United States Court of Appeals
FOR THE DISTRICT OF COLUMBIA CIRCUIT
Argued September 20, 2010 Decided November 9, 2010
No. 10-5066
ACTAVIS ELIZABETH LLC,
APPELLANT
v.
UNITED STATES FOOD AND DRUG ADMINISTRATION, ET AL.,
APPELLEES
Appeal from the United States District Court
for the District of Columbia
(No. 1:09-cv-00362)
Chad A. Landmon argued the cause for appellant. With him
on the briefs was Robert B. Greenbaum.
Andrew E. Clark, Senior Litigation Counsel, U.S.
Department of Justice, argued the cause for federal appellees.
With him on the brief were Eugene M. Thirolf Jr., Director, and
Eric M. Blumberg, Deputy Chief Counsel, U.S. Department of
Health & Human Services. R. Craig Lawrence, Assistant U.S.
Attorney, entered an appearance.
George F. Pappas, Peter O. Safir, and Emily J. Henn were
on the brief for appellee Shire Pharmaceuticals, Inc.
2
Before: BROWN, Circuit Judge, and EDWARDS and
RANDOLPH, Senior Circuit Judges.
Opinion for the Court filed by Senior Circuit Judge
RANDOLPH.
RANDOLPH, Senior Circuit Judge: This is an appeal from
the order of the district court granting summary judgment
against Actavis Elizabeth LLC. In 2007, the Food and Drug
Administration approved Vyvanse, a name-brand drug for the
treatment of attention deficit hyperactivity disorder. Two years
later, Actavis submitted an application for lisdexamfetamine
dimesylate, a generic version of the same drug. The FDA
returned Actavis’ application. It did so because it had
previously determined that Vyvanse was entitled to five years of
marketing exclusivity under the Hatch-Waxman Amendments
to the Federal Food, Drug, and Cosmetic Act. Actavis brought
this action claiming that Vyvanse was not entitled to five years
of exclusivity.
I
New drugs, including generic versions of previously
approved drugs, may not be marketed without the FDA’s
approval. Purepac Pharm. Co. v. Friedman, 162 F.3d 1201,
1201 (D.C. Cir. 1998). The approval process is governed by the
Federal Food, Drug, and Cosmetic Act, as amended by the Drug
Price Competition and Patent Term Restoration Act of 1984
(known as the “Hatch-Waxman Amendments”), Pub. L. No.
98-417, 98 Stat. 1585. So-called “new drug
applications”—required for “pioneer” drugs that have never
before received FDA approval—must be supported by full
reports of investigations showing the drug is safe and effective.
21 U.S.C. § 355(b)(1); Serono Labs., Inc., v. Shalala, 158 F.3d
1313, 1316 (D.C. Cir. 1998). The Hatch-Waxman
3
Amendments allowed generic versions of previously approved
drugs to gain approval through the submission of an
“[a]bbreviated new drug application.” 21 U.S.C. § 355(j).1
These abbreviated applications reduce the effort required to gain
marketing approval by, among other things, allowing the
applicant to rely on clinical studies submitted as part of a
previous new drug application. Id. § 355(j)(2)(A)(i)-(v); Mylan
Labs., Inc. v. Thompson, 389 F.3d 1272, 1275 (D.C. Cir. 2004).
The Hatch-Waxman Amendments also grant various
periods of marketing exclusivity to certain pioneer drugs
approved under § 355(b). The exclusivity provisions protect
these drugs from generic competition for the specified terms by
preventing the submission of abbreviated applications that refer
to them. See 21 U.S.C. § 355(j)(5)(F)(i)-(v). At issue here,
§ 355(j)(5)(F)(ii) provides that
[i]f an application submitted under subsection (b) of this
section for a drug, no active ingredient (including any ester
or salt of the active ingredient) of which has been approved
in any other application under subsection (b) of this section,
is approved after September 24, 1984, no application may
be submitted under this subsection which refers to the drug
before the expiration of five years from the date of the
approval . . ..
Id. § 355(j)(5)(F)(ii).
In addition to this five-year period, the Amendments grant
three-year exclusivity to drugs that include previously approved
active ingredients if the application for the drug “contains
1
Among other requirements, generic drugs must contain the
same active ingredients as a “listed drug” that has already received
FDA approval. See 21 U.S.C. § 355(j)(2)(A)(i)-(viii).
4
reports of new clinical investigations . . . essential to the
approval of the application and conducted or sponsored by the
applicant . . ..” Id. § 355(j)(5)(F)(iii).
The FDA has implemented these exclusivity provisions
through regulations. 21 C.F.R. § 314.108. The regulations give
five years of exclusivity for each “drug product that contains a
new chemical entity.” Id. § 314.108(b)(2). A “new chemical
entity” is “a drug that contains no active moiety that has been
approved by FDA in any other” new drug application. Id.
§ 314.108(a). “Active moiety” is defined as “the molecule or
ion, excluding those appended portions of the molecule that
cause the drug to be an ester, salt (including a salt with hydrogen
or coordination bonds), or other noncovalent derivative (such as
a complex, chelate, or clathrate) of the molecule, responsible for
the physiological or pharmacological action of the drug
substance.” Ibid. Thus, to qualify for five-year exclusivity
under § 355(j)(5)(F)(ii), an approved drug must contain no
previously approved active moieties.
In 2005, New River Pharmaceuticals, the predecessor in
interest to intervenor-defendant Shire Pharmaceuticals, sought
approval to market lisdexamfetamine dimesylate for the
treatment of attention deficit hyperactivity disorder under the
brand name Vyvanse. Vyvanse received FDA approval on
February 23, 2007. The agency determined that the drug was
entitled to a five-year period of exclusivity under its regulations.
In January 2009, Actavis submitted its abbreviated application
for the generic drug lisdexamfetamine dimesylate.2 Its
application referenced Vyvanse. The FDA returned Actavis’
2
Because the FDA returned Actavis’ abbreviated application,
it never determined whether the drug qualified for approval under
§ 355(j). For sake of simplicity, we refer to lisdexamfetamine
dimesylate as the generic version of Vyvanse.
5
application unfiled because Vyvanse’s period of market
exclusivity had not expired. See 21 C.F.R. § 314.101(e)(2).
Actavis brought this suit in the district court under the
Administrative Procedure Act, seeking to force the agency to
rescind its grant of exclusivity to Vyvanse and to accept
Actavis’ abbreviated application. In response, the agency
began its own administrative review of the matter, during which
the suit was stayed. In October 2009, the FDA affirmed its
original determination, and the case resumed. The district court
eventually granted summary judgment to the agency and Shire
on all claims.
II
A
To understand Actavis’ arguments, it is necessary briefly to
describe the chemical structure of lisdexamfetamine dimesylate,
the drug molecule in question. Lisdexamfetamine dimesylate
is a salt of lisdexamfetamine. Since, under the agency’s
regulations, salts are not considered active moieties, the
agency’s analysis centered on the lisdexamfetamine molecule
alone. Lisdexamfetamine consists of a portion of lysine, a
common amino acid, connected to dextroamphetamine. These
two parts are linked by an amide bond, a type of covalent bond
that utilizes a nitrogen atom to perform the linking function.3
What is important is that once it enters the body,
lisdexamfetamine undergoes a chemical conversion to produce
dextroamphetamine. In industry parlance, this makes
3
Covalent bonds are formed between two atoms when those
atoms share a pair of electrons. HAWLEY’S CONDENSED CHEMICAL
DICTIONARY 342 (15th ed. 2007).
6
lisdexamfetamine a “prodrug” of dextroamphetamine.4
HAWLEY’S CONDENSED CHEMICAL DICTIONARY 1043 (15th ed.
2007). Drugs containing dextroamphetamine, but not
lisdexamfetamine, had received FDA approval before New
River filed its application for Vyvanse.
B
There is little to Actavis’ argument that the award of
five-year exclusivity to Vyvanse conflicted with the FDA’s
regulations. The agency interprets its regulations to allow
five-year exclusivity for drugs containing derivative molecules
of previously approved “active moieties” when those derivative
molecules contain non-ester covalent bonds.5 As the FDA
explained in its final decision with regard to Vyvanse: “Under
FDA’s interpretation of its regulation, the active moiety of a
molecule with a non-ester covalent bond is the entire molecule,
even if the molecule includes a covalent bond to a molecule that
was itself previously an active moiety.”
An agency’s interpretation of its own regulations is entitled
to judicial deference. Mistick PBT v. Chao, 440 F.3d 503, 511
(D.C. Cir. 2006). Although a court will reject an agency’s
interpretation when it is shown to be “plainly erroneous or
inconsistent with the regulation,” Actavis has not met that
standard. Thomas Jefferson Univ. v. Shalala, 512 U.S. 504, 512
(1994); see also Office of Commc’n, Inc. v. FCC, 327 F.3d 1222,
1224-25 (D.C. Cir. 2003).
4
The parties also refer to the lisdexamfetamine molecule as
a “derivative” of dextroamphetamine.
5
An ester bond is a type of covalent bond that uses an oxygen
atom to perform the linking function.
7
The regulatory definition of “active moiety” excludes only
“those appended portions of the molecule that cause the drug to
be an ester, salt . . ., or other noncovalent derivative.” 21 C.F.R.
§ 314.108(a). When the drug molecule is not in the form of an
ester, salt, or other noncovalent derivative, the FDA treats the
entire molecule as that “responsible for the physiological or
pharmacological action of the drug substance,” and therefore a
separate “active moiety.” Ibid. Any drug that does not contain
a previously approved active moiety is entitled to five-year
exclusivity. Id. § 314.108(a), (b)(2). This leaves certain types
of prodrugs eligible for five-year exclusivity—namely, those
that are not esters, salts, or other types of noncovalent
derivatives. The FDA’s interpretation is squarely within the
language of its regulations. And since lisdexamfetamine
contains an amide bond, the FDA properly treated it as an
“active moiety” of its own.
C
Actavis spends the bulk of its briefs arguing that the FDA’s
interpretation is inconsistent with the clear meaning of the
statute. Where Actavis sees clarity we see ambiguity.
Under the Hatch-Waxman Amendments, five-year
exclusivity is granted to drugs “no active ingredient (including
any ester or salt of the active ingredient) of which” has been
approved in a prior new drug application. 21 U.S.C.
§ 355(j)(5)(F)(ii). Actavis thinks this language prevents the
FDA from granting five-year exclusivity to any drug containing
a drug molecule (such as lisdexamfetamine) that eventually
produces a previously approved drug molecule in the body. In
addition, the company believes that the FDA’s interpretation
allowing such exclusivity upends the incentive scheme created
by Congress and “eviscerates” the distinction between three- and
five-year exclusivity.
8
Actavis relies mainly on the term “active ingredient,” which
it says obligates the FDA to identify the particular drug
molecule that reaches the “site” of the drug’s action. This
molecule, Actavis argues, is necessarily the “active ingredient”
of the drug in question, regardless of the form of the molecule
before it enters the body. But there is nothing to indicate that
Congress used the term in the sense Actavis urges. The Hatch-
Waxman Amendments do not define active ingredient. The
legislative history establishes only that Congress was concerned
with providing incentives for innovation by granting five-year
exclusivity to “new chemical entities” and is silent on what
determines novelty. See 130 Cong. Rec. 24425 (1984)
(statement of Rep. Waxman).6
The word “active,” standing alone, does not get Actavis any
further. Actavis argues that by using the term “active,”
Congress was requiring the FDA to determine the particular
molecule that provides the drug’s “activity,” which it claims is
limited to the drug’s specific therapeutic effect. If this molecule
has been previously approved, then five-year exclusivity is not
warranted. But the FDA is right—or at least we have been given
no reason to doubt—that the activity of a drug cannot be
reduced to such a simple formulation. The agency has
concluded that, for certain types of prodrugs, the entire
pre-ingestion drug molecule should be deemed responsible for
6
We note that FDA has adopted different definitions of
“active ingredient” in different statutory contexts. See 21 C.F.R.
§ 210.3(b)(7); 54 Fed. Reg. 28872, 28881 (July 10, 1989). None of
these definitions accord with the “plain meaning” of “active
ingredient” urged by Actavis. In addition, the Federal Circuit has held
that “active ingredient” has a plain meaning that, if adopted, would
allow more prodrugs to attain five-year exclusivity than the FDA’s
current interpretation. See Photocure ASA v. Kappos, 603 F.3d 1372,
1376 (Fed. Cir. 2010).
9
the drug’s activity, which can include its “distribution within the
body, its metabolism, its excretion, or its toxicity.” There is no
reason to believe Congress thought differently—or thought
about it at all.
Our court has dealt with this particular language of the
Hatch-Waxman Amendments before. In Abbott Laboratories v.
Young, we held that the parenthetical “(including any ester or
salt of the active ingredient)” in § 355(j) could refer to “either
the active ingredient of the original approved drug or to the
active ingredient in the new drug.”7 920 F.2d at 987. Each side
claims support from Abbott. This is partly because the Abbott
opinion was not entirely clear about what “active ingredient”
means under § 355(j)(5)(F). At one point the Abbott opinion
referred to “active ingredient” as “the substance prior to the
introduction into the human body.” Id. at 986. But then the
court based its holding, in part, on the potential ambiguity of
that phrase. See id. at 987-88. Abbott certainly did not adopt an
interpretation of “active ingredient” that “unambiguously
foreclose[d]” the agency’s current approach. Nat’l Cable &
Telecomm. Ass’n v. Brand X Internet Servs., 545 U.S. 967, 983
(2005).
Neither does the structure or purpose of § 355(j) foreclose
the agency’s interpretation. The Hatch-Waxman Amendments
“struck a balance between expediting generic drug applications
and protecting the interests of the original drug manufacturers.”
Abbott Labs., 920 F.2d at 985. Actavis argues that the FDA’s
current approach violates the statutory scheme, which it claims
“reserves five-year exclusivity only for major innovations.”
7
Abbott dealt with another exclusivity provision, then codified
at 21 U.S.C. § 355(j)(4)(D)(i), that governed drugs approved between
January 1, 1982, and September 24, 1984. The relevant language is
identical to that in current § 355(j)(5)(F)(ii).
10
Actavis Br. 37. In this view, a drug containing a derivative
molecule such as lisdexamfetamine should be entitled, at most,
to three years of exclusivity. To buttress its claim, Actavis
offers a scenario in which drug companies such as Shire are able
to maintain never-ending periods of five-year exclusivity for
“minor” variations on already approved drug molecules simply
by adding different covalent appendages to them. Actavis Br.
42-43.
Shire is right that “Actavis’ structural arguments represent
little more than question-begging.” Shire Br. 27. In the FDA’s
view, drug derivatives such as lisdexamfetamine are “major
innovations” deserving five-year exclusivity. The FDA’s
regulations leave many types of drug derivatives eligible only
for three-year exclusivity. For example, an ester derivative of
a previously approved drug molecule remains entitled to
three-year exclusivity if the application required for its approval
“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(j)(5)(F)(iii). The FDA is
defining the line between three- and five-year exclusivity, not
eviscerating it.
Actavis’ prediction of multiple repeated periods of five-year
exclusivity for minor variations on existing drug products
assumes a view (contrary to the agency’s) of what constitutes a
minor variation. It also finds little support in reality. In the
nearly two decades since the current FDA regulations came into
effect, there is no such example, or at least none Actavis has
identified. This is hardly surprising, given the time and effort
required to gain approval under § 355(b). See Teva Pharm.,
USA, Inc., v. Leavitt, 548 F.3d 103, 104 (D.C. Cir. 2008).
Since nothing in the text, structure, purpose, or legislative
history of the statute “speaks directly to the precise question at
11
issue,” the agency’s interpretation must stand if it is reasonable.
Citizens Coal Council v. Norton, 330 F.3d 478, 481 (D.C. Cir.
2003); see also Brand X, 545 U.S. at 986.
The FDA’s policy is based on its view that drug derivatives
containing non-ester covalent bonds are, on the whole, distinct
from other types of derivative drugs such that the former are
uniquely deserving of “new chemical entity” status and the
resulting five-year exclusivity. The FDA explained its
distinction in a 1989 response to a citizens’ petition:
It has been FDA’s longstanding experience that even minor
covalent structural changes are capable of producing not
only major changes in the activity of a drug but changes
that are not readily predicted . . . . In contrast to most
changes in the covalent structure of a molecule, the
formation of a salt or a complex, or of an ester, is not
intended to, and generally cannot, alter the basic
pharmacologic or toxicologic properties of the
molecule . . ..
We are hard pressed to second-guess the FDA’s view,
especially since it “rests on the agency’s evaluations of scientific
data within its area of expertise.” Serono Labs., Inc. v. Shalala,
158 F.3d 1313, 1321 (D.C. Cir. 1998) (internal quotation marks
omitted). At best, Actavis has offered evidence that some
covalent structural changes do not alter the basic properties of
the drug in question and that some noncovalent structural
changes do. But agencies may “employ bright-line rules for
reasons of administrative convenience, so long as those rules fall
within a zone of reasonableness and are reasonably explained.”
Emily’s List v. Fed. Election Comm’n, 581 F.3d 1, 22 n.20 (D.C.
Cir. 2002). The FDA has explained that its policy is based in
part on the “difficulty in determining precisely which molecule,
or portion of a molecule, is responsible for a drug’s effects.”
12
Nothing in the record establishes that the FDA’s approach is
unreasonable. Given the complexity of the statutory regime, we
defer to the agency’s interpretation. See Cmty. Care Found. v.
Thompson, 318 F.3d 219, 225 (D.C. Cir. 2003).
III
Actavis has other arguments designed to show that the
FDA’s grant of five-year exclusivity to Vyvanse was “arbitrary
[and] capricious.” 5 U.S.C. § 706(2)(A). Primary among these
is that the Vyvanse decision was in tension with past agency
decisions, which, Actavis claims, establish that the FDA
generally followed an “activity-based” approach to five-year
exclusivity under the Hatch-Waxman Amendments. We do not
consider it necessary to go into the details of these prior
decisions. None of them rendered the FDA’s grant of
exclusivity to Vyvanse arbitrary and capricious.
The district court’s grant of summary judgment to the FDA
and to Shire is affirmed.
So ordered.