Takeda Pharmaceuticals U.S.A., Inc. v. West-Ward Pharmaceutical Corp. ( 2015 )

United States Court of Appeals
for the Federal Circuit
______________________
TAKEDA PHARMACEUTICALS U.S.A., INC.,
Plaintiff-Appellant
v.
WEST-WARD PHARMACEUTICAL CORPORATION,
HIKMA AMERICAS INC., HIKMA
PHARMACEUTICALS PLC,
Defendants-Cross-Appellants
______________________
2015-1139, 2015-1142
______________________
Appeals from the United States District Court for the
District of Delaware in No. 1:14-cv-01268-SLR, Judge Sue
L. Robinson.
______________________
Decided: May 6, 2015
______________________
JEFFREY I. WEINBERGER, Munger, Tolles & Olson LLP,
Los Angeles, CA, argued for plaintiff-appellant. Also
represented by TED G. DANE, ELIZABETH LAUGHTON; ERIC
KELVIN CHIU, AMY GREYWITT, San Francisco, CA; MARY
W. BOURKE, Womble, Carlyle, Sandridge & Rice, PLLC,
Wilmington, DE; TRYN T. STIMART, Tysons Corner, VA .
2 TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC.
CHARLES B. KLEIN, Winston & Strawn LLP, Washing-
ton, DC, argued for defendants-cross appellants. Also
represented by JOVIAL WONG, STEFFEN NATHANAEL
JOHNSON; SAMUEL S. PARK, Chicago, IL; WILLIAM G.
JAMES, II, WILLIAM M. JAY, Goodwin Procter LLP, Wash-
ington, DC.
EDWARD A. MARSHALL, Arnall Golden Gregory LLP,
Atlanta, GA, for amicus curiae The American College of
Rheumatology.
MELISSA ARBUS SHERRY, Latham & Watkins LLP,
Washington, DC, for amicus curiae Generic Pharmaceuti-
cal Association.
______________________
Before NEWMAN, DYK, and HUGHES, Circuit Judges.
Opinion for the court filed by Circuit Judge DYK.
Dissenting opinion filed by Circuit Judge NEWMAN.
DYK, Circuit Judge.
Takeda Pharmaceuticals U.S.A., Inc. (“Takeda”) ap-
peals the order of the United States District Court for the
District of Delaware denying its motion for preliminary
injunction. Takeda sought to enjoin West-Ward Pharma-
ceutical Corporation, Hikma Americas Inc., and Hikma
Pharmaceuticals PLC (collectively “Hikma”) from continu-
ing its launch of Mitigare, a colchicine product for prophy-
lactic treatment of gout, and from launching an
authorized generic version of Mitigare. We affirm.
TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC. 3
BACKGROUND
Takeda owns several asserted patents 1 that cover
several methods of administering colchicine products to
treat gout. Colchicine itself, which has been used for
centuries, is not covered by Takeda’s patents. The ’647
and ’938 patents (the “acute gout patents”) are directed to
methods of treating acute gout flares. The ’655, ’648 and
’722 patents (the “drug-drug-interaction (DDI) patents”)
are directed to methods for administering colchicine for
prophylaxis of gout in patients who are concomitantly
taking certain drug inhibitors known as “CYP3A4” and
“P-gp” inhibitors.
The acute gout patents recite methods of treating
acute gout by administering 1.2 mg of oral colchicine at
the onset of the flare, followed by 0.6 mg of colchicine
about one hour later.
DDI patent ’655 recites administering colchicine con-
comitantly with clarithromycin by reducing the typical
prophylactic dosage of colchicine by 75%, including a dose
of 0.3 mg once a day. DDI patent ’648 recites concomitant
administration with ketoconazole, where the reduced
daily dose of colchicine is 25% to 50% of the daily dose,
including a dose of 0.3 mg once a day. DDI patent ’722
recites concomitant administration with 240 ml of vera-
pamil, where the reduced daily dose of colchicine is 50% to
75% of the daily dose.
In 2009, Mutual was the first drug manufacturer to
receive approval from the Food and Drug Administration
(“FDA”) to market colchicine for treatment and prophylax-
1 The asserted patents are U.S. Patent Nos.
7,964,648 (“the ’648 patent”), 7,981,938 (“the ’938 pa-
tent”), 8,097,655 (“the ’655 patent”), 8,440,722 (“the ’722
patent”), and 7,964,647 (“the ’647 patent”).
4 TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC.
is of gout flares. Takeda acquired Mutual and the ap-
proved New Drug Application (“NDA”). Takeda sells the
colchicine product under the brand name Colcrys.
In 2010, Hikma sought FDA approval of a colchicine
product for prophylaxis of gout flares. It submitted an
NDA under § 505(b)(2) of the Drug Price Competition and
Patent Term Restoration Act of 1984 (the “Hatch-
Waxman Act”), codified at 21 U.S.C. § 355(b)(2). On
September 26, 2014, the FDA granted Hikma approval to
market its Mitigare colchicine capsule.
On October 3, 2014, Hikma launched Mitigare, and
Takeda filed suit against Hikma, asserting induced
infringement under 35 U.S.C. § 271(b) based on Hikma’s
labeling of the Mitigare product. Hikma planned on
launching an authorized generic version of Mitigare as
early as October 10, 2014. However, the district court
granted Takeda’s request for a temporary restraining
order (“TRO”) on October 9, 2014, restraining Hikma from
selling Mitigare and from launching a generic colchicine
product. The district court also restrained Takeda from
launching an authorized generic version of its branded
Colcrys product during the TRO and required that
Takeda “provide notice to Hikma at least 10 business
days before the launch of any authorized generic of Col-
crys.” J.A. 20.
On November 4, 2014, the district court denied
Takeda’s motion for preliminary injunction on the
grounds that Takeda did not meet its burden of showing a
likelihood of success on the merits for its induced in-
fringement claims or irreparable injury. On the issue of
the likelihood of success on the merits, the district court
concluded that, although Hikma failed to raise a substan-
tial question regarding the validity of the patents, Takeda
had not met its burden of showing likelihood of proving
induced infringement. On the issue of irreparable harm,
TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC. 5
the district court concluded that Takeda had not shown a
causal nexus between Hikma’s infringement and Takeda’s
alleged harm.
In the order denying a preliminary injunction, the
court also ordered that, if Takeda took an immediate
appeal (the next day), “the status quo [would] be main-
tained pending appeal” by extending the TRO, including
its 10-day notice provision. J.A. 16–17.
Takeda timely appealed the denial of preliminary in-
junction, and Hikma cross-appealed. In its cross-appeal,
Hikma argues that the extension of the TRO was based
solely on its “consent,” and it should not have been ex-
tended past oral argument in this appeal. After oral
argument on January 9, 2015, we issued, without dissent,
an order affirming the district court’s denial of prelimi-
nary injunction and vacating the TRO, including its 10-
day notice provision. 2 Our order mooted Hikma’s cross-
appeal and Takeda’s argument that the 10-day notice
provision in the TRO was improper. Our vacating of the
order did not affect Takeda’s liability under the bond. We
have jurisdiction pursuant to 28 U.S.C. § 1292(c).
2 The order stated:
The district court’s order denying Takeda
Pharmaceuticals U.S.A., Inc.’s motion for prelim-
inary injunction is affirmed, opinion to follow.
The injunction pending appeal ordered by the
district court is vacated effective immediately.
The consequence of vacating the injunction pend-
ing appeal is that both parties are free to imme-
diately offer colchicine products for prophylactic
use, without regard to the 10-day provision of the
district court’s order.
6 TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC.
DISCUSSION
We review a denial of a preliminary injunction for
abuse of discretion. Abbott Labs. v. Sandoz, Inc., 544 F.3d
1341, 1345 (Fed. Cir. 2008) (citing Doran v. Salem Inn,
422 U.S. 922, 932 (1975)). A court abuses its discretion if
it “ma[kes] a clear error of judgment in weighing relevant
factors or exercise[s] its discretion based upon an error of
law or clearly erroneous factual findings.” Id. (quoting
Novo Nordisk of N. Am., Inc. v. Genentech, Inc., 77 F.3d
1364, 1367 (Fed. Cir. 1996)).
In general, a party seeking a preliminary injunction
must establish that it is likely to succeed on the merits,
that it is likely to suffer irreparable harm in the absence
of relief, that the balance of equities is in its favor, and
that an injunction is in the public interest. See Titan Tire
Corp. v. Case New Holland, Inc., 566 F.3d 1372, 1375–76
(Fed. Cir. 2009).
I
The relevant statutory provisions here are in the
Hatch-Waxman Act. The Hatch-Waxman Act allows
generic manufacturers to rely on certain streamlined FDA
approval processes by which generic drug manufacturers
can bring their products to market without submitting all
of the extensive drug and clinical data ordinarily required
of an NDA under 21 U.S.C. § 355(b)(1). In particular, an
applicant seeking approval to market a generic version or
variant of a drug may file either an Abbreviated New
Drug Application (“ANDA”) or a “505(b)(2) application,”
sometimes called a “paper NDA.” Id. §§ 355(b)(2), (j). An
ANDA allows applicants seeking approval for generic
versions of existing drugs to rely on the safety and effica-
cy information for an approved drug listed in the Ap-
proved Drug Products with Therapeutic Equivalence
Evaluations, or the “Orange Book.” A paper NDA allows
applicants seeking approval for a new drug or a change to
TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC. 7
an approved drug to rely on existing FDA findings of
safety and effectiveness or studies not performed by the
NDA applicant.
Both the ANDA and paper NDA pathways generally
require applicants to submit one of several kinds of patent
certifications, see id. §§ 355(j)(2)(A)(vii)(I)-(IV),
355(b)(2)(A)–(B), including a “Paragraph IV” certification
that the relevant patents are either invalid or not in-
fringed, which may in turn trigger patent litigation under
the artificial act of infringement created by 35 U.S.C.
§ 271(e)(2)(A). See §§ 355(j)(2)(A)(vii)(IV),
355(b)(2)(A)(iv); Eli Lilly & Co. v. Medtronic, Inc., 496
U.S. 661, 675 (1990).
Here Colcrys was an FDA-approved drug, and Hikma
elected to file a paper NDA pursuant to 21 U.S.C.
§ 355(b)(2). Hikma did not, however, file a Paragraph IV
certification with respect to Takeda’s patents because it
relied on prior FDA findings of safety and efficacy con-
cerning colchicine, and did not seek FDA approval for a
use covered by Takeda’s patents. As Takeda concedes,
“[a]dministering colchicine for prophylaxis of gout flares is
not covered by Takeda’s asserted patents, except when it
involves concomitant administration with certain other
drugs.” Appellant’s Br. 4 n.1.
As we explained in Warner-Lambert Co. v. Apotex
Corp., 316 F.3d 1348 (Fed. Cir. 2003), Congress intended
“that a single drug could have more than one indication
and yet that [an] ANDA applicant could seek approval for
less than all of those indications.” Id. at 1360. A patent
certification such as a Paragraph IV certification need not
be provided “for a patent claiming a use for which the
ANDA applicant is not seeking approval.” Id. at 1361; see
21 U.S.C. § 355(j)(2)(A)(viii); Caraco Pharm. Labs. v. Novo
Nordisk A/S, 132 S. Ct. 1670, 1677 (2012); see also 21
U.S.C. §§ 355(b)(2)(A)(i)–(iv), (b)(2)(B) (parallel provisions
8 TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC.
in the paper NDA process). In such a situation, a generic
manufacturer may avoid infringement by proposing a
label that does not claim a patented method of use, Cara-
co, 132 S. Ct. at 1676–77, ensuring that “one patented use
will not foreclose marketing a generic drug for other
unpatented ones,” id. at 1682.
II
With this statutory scheme in mind, we address the
question of whether Takeda showed a likelihood of suc-
cess on the merits of the induced infringement claim.
Such likelihood is not shown if an alleged infringer raises
a substantial question regarding either infringement or
validity of the asserted patents. See Genentech, Inc. v.
Novo Nordisk A/S, 108 F.3d 1361, 1364 (Fed. Cir. 1997).
A
We first consider induced infringement with respect to
the acute gout patents. Since Hikma did not seek FDA
approval to market Mitigare for treatment of acute gout
flares, Mitigare’s label stated that Mitigare is “indicated
for prophylaxis” and that the “safety and effectiveness of
[it] for acute treatment of gout flares during prophylaxis
has not been studied.” J.A. 138. The label also said that
“[i]f you have a gout flare while taking [Mitigare], tell
your healthcare provider.” J.A. 148. Takeda argued that
this latter statement induced infringement because, in
the case of the patient taking Mitigare for prophylaxis,
the physician would likely tell the patient to use the
Mitigare product to treat the acute flare. The district
court concluded that the latter instruction was not suffi-
cient to establish induced infringement. We agree.
“Whoever actively induces infringement of a patent
shall be liable as an infringer.” 35 U.S.C. § 271(b). “[The]
sale of a lawful product by lawful means, with the
knowledge that an unaffiliated, third party may infringe,
TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC. 9
cannot, in and of itself, constitute inducement of in-
fringement.” Dynacore Holdings Corp. v. U.S. Philips
Corp., 363 F.3d 1263, 1276 n.6 (Fed. Cir. 2004) (internal
quotation marks and citation omitted). The accused
infringer must have “knowingly aided and abetted” direct
infringement. Warner-Lambert, 316 F.3d at 1363 (cita-
tions omitted).
As the Supreme Court held in the analogous context
of copyright infringement, there is no indirect infringe-
ment “when a defendant merely sells a commercial prod-
uct suitable for some lawful use.” Metro-Goldwyn-Mayer
Studios Inc. v. Grokster, Ltd., 545 U.S. 913, 936 (2005)
(citing Water Techs. Corp. v. Calco, Ltd., 850 F.2d 660,
668 (Fed. Cir. 1988)). Infringement only exists where
there is evidence that “goes beyond a product’s character-
istics or the knowledge that it may be put to infringing
uses.” Id. at 935. Inducement can be found where there is
“[e]vidence of active steps taken to encourage direct
infringement,” which can in turn be found in “advertising
an infringing use or instructing how to engage in an
infringing use.” Id. at 936 (citations and internal quota-
tion marks omitted). 3 But such instructions need to
3 We have specifically approved Grokster’s defini-
tion in the patent context. See Ricoh Co., Ltd. v. Quanta
Computer Inc., 550 F.3d 1325, 1341 (Fed. Cir. 2008)
(noting that “we turn to Grokster and its analysis of the
law of active inducement,” quoting Grokster, and stating
that inducement requires evidence of promotion, active
steps, or encouragement). Well before Grokster, we had
adopted a virtually identical test. For example, in Water
Technologies (a patent case cited approvingly by the
Supreme Court in Grokster in its analysis of inducement,
see 545 U.S. at 936), we noted that inducement requires
“actively . . . aiding and abetting another’s direct in-
10 TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC.
evidence “intent to encourage infringement.” Vita-Mix
Corp. v. Basic Holding, Inc., 581 F.3d 1317, 1329 (Fed.
Cir. 2009) (emphasis added). The question is not just
whether instructions “describ[e] the infringing mode,”
Toshiba Corp. v. Imation Corp., 681 F.3d 1358, 1365 (Fed.
Cir. 2012) (distinguishing Fujitsu Ltd. v. Netgear Inc., 620
F.3d 1321 (Fed. Cir. 2010)), but whether the “instructions
teach an infringing use of the device such that we are
willing to infer from those instructions an affirmative
intent to infringe the patent,” Vita-Mix, 581 F.3d at 1329
n.2 (emphasis added). Merely “describ[ing],” Toshiba, 681
F.3d at 1365, an infringing mode is not the same as
“recommend[ing],” id., “encourag[ing],” Grokster, 545 U.S.
at 930, or “promot[ing],” Metabolite Labs., Inc. v. Lab.
Corp. of Am. Holdings, 370 F.3d 1354, 1365 (Fed. Cir.
2004), an infringing use, or suggesting that an infringing
use “should” be performed, see Arthrocare Corp. v. Smith
& Nephew, Inc., 406 F.3d 1365, 1377 (Fed. Cir. 2005)
(finding inducement where instruction manuals indicated
product should be used in infringing manner).
fringement.” Water Techs., 850 F.2d at 668 (emphasis
added); see also Warner-Lambert, 316 F.3d at 1364 (“In
the absence of any evidence that Apotex has or will pro-
mote or encourage doctors to infringe the neurodegenera-
tive method patent, there has been raised no genuine
issue of material fact [as to inducement]” (emphases
added)); Tegal Corp. v. Tokyo Electron Co., 248 F.3d 1376,
1378–79 (Fed. Cir. 2001) (explaining that inducement
requires an “affirmative act,” including that which “caus-
es, or urges, or encourages, or aids another to infringe a
patent” (citation omitted)); Manville Sales Corp. v. Para-
mount Sys., Inc., 917 F.2d 544, 553 (Fed. Cir. 1990) (in-
ducement requires “intent to encourage another’s
infringement”).
TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC. 11
The principles that can be distilled from these cases
are applicable in the Hatch-Waxman Act context where,
as here, it is alleged that the drug label induces infringe-
ment by physicians. The label must encourage, recom-
mend, or promote infringement. See Grokster, 545 U.S. at
936; Toshiba, 681 F.3d at 1365; Metabolite, 370 F.3d at
1365. The mere existence of direct infringement by physi-
cians, while necessary to find liability for induced in-
fringement, is not sufficient for inducement. As we stated
in Warner-Lambert in the ANDA context, it is well-
established that “mere knowledge of possible infringe-
ment by others does not amount to inducement; specific
intent and action to induce infringement must be proven.”
316 F.3d at 1364 (citation omitted).
This requirement of inducing acts is particularly im-
portant in the Hatch-Waxman Act context because the
statute was designed to enable the sale of drugs for non-
patented uses even though this would result in some off-
label infringing uses. See Caraco, 132 S. Ct. at 1681–82
(“Congress understood [that] a single drug may have
multiple methods of use, only one or some of which a
patent covers” and that the statute “contemplates that
one patented use will not foreclose marketing a generic
drug for other unpatented ones.”); Warner-Lambert, 316
F.3d at 1359 (the Hatch-Waxman Act was not intended
“as a sword against any competitor’s ANDA seeking
approval to market an off-patent drug for an approved use
not covered by the patent”).
Takeda concedes that mere knowledge of off-label in-
fringing uses of Mitigare’s product would not establish
inducement. Similarly insufficient is Hikma’s knowledge,
acquired from the FDA, that colchicine is used to treat
acute gout flares. The FDA has previously told healthcare
providers to prescribe Colcrys for acute gout flares, and
the FDA told Hikma that “it may be natural for the
provider to use [Mitigare] for acute treatment.” Appel-
12 TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC.
lant’s Br. 37. So too the guidelines from the American
College of Rheumatology (“ACR”) that recommend pre-
scribing Colcrys for acute gout flares are irrelevant to the
question of inducement. All of this, without more, is mere
knowledge of infringing uses and does not establish
inducement.
But Takeda argues that Mitigare’s label, though indi-
cated only for prophylaxis of gout, induces infringement
by stating that “[i]f you have a gout flare while taking
Mitigare, tell your healthcare provider,” J.A. 148. Alt-
hough this is neither an explicit nor implicit instruction to
take Mitigare for acute gout treatment, Takeda argues
that the instruction to “tell your healthcare provider” will
“inevitably” lead to physicians who are consulted to advise
patients taking Mitigare for prophylaxis to simply in-
crease their dose of Mitigare to treat acute gout flares,
and that Hikma was aware of or willfully blind to this
possibility. Hikma argues that the label’s statement that
the “safety and effectiveness” of Mitigare “for acute
treatment of gout flares during prophylaxis has not been
studied” bars a finding of inducement, relying on Bayer
Schering Pharma AG v. Lupin, Ltd., 676 F.3d 1324 (Fed.
Cir. 2012). We need not address whether or not lack of
approval language precludes a finding of inducement.
Given the statutory scheme explained above, vague
label language cannot be combined with speculation about
how physicians may act to find inducement. This would
seem to too easily transform that which we have held is
“legally irrelevant,” Warner-Lambert, 316 F.3d at 1364—
mere knowledge of infringing uses—into induced in-
fringement. 4
4 Takeda even goes so far as to suggest that the la-
bel needs to contain a “clear statement” to show that it
TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC. 13
But we need not decide whether evidence as to the in-
variable response of physicians could ever transform a
vague label into active encouragement. Here, even if we
do look outside the label, there is no evidence that the
label would necessarily lead doctors who are consulted by
patients taking Mitigare to prescribe an off-label use of it
to treat acute gout flares.
First, Takeda does not dispute that there are a host of
alternatives for treating gout flares. These alternatives
include non-steroidal anti-inflammatory drugs such as
indomethacin or naproxen and systemic and intra-
articular corticosteroids. As the 2012 ACR Guidelines for
Gout Management explain, “it is at the discretion of the
prescribing physicians to choose the most appropriate
monotherapy based on the patient’s preference, prior
response to pharmacologic therapy for an acute gout
attack, and associated comorbidities.” J.A. 387. Takeda
points to no record evidence that physicians would forego
these alternatives and simply increase the dose of Mitiga-
re when it failed to work as a prophylactic. Indeed, the
ACR says that because colchicine can cause various
adverse side effects, “[r]heumatologists rarely use colchi-
cine for acute gout flares but utilize colchicine frequently
for chronic gout prophylaxis.” J.A. 1505. Instead, non-
steroidal anti-inflammatory drugs have become the
“treatment choice for most acute attacks of gout.” Appel-
lee’s Br. 32.
was avoiding gout flare indication, and that Hikma needs
to “believe[] Mitigare will be used for prophylaxis only.”
Appellant’s Reply Br. 12. This turns the legal test on its
head. Takeda needs to show that Hikma took affirmative
steps to induce, not affirmative steps to make sure others
avoid infringement.
14 TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC.
Second, even with respect to physicians who would
prescribe colchicine for the acute gout flares, there is
insufficient evidence that doctors would inevitably pre-
scribe Mitigare. Evidence that colchicine is prescribed for
acute gout flares says nothing about whether Mitigare
would be so prescribed. Takeda argues that, where the
physician prescribes colchicine for an acute gout flare, it
would be “impractical” for a patient already taking colchi-
cine for prophylaxis not to “reach for the colchicine they
have on hand” and follow Takeda’s patented methods.
Appellant’s Reply Br. at 5. Takeda also suggested that it
is “common sense” that doctors would prescribe Mitigare
for an infringing use because it is already available on the
shelf of the patient taking it for prophylaxis. But in
Warner-Lambert, we already rejected the argument that
it was “common knowledge” in the field that physicians
routinely prescribe approved drugs for off-label uses, that
information regarding the off-label prescriptions was
“readily available” to the public, and that generic drugs
are “commonly substitute[d]” for branded drugs. 316 F.3d
at 1364; see also ACCO Brands, Inc. v. ABA Locks Mfr.
Co., 501 F.3d 1307, 1312–13 (Fed. Cir. 2007) (rejecting the
argument that infringement can be found because a
“natural and intuitive way to employ” the accused product
was infringing).
Attempting to bridge this evidentiary deficit, Takeda
also submitted physicians’ declarations allegedly showing
what physicians would do when patients consult them
about acute gout flares. One of Takeda’s physician
declarations stated that “[e]ven though the [Mitigare]
label states that the product has not been tested for use in
treating gout flares, [he] believe[s] treating physicians
would encourage patients to use Mitigare for this pur-
pose” anyway because “in [his] experience, physicians will
not recommend that a patient suffering a gout flare have
two very similar colchicine products, i.e., Colcrys and
TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC. 15
Mitigare, on hand.” J.A. 2658–59 (emphasis added). The
other declarant stated that he would “understand” that
either Colcrys or Mitigare “could be used with equal
effectiveness for the indications for which the other drug
is approved,” and that “[b]ecause the Mitigare product
label does not provide a low-dose regimen for treating
acute flares . . . [he] expect[s] that some doctors would
consult the Colcrys product label to inform a patient using
Mitigare to take colchicine according to the low-dose
regimen specified in the Colcrys label.” J.A. 99. Takeda
contends that these declarations establish a “likelihood
that some prescribers would practice the claimed method.”
Appellant’s Br. 36.
Speculation or even proof that some, or even many,
doctors would prescribe Mitigare for acute flares is hardly
evidence of inevitability. This evidence does not show
anything more than that there may be some infringing
uses of Mitigare. 5
Finally, Takeda relies heavily on Astrazeneca LP v.
Apotex, Inc., 633 F.3d 1042 (Fed. Cir. 2010), to argue that
the label induces infringement. The asserted method
claims there covered treating respiratory diseases such as
asthma by administering “a nebulized dose” of
budesonide, i.e., an anti-inflammatory corticosteroid
5 One declaration also stated that, “for a patient
suffering a new or recurring acute gout attack, the patient
will reach for his colchicine and follow the Colcrys low-
dose regimen.” J.A. 2659. This evidence does not suggest
physicians would prescribe Mitigare in accordance with
Colcrys’ product label when consulted by patients. In fact,
it seems to indicate something that undermines Takeda’s
argument: that a physician believes that patients will
simply ignore Mitigare’s label instructing them to consult
their physician and use the drug off-label themselves.
16 TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC.
suspended in a liquid to be inhaled, at a frequency of “not
more than once per day.” Id. at 1048. An accused infring-
er’s label for a generic version of such an asthma inhaler
instructed patients to take the drug “twice daily in divid-
ed doses” for a total daily dose of 0.5 mg, and that pa-
tients should “downward-titrate to the lowest effective
dose.” Id. at 1057. Because the label stated that the
lowest available dose was a 0.25 mg vial, titrating down
required going down from taking 0.25 mg twice a day to
taking it once a day. Id. Thus the patient did not have to
consult anything outside of the label to infringe. The
instruction would “necessarily lead” to infringement. Id.This, we explained, was enough for “active steps” taken to
“encourage” direct infringement. Id. at 1059. Here, in
contrast, Takeda asks us to look outside the label to
understand the alleged implicit encouragement in the
label, even while it admits that evidence of mere
knowledge of infringing uses is not sufficient.
The district court correctly concluded that Takeda did
not establish a probability of success on the issue of
infringement.
B
Takeda’s arguments with respect to the DDI patents
are similarly insufficient to support a finding of induce-
ment. The Mitigare label warns patients that co-
administration of colchicine and certain inhibitors “have
been reported to lead to colchicine toxicity,” that drug-
drug interactions must thus “be considered prior to and
during therapy,” and that concomitant use “should be
avoided if possible.” J.A. 137. The label also warns that if
co-administration “is necessary, the dose of Mitigare
should be reduced and the patient should be monitored
carefully for colchicine toxicity.” Id. At one point the label
also suggests that if co-administration is necessary, “the
dose . . . should be adjusted by either reducing the daily
TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC. 17
dose or reducing the dose frequency.” J.A. 140. Takeda
argues that this language constitutes inducement because
a healthcare provider will have to determine whether co-
administration is “necessary,” and the physician would
then follow the patented methods. Takeda submitted
declarations in which a physician hypothesized that he
would “typically” follow Takeda’s patented methods if it
was necessary to co-administer colchicine and medications
“such as” the relevant inhibitors. J.A. 100.
Noting that this label language failed to recommend
or suggest to physicians that the patented DDI methods
should be followed, the district court found that, in any
case, there was insufficient evidence “that any healthcare
provider has actually practiced the methods of the DDI
patents,” J.A. 13. The district court concluded that
Takeda did not even meet its burden to show likelihood of
direct infringement, which is a prerequisite for indirect
infringement. See Ricoh, 550 F.3d at 1341.
With respect to the ’655 and ’648 patents requiring a
0.3 mg dose of colchicine, the district court found that
Mitigare would not likely be used to directly infringe
because it comes in 0.6 mg capsules that cannot feasibly
be split to reach a 0.3 mg dose of colchicine per day.
Takeda argues that the capsules can be taken every other
day to reach an average of 0.3 mg per day, citing in par-
ticular the language in Mitigare’s label that warned
patients to “either reduc[e] the daily dose or reduc[e] the
dose frequency” if concomitant administration is neces-
sary. But the district court found that, given that colchi-
cine has a “narrow therapeutic index” whereby the
margin between an effective dose and a toxic dose is
narrow, this possibility was not likely. In any case, as
Hikma argues, given that Mitigare’s label recites a 0.6 mg
“once or twice daily” recommendation and a “maximum
dose” recommendation, J.A. 137, it is natural to read
“reducing the dose frequency” as just instructing reducing
18 TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC.
0.6 mg from twice daily to once daily and not to achieve
the 0.3 mg dose by administering 0.6 mg every other day.
The district court’s findings on this issue were not clearly
erroneous.
With respect to the ’722 patent, which requires 0.6 mg
of colchicine concomitantly administered with 240 ml of
verapamil, the district court found that Takeda cited
insufficient evidence this method would actually be prac-
ticed. While Takeda points out that it submitted evidence
that 240 ml was the “usual” dose of verapamil, we see no
clear error in the district court’s finding that this was
insufficient, especially since the issue is whether the
concomitant administration occurs, and Hikma’s physi-
cian experts declared that they try to and can easily avoid
concomitant administration of the drugs. 6 Since there was
insufficient proof of direct infringement here, we need not
reach the question of whether there was evidence of
inducement.
CONCLUSION
We conclude that the district court did not abuse its
discretion in denying a preliminary injunction on the
ground that Takeda had failed to meet its burden to show
a likelihood of success on the merits. Because of our
disposition, we need not reach Takeda’s other arguments.
The main appeal is:
AFFIRMED
The cross-appeal is:
6 The fact that one doctor said that he has pre-
scribed colchicine concomitantly with the inhibitors is not
evidence that other doctors would do the same, nor is it
evidence of direct infringement since he did not speak of
using Mitigare.
TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC. 19
DISMISSED AS MOOT
COSTS
Costs to Hikma.
United States Court of Appeals
for the Federal Circuit
______________________
TAKEDA PHARMACEUTICALS U.S.A., INC.,
Plaintiff-Appellant
v.
WEST-WARD PHARMACEUTICAL CORPORATION,
HIKMA AMERICAS INC., HIKMA
PHARMACEUTICALS PLC,
Defendants-Cross-Appellants
______________________
2015-1139, 2015-1142
______________________
Appeals from the United States District Court for the
District of Delaware in No. 1:14-cv-01268-SLR, Judge Sue
L. Robinson.
______________________
NEWMAN, Circuit Judge, dissenting.
This is not a simple question of the legal status of pa-
tented uses of unpatented drugs. This is a legal policy
issue, for the patent law implements a complex balance
between the incentive to develop new medicinal treat-
ments in the public interest, while facilitating competition
after patent expiration.
The product colchicine has been used to treat gout for
centuries, but was known to have highly toxic side effects.
Takeda discovered and developed modes of treatment at
reduced toxicity. Takeda took these methods and prod-
ucts through clinical trials and FDA approval, and ob-
2 TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC.
tained patents on the treatment methods. My colleagues
hold that none of these patents is enforceable against
Hikma, a new provider of colchicine.
It is agreed that Hikma is not a direct infringer of the
Takeda patents, and my colleagues hold that Hikma does
not induce infringement because the official Hikma “la-
bel” does not contain directions to use colchicine in ac-
cordance with the Takeda patented uses. Takeda argued
that it suffices that the Hikma label directs patients to
tell a health care provider if the affliction of acute gout
flares arises, because the health care provider will pre-
scribe the Takeda method of use. My colleagues hold that
such circumstance cannot produce induced infringement.
In my view, these events do not produce a simple,
bright line rule of law. In this preliminary injunction
proceeding, the parties produced conflicting evidence as to
the prevalence of gout flares and the likelihood that a
doctor would prescribe the patented Takeda treatments.
Precedent is also conflicting if generalized to all circum-
stances. In Toshiba Corp. v. Imation Corp., 681 F.3d
1358, 1364 (Fed, Cir. 2012), this court held that “[t]he
existence of a substantial non-infringing use does not
preclude a finding of inducement.” But in Warner-
Lambert Co. v. Apotex Corp., 316 F.3d 1348, 1366 (Fed.
Cir 2002) this court said that “[w]here a product has
substantial noninfringing uses, intent to induce infringe-
ment cannot be inferred even when [the accused infring-
er] has actual knowledge that some users of its product
may be infringing the patent.”
The panel majority today adopts a rule that induce-
ment cannot be found, whatever the facts of the particular
medicament and use. That is seriously flawed, for the
variety of medicinal situations is unlimited. In turn, the
public interest in new uses, new methods, and new com-
bination treatments is disserved by a rule that is a disin-
TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC. 3
centive to the development of new uses of unpatented
medicinal products.
Thus I dissent from the court’s ruling that the provid-
er of a known drug product, with knowledge that it is
likely to be used in direct infringement, can never be
liable for induced infringement. These are fact-specific
circumstances, and are not amenable to final disposition
at a preliminary injunction hearing. The question re-
quires trial on the facts of this case.
DISCUSSION
The panel majority presents an incomplete picture of
the facts and the law and ignores the public interest in
the development of improved methods of treatment.
Although colchicine is a known gout treatment,
Takeda, through its predecessor Mutual, developed new
treatment protocols for acute gout flares, conducted
clinical trials, including treatment for patients concomi-
tantly taking other drugs, and secured FDA approval for
safety and efficacy of specified dosages and combinations
and schedule of administration. This information is
included on the FDA-approved Takeda label, and omitted
from the Hikma label.
Hikma provides colchicine capsules in the same 0.6
mg dosage as the Takeda approved product, but the FDA
permitted Hikma to omit from its label the combinations
and acute flare treatment method patented by Takeda.
Instead, the Hikma label instructs users that if acute gout
flares arise, “tell your healthcare provider.” 1
1 The FDA initially objected to this omission from
the Hikma label, stating that “If Mitigare is being used
for prophylaxis, it may be natural for the provider to use
it for acute treatment as well.” Hikma then added to its
label that Mitigare was not “studied” for “safety and
4 TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC.
Takeda argues that the Hikma label statement is an
inducement to infringe, providing testimony from physi-
cians that they would tell the patient to use the Takeda
protocol. Hikma provided contrary testimony. My col-
leagues on this panel hold that it is “not sufficient for
inducement” that physicians and patients would directly
infringe the Takeda patents. Maj. Op. at 11. To the
contrary, it is highly relevant, for this situation does not
lend itself to a rigid, all-purpose rule of law. This should
be a fact-dependent, case-by-case determination based on
evidence of likelihood and intent for the particular unpat-
ented drug and patented new use.
The panel majority goes too far, and states a general
rule that provides easy avoidance of patents on new uses
and improvements. The Hatch-Waxman Act is intended
to encourage drug research and development, not to
provide a disincentive by negating enforcement of im-
provement patents by the simple expedient of omitting
the improvement from the label. With the removal of the
patent incentive for improvements, the loser is the afflict-
ed public.
The panel majority is incorrect in stating that “in the
Hatch-Waxman Act context . . . . [t]he label must encour-
age, recommend, or promote infringement.” Maj. Op. at
11 (citing Metro-Goldwyn-Mayer Studios Inc. v. Grokster,
Ltd., 545 U.S. 913, 936 (2005). The FDA label is not a
vehicle of promotion of any use; it is a record of approved
safety and efficacy of the product as used in accordance
with the label. Nor does the FDA “aid and abet” in-
fringement by including approved uses on the label.
Grokster is a copyright case, and although there is com-
mon law commonality in the word “inducement,” ques-
tions of intent and scienter are as fact-specific in the
effectiveness” of treatment of acute gout flares. On this
statement, the FDA withdrew its objection.
TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC. 5
copyright field as in connection with patents. An over-
simplified analogy between copyright and patent causes
does not aid understanding of these complex issues.
The panel majority also appears to misunderstand the
Hatch-Waxman Act. The majority says “the statute was
designed to enable the sale of drugs for non-patented uses
even though this would result in some off-label infringing
uses,” Maj. Op. at 11, citing purported authority in Cara-
co Pharm. Labs., Ltd. v. Novo Nordisk A/S, 132 S. Ct.
1670, 1681-82 (2012); Warner-Lambert, 316 F.3d at 1359.
That is a misreading of statute and precedent. The
Hatch-Waxman Act is not designed to enable off-label
uses, whether or not they are infringing.
The cited cases do not hold otherwise. To the contra-
ry, Warner-Lambert states that “‘[I]f there are indications
which are claimed by any use patent and for which the
[ANDA] applicant is not seeking approval, then an ANDA
must state that the applicant is not seeking approval for
those indications which are claimed by such use patent.’”
316 F.3d at 1359 (quoting House Report No. 98-857).
Takeda argues that the Hikma label, which mentions
acute gout flares but advises afflicted persons to see a
physician instead of reciting the FDA-approved protocol,
suffices to induce infringement. Unlike the facts of Warn-
er-Lambert, Takeda is not “asserting patents on unap-
proved uses,” 316 F.3d at 1359. It is infringement of the
approved patented uses that Takeda states is induced by
instructing the patient to tell a doctor in the event of
acute flares. Takeda offered evidence that the physician
is likely to prescribe the Takeda protocol and dosage for
treatment of acute flares. Resolution of the question of
inducement depends on the facts of the case. However,
the panel majority rejects even the need for such resolu-
tion, stating that “we need not decide whether evidence as
to the invariable response of physicians could ever trans-
6 TAKEDA PHARMACEUTICALS U.S.A. v. HIKMA AMERICAS INC.
form a vague label into active encouragement.” Maj. Op.
13. To the contrary: that is the issue of this case.
The trier of fact must have the opportunity to consider
the evidence of how particular uses are made known and
implemented for the Hikma product. The panel majority
misstates my argument, for I do not propose that liability
for inducement is automatic. Here, Hikma instructs that
if acute flares arise, “tell your healthcare provider”; and
Takeda presented evidence that the doctor is likely to
prescribe the Takeda protocol, for that protocol is ap-
proved by the FDA and is known to physicians who treat
gout. The panel majority errs in discarding all this as
irrelevant, for the knowledge and extent and likelihood of
infringement are highly relevant to whether infringement
is deemed induced.
These aspects warrant full development of fact and
law, and thoughtful application to this case.