United States Court of Appeals, District of Columbia Circuit
December 12, 2016
from the United States District Court for the District of
Columbia (No. 1:15-cv-01688)
G. Saunders argued the cause for appellants. With him on the
briefs were Seth P. Waxman and Robbie Manhas.
C. Whitaker, Attorney, U.S. Department of Justice, argued the
cause for federal appellees. With him on the brief were
Benjamin C. Mizer, Principal Deputy Assistant Attorney
General, and Scott R. McIntosh, Attorney.
William M. Jay argued the cause for intervenors-appellees
Alkermes, Inc., et al. With him on the brief were Brian T.
Burgess, Andrew Kim, Sarah K. Frederick, and Christopher T.
Before: Brown and Srinivasan, Circuit Judges, and Williams,
Senior Circuit Judge.
SRINIVASAN, CIRCUIT JUDGE
Food, Drug, and Cosmetic Act affords periods of
"marketing exclusivity" to pioneering drug
products. When a drug earns a period of exclusivity, the Food
and Drug Administration must withhold approval of certain
competing drugs if various conditions are satisfied. But how
does the FDA determine if a new drug bears a sufficiently
close relationship to a pioneering drug to fall within the
latter's zone of exclusivity? This case concerns the
FDA's test for making that determination.
drugs at issue in this case are antipsychotics primarily used
to treat schizophrenia and bipolar disorder. The first drug,
manufactured by Otsuka Pharmaceutical, is called Abilify
Maintena. The second, made by Alkermes, is named Aristada.
Alkermes sought FDA approval for Aristada, Otsuka opposed the
application on the ground that Aristada's approval would
violate an ongoing period of marketing exclusivity enjoyed by
Abilify Maintena. Otsuka emphasized that both drugs
ultimately metabolize in the body into the same molecule, and
that Alkermes's application for Aristada relied in part
on studies showing the safety and efficacy of a precursor
product to Abilify Maintena. Otsuka argued that, in light of
the relationship between the two drugs, approving Aristada
would infringe on Abilify Maintena's exclusivity.
rejected Otsuka's arguments and granted approval to
Aristada. The agency relied on the fact that the two products
have different "active moieties"-roughly, active
ingredients. A drug's active moiety has long played a key
role in determining its eligibility to receive marketing
exclusivity: to be entitled to exclusivity, a drug must
either contain a previously unapproved active moiety or use
an approved moiety in a new way. In approving Aristada, the
FDA staked out the position that a drug's active moiety
not only determines its eligibility for marketing
exclusivity, but also defines the field of drugs subject to
sought judicial review, contending, among other things, that
the agency's same-moiety limitation on the scope of a
drug's marketing exclusivity conflicts with the FDCA. The
district court granted summary judgment in favor of the FDA
and Alkermes. The court concluded that the FDA's
same-moiety test is a reasonable construction of the statute
and is consistent with the agency's regulations. We agree
with the district court and affirm its decision.
a company can make a drug available for public consumption,
the FDA must approve a new drug application certifying the
drug's safety and efficacy. 21 U.S.C. § 355(a), (b).
Until 1984, all such applications were standalone
applications: applications for which the drug's proponent
either conducted, or secured a right to reference, all the
investigations used to demonstrate the drug's safety and
efficacy. See id. § 355(b)(1). As a result, a
company seeking approval of a new drug would regularly need
to reestablish the safety and efficacy of chemical compounds
used in previously approved drugs.
order to reduce the need to conduct duplicative studies, the
Drug Price Competition and Patent Term Restoration Act of
1984-better known as the Hatch-Waxman Amendments-amended the
FDCA to establish two streamlined pathways to FDA approval.
See H.R. Rep. No. 98-857, pt. 1, at 16-17 (1984).
The first abbreviated route, known as an Abbreviated New Drug
Application (ANDA), permits approval of
"bioequivalent" (e.g., generic) versions of
previously approved drugs without an independent showing of
their safety and efficacy. 21 U.S.C. § 355(j)(2)(A).
second abbreviated route, directly at issue here, enables new
drug applications for non-generic drug products to rely, in
part or in whole, on studies that "were not conducted by
or for the applicant and for which the applicant has not
obtained a right of reference" to show the applied-for
drug's safety and efficacy. Id. §
355(b)(2). That route, known as a "(b)(2)
application" due to the statutory subsection
establishing it, requires an applicant to show the propriety
of relying on the preexisting studies to demonstrate the
applied-for drug's safety and efficacy. A (b)(2)
application must also certify that sales of the applied-for
drug would not infringe upon active, valid patents for any
previously approved drugs invoked in support of the
application. Id. § 355(b)(2)(A).
Hatch-Waxman Amendments' abbreviated pathways in theory
could enable competitors to "free ride" off of the
work of innovators without having to foot the substantial
expenses associated with safety-and-efficacy testing. As a
result, the Amendments also introduced a regime of marketing
exclusivity into the FDCA.
that system, the statute grants a first-in-time innovator a
period of exclusivity during which the FDA must deny approval
of second-in-time abbreviated applications (both ANDAs and
(b)(2) applications) for drug products meeting certain
conditions. If an applicant seeking to use an abbreviated
pathway is blocked by a previously approved drug's
exclusivity, the applicant can either wait for the
exclusivity period to expire, or instead submit a standalone,
non-abbreviated application that does not rely on
any previously approved drugs.
FDCA confers marketing exclusivity under three distinct
provisions, the full text of which are set out in an appendix
to this opinion. We will adhere to the parties'
convention by referring to the three provisions as
"romanette ii, " "romanette iii, " and
"romanette iv." 21 U.S.C. §
ii, the FDCA's broadest grant of marketing exclusivity,
applies to what FDA regulations refer to as "New
Chemical Entities": drugs for which "no active
ingredient (including any ester or salt of the active
ingredient) . . . has been approved in any other
application." 21 U.S.C. § 355(c)(3)(E)(ii); 21
C.F.R. § 314.108(a). The statutory reference to a
drug's "active ingredient" captures the
drug's active moiety, which the regulations define as
"the molecule or ion . . . responsible for the
physiological or pharmacological action of the drug
substance." 21 C.F.R. § 314.3(b).
ii confers an exclusivity period of five years, during which
"no [abbreviated] application which refers to the
[first-in-time] drug" may be approved. 21 U.S.C. §
355(c)(3)(E)(ii). FDA regulations interpret exclusivity under
romanette ii to block any abbreviated application for a drug
whose active moiety is the same as the New Chemical Entity.
21 C.F.R. § 314.108(a).
iii and iv award marketing exclusivity to innovations more
modest than the introduction of a New Chemical Entity. The
exclusivity conferred by those provisions correspondingly is
more confined in scope and duration than the five-year
exclusivity afforded under romanette ii.
romanette iii, an application "for a drug, which
includes an [active moiety] that has been approved in another
application, " is entitled to three years of exclusivity
"if such application contains reports of new clinical
investigations . . . essential to the approval of the
application and conducted or sponsored by the
applicant." 21 U.S.C. § 355(c)(3)(E)(iii). In other
words, romanette iii confers exclusivity when a
pharmaceutical company obtains approval to market a
previously approved active moiety in a new formulation or for
new purposes, and doing so requires it to furnish new
clinical investigations to the FDA. With regard to the scope
of drugs affected by the three-year exclusivity period, the
FDA may not approve an abbreviated application for the same
"conditions of approval of such drug in the
[first-in-time] application." Id.
iv similarly grants a three-year exclusivity period to
applicants that "supplement" a previously approved
application if obtaining approval of the supplement requires
submitting additional reports and investigations to the
agency. Id. § 355(c)(3)(E)(iv). Romanette iv
thus applies, for instance, to companies seeking to indicate
an existing drug product for additional illnesses or
otherwise alter the product's labeling. The scope of
exclusivity encompasses abbreviated applications "for a
change approved in the supplement" to the first-in-time
drug's application. Id. As with the
scope-delimiting phrase "conditions of approval of such
drug" in romanette iii, the FDCA does not define the
precise meaning of the scope-delimiting phrase "for a
change approved in the supplement" in romanette iv.
2002, Otsuka obtained FDA approval for Abilify Tablets, an
antipsychotic drug. In the ensuing fifteen years, Otsuka has
received FDA approval for a number of additional drug
products sharing Abilify Tablets' active moiety:
aripiprazole. The formulation of aripiprazole at issue in
this case, Abilify Maintena, is taken on a monthly basis by
Tablets earned a five-year exclusivity period under romanette
ii for introducing aripiprazole as a New Chemical Entity.
Although the five-year period for Abilify Tablets lapsed
nearly a decade ago, Abilify Maintena subsequently received
two successive marketing-exclusivity periods of three years
each. The first three-year period, which expired on February
28, 2016, came under romanette iii in connection with Abilify
Maintena's initial approval. The second three-year period
remains ongoing-it expires on December 5, 2017-and was
awarded under romanette iv in connection with a supplemental
application filed by ...