does not
mean that the FDA’s decision was arbitrary and capricious. To
the contrary, a review of the FDA’s response to Sanofi’s citizen
petition demonstrates that the FDA “‘examine[d] the relevant data
and articulate[d] a satisfactory explanation for its decision.’”
FCC v. Fox Television Stations, Inc., 129 S. Ct. 1800, 1810
(2009) (quoting Motor Vehicle Mfrs. Assn., 463 U.S. at 43). The
Court, therefore, finds it unlikely that Sanofi will succeed on
the merits of its claims.
B. Irreparable Harm
Next, the Court must determine whether Sanofi will suffer
irreparable harm in the absence of injunctive relief. Explaining
that its annual domestic net sales for Lovenox were approximately
27
$2.5 billion in 2009, Sanofi argues that it would suffer “very
substantial economic loss if generic sales could continue until a
merits ruling issued.” Pl.’s Mem. at 37-38. Sanofi further
argues that because the FDA would be shielded by sovereign
immunity in any subsequent lawsuit based on the agency’s
allegedly unlawful approval of Sandoz’s ANDA, its harm would be
“‘irreparable per se’” as it has no adequate remedy at law to
recover its lost sales. Pl.’s Mem. at 38-39 (quoting Feinerman
v. Bernardi, 558 F. Supp. 2d 36, 51 (D.D.C. 2008)). Sanofi also
asserts that “permitting Sandoz’s product to reach the market
without sufficient evidence that it is indeed clinically
identical to Lovenox could permanently damage [Sanofi’s]
reputation and the reputation of the Lovenox brand, as well as
present significant risks of harm to patients.” Pl.’s Mem. at
40.10
In response, the federal defendants argue that the Court
must reject Sanofi’s assertion of irreparable harm, explaining
that “[i]n this circuit, mere economic loss – even irrecoverable
10
Despite its vague assertions regarding potential risk of
harm to patients in its brief, plaintiff’s counsel conceded
during oral argument that Sanofi was not challenging the safety
of Sandoz’s generic enoxaparin. See Hr’g Tr. 32:2-7, Aug. 17,
2010 (Plaintiff’s Counsel: “. . . [O]ur argument is not that
[the generic] product shouldn’t be marketed or sold.”; The
Court: “Right. And I want to say that again, you’re not arguing
that it’s unsafe at all, right?”; Plaintiff’s Counsel: “I’m not
arguing that, no, Your Honor, and we have not taken that
position.”).
28
economic loss, such as Sanofi alleges here – does not constitute
irreperable harm unless the financial injury is so great as to
threaten the continued existence of the movant’s business.” Fed.
Defs.’ Opp’n Br. at 39 (citing Wisc. Gas Co. v. FERC, 758 F.2d
669 (D.C. Cir. 1985) and its progeny). The federal defendants
then explain that even though Lovenox accounted for 26% of
Sanofi’s domestic revenue in 2009, Sanofi has failed to establish
irreparable harm because “Sanofi is a global company with a broad
portfolio of prescription medicines, consumer healthcare
products, generics, and vaccines, and worldwide revenues of some
$40 billion annually.” Fed. Defs.’ Opp’n Br. at 40-41
(emphasizing that the $2.5 billion in domestic sales generated by
Lovenox in 2009 amounted to only 6% of the company’s overall
annual revenue). The federal defendants also point to several
public admissions by Sanofi, belying its claim of irreparable
harm. See Fed. Defs.’ Opp’n Br. at 41-42 and n.25.11
11
The federal defendants cite, among other things: Full Year
2009 SanofiAventis Earnings Conference Call, Full Disclosure
Wire, Feb. 10, 2010, at 14 (explaining that a substitutable
generic such as Sandoz’s ANDA “would have some impact on our 2010
numbers,” but “doesn’t really have an impact longer term”);
Interview with Chris Viehbacher, SanofiAventis Chief Executive
Officer, Q2 Results, available at http://en.sanofi-aventis.com/
events/2010_2ndQR/docs/20100729_Q2_2010_Transcript_en.pdf (“Most
of the volume that we sell is outside of the US. [Lovenox] still
remains a blockbuster product, even without the US sales.”);
Sanofi-aventis Press Release, EPS Growth in Q2 2010, July 29,
2010, available at http://en.sanofi-aventis.com/binaries/
20100729_Q2_2010_Results2_en_tcm28-29020.pdf (“Sanofi-aventis
expects business [earnings per share] for the year 2010 to be
29
While the Court finds it unlikely that Sanofi has met this
Circuit’s stringent standard for irreparable harm, the Court will
nevertheless assume that Sanofi’s unrecoverable loss of sales to
Sandoz constitutes irreparable harm. See Serono, 158 F.3d at
1326 (assuming that the plaintiff would be irreparably injured if
the FDA was not enjoined from approving an ANDA where the
plaintiff would suffer an unrecoverable loss of sales to the
generic manufacturer). As discussed below, however, the Court
finds that this factor does not weigh in favor of Sanofi because
when weighed against the harm that an injunction would inflict on
Sandoz, “that balance of harm results roughly in a draw.”
Serono, 158 F.3d at 1326; see infra Section III.C.
C. Balance of Equities
Because Sandoz has been selling and distributing its generic
enoxaparin for the last month, Sandoz would undoubtedly face
significant harm if the Court entered an interim injunction. See
Sandoz Opp’n Br. at 26-27 (explaining that “millions of doses are
already in the hands of customers and being used by patients” and
arguing that an interim injunction would cause it significant
financial harm as well as an “incalculable impact to its goodwill
and reputation with customers if [the customers] were asked to
flat to minus 4% versus 2009, at constant exchange rates, barring
major unforeseen adverse events. This guidance takes into account
the recent approval of a generic of Lovenox in the U.S. It also
incorporates the financial impact of U.S. healthcare reform and
recent EU price cuts.”).
30
stop their use of the Sandoz generic mid-stream”; noting that
Sandoz is expecting sales in the range of over $40 million in the
next six weeks alone for its generic enoxaparin). Therefore,
because whatever sales Sanofi will lose to Sandoz in the absence
of an injunction, Sandoz will lose to Sanofi in the presence of
one, the Court concludes that the harm alleged by Sanofi and the
harm faced by Sandoz are essentially “a wash.” Serono, 158 F.3d
at 1326; see also id. (quoting Delaware & Hudson Ry. Co. v.
United Transp. Union, 450 F.2d 603, 620 (D.C. Cir. 1971) for the
proposition that: “It often happens that . . . one party or the
other will be injured whichever course is taken. A sound
disposition . . . must [then] depend on a reflective and
attentive appraisal as to the outcome on the merits.”
(alterations in original)).
D. Public Interest
The last factor the Court must consider is whether the
public interest favors entry of a preliminary injunction. Sanofi
argues that an injunction should be granted because “the public
interest would be served by requiring the FDA to comply with the
law.” Pl.’s Mem. at 42. While it is undoubtedly true that the
public has an interest in governmental agencies following the
31
law, given the facts of this case, an injunction would serve the
public interest only if Sanofi is likely to succeed on the
merits. Because, however, the Court has found that Sanofi is
unlikely to establish that the FDA exceeded its authority in
granting Sandoz’s ANDA, the Court concludes that the public would
be harmed by a court-ordered delay in the distribution of a
generic drug that is approximately 30-35% cheaper than Lovenox.
Hr’g Tr. 74:9-10, Aug. 17, 2010;12 see generally AARP Amicus Br.
(arguing that interim injunctive relief would harm the public).
Accordingly, in light of the Court’s determination that Sanofi is
unlikely to succeed on the merits, and given that no parties are
challenging the safety of Sandoz’s generic enoxaparin, the Court
concludes that Sanofi has failed to establish that the public
interest favors interim injunctive relief.
IV. CONCLUSION
For the foregoing reasons, the Court DENIES Sanofi’s motion
for a preliminary injunction. This opinion does not foreclose
the possibility that upon a more developed record, Sanofi may be
able to establish that there are grounds for overturning the
grant of Sandoz’s ANDA. The Court holds only that upon the
12
Although the parties were unable to apprise the Court of the
cost of Lovenox or Sandoz’s generic enoxaparin, the Court was
informed that the cost was substantial. See Hr’g Tr. at 74:5 –
75:13. Indeed, Lovenox represents the single largest pharmacy
expenditure for most hospitals in the United States. See Sandoz
Opp’n Br. at 28.
32
current record, Sanofi has failed to establish that it meets the
criteria for the grant of a preliminary injunction. An
appropriate Order accompanies this Memorandum Opinion.
SIGNED: Emmet G. Sullivan
United States District Court Judge
August 25, 2010
33