Endo Pharmaceuticals Inc. v. Teva Pharmaceuticals USA, Inc. ( 2018 )

NOTE: This disposition is nonprecedential.
United States Court of Appeals
for the Federal Circuit
______________________
ENDO PHARMACEUTICALS INC., GRUNENTHAL
GMBH,
Plaintiffs-Cross-Appellants
v.
TEVA PHARMACEUTICALS USA, INC., ACTAVIS
INC., ACTAVIS SOUTH ATLANTIC LLC, WATSON
PHARMACEUTICALS, INC., AMNEAL
PHARMACEUTICALS OF NEW YORK, LLC,
ROXANE LABORATORIES, INC., AMNEAL
PHARMACEUTICALS, LLC, THORX
LABORATORIES, INC., BARR LABORATORIES,
INC., RANBAXY, INC., RANBAXY
PHARMACEUTICALS, INC., SUN
PHARMACEUTICAL INDUSTRIES, LTD., IMPAX
LABORATORIES, INC.,
Defendants-Appellants
______________________
2015-2021, 2015-2022, 2015-2023, 2015-2024, 2015-2025,
2015-2026, 2015-2028, 2015-2031, 2015-2033, 2015-2034,
2015-2035, 2015-2041, 2015-2042, 2015-2046, 2015-2047,
2015-2049, 2015-2059, 2015-2060, 2016-1025, 2016-1060,
2016-1117, 2016-1118
______________________
Appeals from the United States District Court for the
Southern District of New York in Nos. 1:12-cv-08060-
TPG-GWG, 1:12-cv-08115-TPG-GWG, 1:12-cv-08317-TPG-
2 ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS
USA, INC.
GWG, 1:12-cv-08985-TPG-GWG, 1:13-cv-00435-TPG-
GWG, 1:13-cv-00436-TPG-GWG, 1:13-cv-03288-TPG, 1:13-
cv-04343-TPG, 1:13-cv-08597-TPG, Senior Judge Thomas
P. Griesa.
______________________
Decided: May 16, 2018
______________________
MARTIN JAY BLACK, Dechert LLP, Philadephia, PA,
argued for plaintiff-cross-appellant Endo Pharmaceuticals
Inc. Also represented by SHARON K. GAGLIARDI; BLAKE
GREENE, Austin, TX; JONATHAN LOEB, Mountain View,
CA; ROBERT RHOAD, Princeton, NJ.
JOHN C. O’QUINN, Kirkland & Ellis LLP, Washington,
DC, argued for all defendants-appellants. Defendant-
appellants Actavis Inc., Actavis South Atlantic LLC,
Watson Pharmaceuticals, Inc. also represented by
WILLIAM H. BURGESS; JAMES F. HURST, Chicago, IL;
CHARLES A. WEISS, NICHOLAS P. CHIARA, HOWARD S. SUH,
ERIC H. YECIES, Holland & Knight, LLP, New York, NY.
CHARLES E. LIPSEY, Finnegan, Henderson, Farabow,
Garrett & Dunner, LLP, Reston, VA, for plaintiff-cross-
appellant Grunenthal GMBH. Also represented by
KRISTA E. BIANCO, JENNIFER HOWE ROSCETTI, ERIN
MCGEEHAN SOMMERS, Washington, DC.
JACOB M. HOLDREITH, Robins Kaplan LLP, Minneap-
olis, MN, for defendants-appellants Amneal Pharmaceuti-
cals of New York, LLC, Amneal Pharmaceuticals, LLC.
Also represented by BRENDA L. JOLY, JAMIE R. KURTZ;
OREN D. LANGER, New York, NY.
ELIZABETH HOLLAND, Goodwin Procter LLP, New
York, NY, for defendants-appellants Barr Laboratories,
ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS 3
USA, INC.
Inc., Teva Pharmaceuticals USA, Inc. Also represented
by BRIAN ROBINSON, HUIYA WU.
MAUREEN L. RURKA, Winston & Strawn LLP, Chicago,
IL, for defendants-appellants Impax Laboratories, Inc.,
Thorx Laboratories, Inc. Also represented by GEORGE C.
LOMBARDI, KEVIN E. WARNER; SCOTT R. SAMAY, New York,
NY.
WILLIAM R. ZIMMERMAN, Knobbe, Martens, Olson &
Bear, LLP, Washington, DC, for defendants-appellants
Ranbaxy Pharmaceuticals, Inc., Ranbaxy, Inc., Sun
Pharmaceutical Industries, Ltd. Also represented by
CAROL PITZEL CRUZ, Seattle, WA.
ALAN B. CLEMENT, Locke Lord LLP, New York, NY,
for defendant-appellant Roxane Laboratories, Inc. Also
represented by HUGH S. BALSAM, SCOTT B. FEDER, MYOKA
KIM GOODIN, Chicago, IL.
______________________
Before MOORE, BRYSON, and HUGHES, Circuit Judges.
HUGHES, Circuit Judge.
Endo Pharmaceuticals Inc. and Grünenthal GmbH
sued generic drug manufacturers under the Hatch-
Waxman Act in the U.S. District Court for the Southern
District of New York, alleging infringement of, among
other patents, U.S. Patent Nos. 8,309,122 B2 and
8,329,216 B2. 1 These patents relate to a controlled re-
1 We grant the motions to voluntarily dismiss ap-
peal nos. 15-2022, 15-2023, 15-2025, 15-2028, 15-2033, 15-
2034, 15-2035, 15-2041, 15-2042, 15-2047, 15-2049, 15-
2059, 15-2060, and 16-1118.
Earlier, we granted Grünenthal’s motion to stay ap-
peal nos. 15-2021, 15-2022, 15-2024, 15-2025, 15-2026, 15-
4 ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS
USA, INC.
lease formulation of the painkiller opioid oxymorphone.
The generic drug manufacturers argued generally that
the asserted patents’ claims were invalid or not infringed.
The district court rejected those arguments and found all
asserted claims of the ’122 and ’216 patents not invalid,
and all but two asserted claims infringed. Because there
is no reversible error in the district court’s findings, we
affirm.
I
A
Endo holds the approved new drug application for
OPANA®ER, a controlled release formulation of the
painkiller opioid oxymorphone. Endo also owns the ’122
and ’216 patents, each reciting a controlled release formu-
lation of oxymorphone suitable for twelve-hour dosing and
claimed to cover OPANA®ER. 2
2028, 15-2031, and 15-2033, pending action by the U.S.
Food and Drug Administration related to Endo’s con-
trolled release crush resistant formulation of the painkill-
er opioid oxymorphone. Grünenthal now requests that we
maintain the stay until 30 days after the pending FDA
action has completed. We have granted Endo’s request to
voluntarily dismiss its appeals, so Grünenthal’s request
for a continued stay is applicable only as to appeal nos.
15-2021, 15-2024, 15-2026, and 15-2031. Because the
generic drug manufacturers party to those appeals repre-
sent that they have withdrawn their abbreviated new
drug applications, we exercise our discretion to lift the
stay and dismiss appeal nos. 15-2021, 15-2024, 15-2026,
and 15-2031, but do so without prejudice. We thus do not
address Grünenthal’s arguments or its patents in this
opinion.
2 The two patents essentially have a common speci-
fication. The ’122 patent issued from the U.S. Patent
ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS 5
USA, INC.
Generic manufacturers Amneal Pharmaceuticals of
New York, LLC, Amneal Pharmaceuticals LLC, Impax
Laboratories, Inc., ThoRx Laboratories, Inc., Ranbaxy,
Inc., Ranbaxy Pharmaceuticals, Inc., Sun Pharmaceutical
Industries, Ltd., and Roxane Laboratories, Inc. (collective-
ly, Amneal) as well as Actavis Inc., Actavis South Atlantic
LLC, Teva Pharmaceuticals USA, Inc., Barr Laboratories,
Inc., Watson Pharmaceuticals, Inc. (collectively, Actavis)
filed abbreviated new drug applications (ANDAs) with the
U.S. Food and Drug Administration, seeking its approval
to market generic versions of OPANA®ER. 3 Endo then
sued them for infringement of the ’122 and ’216 patents,
asserting four claims of the ’122 patent and sixteen claims
of the ’216 patent during a consolidated bench trial.
B
The asserted claims of the two patents generally re-
cite the following categories of limitations:
(1) A “dissolution” or “release rate” limitation, which
describes the release of oxymorphone at a specified rate
and is measured using the “USP Paddle Method at 50
rpm in 500 ml media.” See, e.g., ’122 patent, col. 26 l. 59–
col. 27 l. 7.
(2) A pharmacokinetic limitation, which describes
how OPANA®ER tablets affect the human body once
Application No. 11/680,432. Unsurprisingly, both the ’432
application and the ’216 patent trace priority to the same
parent application. The ’432 application was also the
subject of an earlier appeal here. See In re Huai-Hung
Kao, 639 F.3d 1057, 1061–63, 1065–70, 1074 (Fed. Cir.
2011).
3 At the time the district court decided this case,
the FDA had approved Actavis’s ANDA for a generic
version of OPANA®ER, and Actavis had been actively
marketing that generic.
6 ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS
USA, INC.
ingested—where the limitation can be further grouped
into four broad subcategories:
(a) an analgesic effect limitation, which provides that
the tablet will provide pain relief for a certain duration;
(b) a food effect limitation, which describes blood con-
centration level of oxymorphone (recited in the patents as
AUC(0-inf), area under the drug concentration-time curve
from time zero hours to infinity, or as Cmax, maximum
observed drug concentration) upon dosing of controlled
release oxymorphone in fed versus fasting conditions (the
effect refers to a patient’s physiological response to the
drug after having eaten—a pronounced food effect means
a patient experiences much higher concentrations of the
active ingredient if he has recently eaten);
(c) a detectable level limitation, which states that in-
gesting the tablets claimed in the patents will produce
detectable levels of oxymorphone and its metabolite 6-OH
oxymorphone; and
(d) a multiple peaks limitation, which describes when
and how often patients’ blood will exhibit peak concentra-
tions of oxymorphone and 6-OH oxymorphone (multiple
peaks help prevent patients from building tolerance to the
opioid).
Claim 1 of the ’216 patent includes an analgesic effect
limitation, a detectable level limitation, and a multiple
peaks limitation:
1. An oral controlled release oxymorphone formu-
lation, comprising:
a. about 5 mg to about 80 mg of oxymorphone or a
pharmaceutically acceptable salt of oxymorphone;
and
b. a hydrophilic material,
ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS 7
USA, INC.
wherein upon oral administration of the formula-
tion to a subject in need of an analgesic effect:
(i) the formulation provides detectable blood
plasma levels of 6-OH oxymorphone and oxy-
morphone;
(ii) the blood plasma levels of 6-OH oxymorphone
and oxymorphone peak within about 1 hour to
about 8 hours after administration;
(iii) the blood plasma levels of 6-OH oxymorphone
and oxymorphone exhibit a ratio of area under the
curve (AUC(0 to inf)) of blood plasma level versus
time for 6-OH oxymorphone compared to oxy-
morphone in a range of about 0.5 to about 1.5;
(iv) the duration of the analgesic effect is through
at least about 12 hours after administration; and
(v) the blood plasma levels of oxymorphone exhibit
two or three peaks within about 12 hours after
administration.
’216 patent, col. 26 ll. 35–55 (emphases added).
Claim 38, a method claim from which the asserted
claim 40 of the ’216 patent depends, exemplifies a dissolu-
tion limitation and a Cmax-related food effect limitation:
38. A method for treating pain in a human sub-
ject in need of acute or chronic pain relief, com-
prising the steps of:
(a) Providing a solid oral dosage form comprising
about 5 mg to about 80 mg oxymorphone or a
pharmaceutically acceptable salt thereof in a con-
trolled release delivery system with a release rate
profile designed to provide adequate blood plasma
levels over at least 12 hours to provide sustained
pain relief over this same period, wherein oxy-
morphone is the sole active ingredient, and where-
8 ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS
USA, INC.
in upon placement of the composition in an in
vitro dissolution test comprising USP Paddle
Method at 50 rpm in 500 ml media having a pH of
1.2 to 6.8 at 37°C., about 15% to about 50%, by
weight, of the oxymorphone or salt thereof is re-
leased from the tablet at about 1 hour in the test,
about 45% to about 80%, by weight, of the oxy-
morphone or salt thereof is released from the tablet
at about 4 hours in the test, and at least about
80%, by weight, of the oxymorphone or salt thereof
is released from the tablet at about 10 hours in the
test; and
(b) administering a single dose of the dosage form
to the subject, wherein the oxymorphone Cmax is at
least 50% higher when the dosage form is admin-
istered to the subject under fed versus fasted con-
ditions.
Id. at col. 29 l. 49–col. 30 l. 5 (emphases added).
Claim 40 of the ’216 patent depends from claim 38,
and recites an AUC-related food effect limitation: “the
difference in the oxymorphone area under the curve
AUC(0-inf) between fed and fasted conditions is less than
20%.” Id. at col. 30 ll. 10–12 (emphasis added).
Endo asserted claims 2–3 and 19–20 of the ’122 patent
against all defendants. J.A. 18. Three of the four
claims—claims 2–3 and 19—recite a dissolution limita-
tion. Claim 20 recites a food effect limitation.
Endo also asserted sixteen claims of the ’216 patent,
claims 1, 22, 40, 42, 50, 54, 57, 62, 64, 71, 73–74, 78–80,
and 82, but not all claims were asserted against all de-
fendants. J.A. 28. Fifteen of the sixteen asserted claims
recite dissolution limitations; claim 1 is the only asserted
claim without a dissolution limitation. Claims 40, 42, 50,
54, 78, 80, and 82 also recite food effect limitations.
ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS 9
USA, INC.
C
The district court concluded that the generic drug
manufacturers failed to show that the asserted claims of
the two patents are invalid. J.A. 128–29. Specifically, the
court found that the asserted claims of the two patents
are not invalid for obviousness; that the asserted claims
with the dissolution limitations are not invalid for lack of
written description; and that the asserted claims reciting
the multiple peaks limitations are not invalid for indefi-
niteness. The court also found that Endo carried its
burden to show that defendants infringe or will infringe
all but two of the asserted claims of the ’122 and ’216
patents. J.A. 72–73. The court then issued a permanent
injunction against Actavis’s manufacture, use, offer to
sell, or sale of its generic version of OPANA®ER prior to
the expiration of the ’122 and ’216 patents. J.A. 182.
Both Amneal and Actavis appeal the district court’s
conclusions on invalidity. Amneal also appeals the court’s
infringement determination, and Actavis additionally
challenges the permanent injunction against it. 4 We have
jurisdiction under 28 U.S.C. § 1295(a)(1).
II
Obviousness is a question of law that we review de
novo, and we review any underlying factual questions for
clear error. Honeywell Int’l, Inc. v. United States, 609
F.3d 1292, 1297 (Fed. Cir. 2010). “Whether a claim
satisfies the written description requirement is a question
4 Endo cross-appeals the district court’s determina-
tion that the relief Endo requested under 35 U.S.C.
§ 271(e)(4) is not warranted. But Endo conceded at oral
argument that its cross-appeal is conditional on our
vacating the district court’s grant of a permanent injunc-
tion. We affirm the district court in toto; thus, we need
not reach Endo’s cross-appeal.
10 ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS
USA, INC.
of fact that, on appeal from a bench trial, we review for
clear error.” Alcon Research Ltd. v. Barr Labs., Inc., 745
F.3d 1180, 1190 (Fed. Cir. 2014). Indefiniteness is a
question of law that we review de novo, although any
factual findings by the district court based on extrinsic
evidence are reviewed for clear error. UltimatePointer,
L.L.C. v. Nintendo Co., 816 F.3d 816, 826 (Fed. Cir. 2016).
Infringement is a question of fact that we review for clear
error. Alcon Research, 745 F.3d at 1186. “The decision to
grant or deny permanent injunctive relief is an act of
equitable discretion by the district court, reviewable on
appeal for abuse of discretion.” eBay Inc. v. Mer-
cExchange, L.L.C., 547 U.S. 388, 391 (2006).
A
Appellants first argue that the district court erred in
concluding that the asserted claims are not invalid as
obvious. We disagree. Appellants fail to carry their
burden to show, by clear and convincing evidence, that
the asserted claims would have been obvious because,
among other things, the prior art references in the record
strongly discourage a controlled release formulation of
opioids with low bioavailability, such as oxymorphone,
and, more critically, do not suggest the dissolution and
pharmacokinetic limitations recited in the asserted claims
of the ’122 and ’216 patents.
A claim is invalid if, at the time of invention, a person
having ordinary skill in the art would have found the
patented invention obvious in light of the prior art. See
35 U.S.C. § 103; 5 KSR Int’l Co. v. Teleflex Inc., 550 U.S.
5 Congress amended 35 U.S.C. § 103 in 2011 as part
of the America Invents Act (AIA). See Leahy-Smith
America Invents Act, Pub. L. No. 112-29, § 35, 125 Stat.
84, 341 (2011). References to § 103 and other sections of
Title 35 of the United States Code in this opinion refer to
ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS 11
USA, INC.
398, 415–16 (2007). A determination of obviousness is
based on underlying factual findings, including what a
prior art reference teaches, whether a person of ordinary
skill in the art would have been motivated to combine
references, and any relevant objective indicia of nonobvi-
ousness. Apple Inc. v. Samsung Elecs. Co., 839 F.3d 1034,
1047–48, 1051 (Fed. Cir. 2016) (en banc). Patents are
presumed to be valid and overcoming that presumption
requires clear and convincing evidence. 35 U.S.C.
§ 282; Microsoft Corp. v. i4i Ltd. P’ship, 564 U.S. 91, 95
(2011).
Appellants argue that the district court failed to
acknowledge that explicit disclosures in the prior art
teach the use of oxymorphone in a controlled release
formulation. They mainly rely on the following prior art
references in the record:
(1) Maloney, a published patent application that dis-
closes controlled release opioid formulations. The refer-
ence specifically discloses a dissolution profile for a
controlled release formulation containing oxycodone, an
opioid with markedly better bioavailability than oxy-
morphone, and teaches that its dosage form provides a
dissolution rate of 60–80% active agent released after 12
hours. It also lists oxymorphone as a preferred opioid for
use in its invention, alongside heroin, opium, and fenta-
nyl.
(2) Oshlack, a U.S. patent which teaches that “disso-
lution time and . . . bioavailability . . . are two of the most
significant fundamental characteristics for consideration
when evaluating sustained-release compositions.” J.A.
92. In describing suitable active ingredients, the refer-
the pre-AIA version of the statute, the version that ap-
plies here.
12 ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS
USA, INC.
ence includes opioid analgesics, listing 72 molecules
including oxymorphone, heroin, opium, and fentanyl.
(3) Penwest S-1, a registration statement on Form S-
1 filed with the U.S. Securities and Exchange Commission
in 1997 by Penwest Pharmaceuticals, which discloses that
Penwest was co-developing controlled release oxy-
morphone with Endo using Penwest’s TIMERx system.
(4) Baichwal, a U.S. patent which teaches the use of
the TIMERx system (the controlled release system Endo
used in OPANA®ER) with a wide variety of active ingre-
dients, including the analgesics aspirin, codeine, mor-
phine, dihydromorphone, and oxycodone.
(5) Cleary, a research article published in 2000 in the
“Cancer Control” journal that discloses that oxymorphone
was under development in “sustained-release” formula-
tion.
Amneal contends that the court erred by finding that
oxymorphone’s low bioavailability teaches away from
attempting a controlled release formulation. Overwhelm-
ing evidence at trial, however, supports that factual
finding. Expert testimony showed that a skilled artisan
would not have been motivated to select oxymorphone for
use in a controlled release setting because of its “excep-
tionally low bioavailability.” J.A. 98. As the district court
noted, the Oshlack reference also taught that “bioavaila-
bility is a significant, even crucial, factor in evaluating a
drug’s suitability for placement in a controlled release
vehicle.” J.A. 92. The court also observed that “[t]he
notion that low-bioavailability drugs were considered
unsuitable for extended-release formulation is reinforced
by the fact that, until Endo’s development of OPANA®ER,
there were remarkably few such examples.” J.A. 94. For
example, the existence of another low-bioavailability
drug, oxybutynin—a non-opioid analgesic, unlike oxy-
morphone—which had previously been developed into a
controlled release formulation, served to underscore “the
ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS 13
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fact that low bioavailability drugs were remarkably rare
in controlled-release settings.” J.A. 95. Indeed, “its total
absence from the expert reports of both sides, impressed
on the court that low-bioavailability drugs were, at the
time of the invention, perceived as unsuited for develop-
ment into controlled release forms.” Id. Tellingly, Appel-
lants’ own expert maintained the view that active
ingredients with poor bioavailability would not be good
candidates for controlled release dose forms. J.A. 2769.
Appellants contend that the low bioavailability of ox-
ymorphone could be addressed by increasing the dosage.
The district court did not err in rejecting that argument.
The court found, based on published research, that such
an approach “risk[ed] toxicity.” J.A. 93. As such, one of
ordinary skill in the art would have been strongly dis-
couraged from using a low bioavailability opioid like
oxymorphone as the main ingredient in a controlled
release formulation versus viable candidates such as
oxycodone with reasonably high bioavailability. See
Allergan, Inc. v. Sandoz Inc., 796 F.3d 1293, 1305 (Fed.
Cir. 2015) (explaining that the prior art teaches away
when “a person of ordinary skill, upon reading the refer-
ence, would be discouraged from following the path set
out in the reference, or would be led in a direction diver-
gent from the path that was taken by the applicant”
(quoting In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994))).
Relatedly, a skilled artisan would not have had a reason-
able expectation that beneficial results could be achieved
using a controlled release formulation of oxymorphone.
Cf. In re Merck & Co., Inc., 800 F.2d 1091, 1097 (Fed. Cir.
1986) (concluding that obviousness does not require
absolute predictability, only a reasonable expectation that
the beneficial result will be achieved).
Oxymorphone’s inclusion in Maloney’s and Oshlack’s
lists of candidate molecules does not alter this conclusion.
Those lists mention oxymorphone among a vast number of
other molecules, including drugs such as heroin, opium,
14 ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS
USA, INC.
and fentanyl, so the district court doubted that the lists
would be taken seriously as indicating suitability for
controlled release treatment. J.A. 96–98. The court
noted, for example, that fentanyl was widely understood
as suitable only for transdermal, not oral, delivery. J.A.
96–97. Given that context, the district court reasonably
found that a skilled artisan would not have viewed oxy-
morphone as suitable for a controlled release setting.
Moreover, neither Penwest S-1 nor Cleary discloses any
technical details, such as dosing interval or twelve-hour
efficacy, for achieving the claimed inventions. J.A. 3144–
45. Accordingly, a person of ordinary skill, upon reading
those references, would have been strongly discouraged
from using oxymorphone in a controlled release setting.
The district court did not clearly err in finding that the
references taught away from the claimed invention.
Actavis argues next that claim 1 of the ’216 patent,
which does not recite a dissolution limitation, claims no
more than the combination of a known drug (oxy-
morphone) with a known controlled release platform
(TIMERx), and recites pharmacokinetic observations from
the administration of the obvious combination. The
district court properly rejected that argument by crediting
expert testimony demonstrating that a comparison of two
controlled release drugs using the same controlled release
technology exhibits significantly different formulations.
J.A. 101–02; J.A. 3117–19. Although Actavis offered its
own expert testimony, the district court found Endo’s
expert testimony more persuasive. We will not disturb
the court’s weighing of the evidence.
We also reject the argument that the district court
erred in finding that no prior reference of record teaches
the dissolution limitations. The Endo patents express the
measurement of dissolution profile for controlled release
oxymorphone using the USP Paddle Method at 50 rpm.
See ’122 patent, col. 25 l. 57. But the prior art references
produced at trial measured dissolution in a different
ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS 15
USA, INC.
manner. Maloney, for instance, measured dissolution of
controlled release oxycodone using the USP Basket Meth-
od at 100 rpm. See J.A. 103. Oshlack measured dissolu-
tion using the USP Paddle Method, but did so at twice the
speed, at 100 rpm, and in nearly twice the aqueous buffer
(900 ml compared to Endo’s 500 ml of media). See id. As
the district court found, a person of ordinary skill in the
art would not have expected a correlation between results
obtained using the Paddle and Basket methods at differ-
ent speeds because a significant body of art shows no such
relationship. J.A. 104–07. In light of that finding and
because there was no way to equate the results obtained
from the different testing methods, a person of ordinary
skill in the art would not have been able to extrapolate
the dissolution limitations claimed in the ’122 and ’216
patents from the prior art.
Appellants argue further that the district court erred
by giving patentable weight to the pharmacokinetic
limitations inherent to the formulations disclosed by the
prior art. 6 The district court found that none of the prior
6 Amneal relatedly asserts that the court legally
erred by ignoring our relevant precedent in Kao in which,
according to Amneal, we examined the Maloney reference
and held, among other things, that the pharmacokinetic
limitations are “inherent” properties of oxymorphone that
add “nothing of patentable consequence.” Kao is inappo-
site for two reasons. First, as an appeal from the Board of
Patent Appeals and Interferences (BPAI), Kao involved a
less fulsome record and a different evidentiary burden for
showing obviousness. Second, the portion Amneal refer-
ences in support of its argument pertains to a different
application, not the ’432 application that issued as the
’122 patent. Indeed, Amneal glosses over our discussion
in Kao that addressed the BPAI’s factual findings related
to the ’432 application. The BPAI had found claims of the
16 ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS
USA, INC.
art references in the record discloses the analgesic effec-
tiveness of oxymorphone over a twelve-hour period; the
claimed food effect limitations; the multiple peaks in
blood concentration levels exhibited by controlled release
oxymorphone over a twelve-hour period; or the detectable
level limitations of the Endo patents. J.A. 113–15.
By arguing that the pharmacokinetic properties are
inherent in the controlled release formulation, Appellants
put the cart before the horse: Endo does not claim any
controlled release oxymorphone dosage for administration
that results in the observed pharmacokinetic properties
upon administration; it instead claims only those specific
controlled release oxymorphone dosages that are config-
ured to result in the observed pharmacokinetic properties
upon administration. In other words, Endo does not claim
any controlled release configuration of oxymorphone
dosage, rather only those which have been specifically
calibrated to produce the pharmacokinetic properties
recited in the claims—excluding those that do not exhibit
such properties. See also J.A. 111–12. Because the prior
art did not give any indication to a person of ordinary skill
that oxymorphone could have been developed into a
controlled release formulation providing effective analge-
’432 application reciting dissolution limitations obvious in
light of Maloney. See Kao, 639 F.3d at 1061–63. We
vacated and remanded, holding that the BPAI’s factual
findings in pertinent parts were unsupported by substan-
tial evidence. Id. at 1065–70, 1074. On remand, the
BPAI found the claims reciting dissolution limitations not
invalid as obvious, reasoning that “the Examiner ha[d]
not provided evidence or sound technical reasoning suffi-
cient to show that the prior art would have directed those
skilled in the art to a composition having the claimed
dissolution rate.” Ex Parte Huai-Hung Kao, 2012 WL
3307358, at *4 (B.P.A.I. Aug. 9, 2012). The ’432 applica-
tion then issued as the ’122 patent.
ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS 17
USA, INC.
sia over a twelve-hour period, the pharmacokinetic limita-
tions were neither “necessarily . . . present” nor “the
natural result of the combination of elements explicitly
disclosed by the prior art.” PAR Pharm., Inc. v. TWI
Pharm., Inc., 773 F.3d 1186, 1195–96 (Fed. Cir. 2014).
For instance, Maloney teaches the analgesic effectiveness
of a different molecule, oxycodone, but gave no indication
of oxycodone’s dosing interval. J.A. 97. It also does not
indicate the dosing interval of sustained release oxy-
morphone. Id. Indeed, the inventor of the invention
disclosed in Maloney herself acknowledged that her
patent “application provides no clinical evidence that the
formulations described in the application could be used to
deliver oxymorphone in a manner sufficient to provide 12
hours of analgesia.” J.A. 8926. The same is true of the
other prior art references, which show dissolution, and in
some instances sustained analgesia, for molecules other
than oxymorphone. J.A. 114 (citing Oshlack and
Baichwal, among other references).
Nor do any of the prior art references disclose the
claimed food effect limitations. The district court noted
that defendants made no attempt at trial to show some
teaching in the prior art of the food effect of controlled
release oxymorphone. J.A. 109. Indeed, Appellants fail to
identify any prior art that discloses developing oxy-
morphone into a controlled release formulation based on
the claimed AUC and Cmax values under fed and fasted
conditions. As the district court aptly noted,
oxymorphone, when administered in an immedi-
ate release formulation, produces a total blood
concentration (AUC) of 30% under fed conditions.
This is considerably higher than the food effect of
controlled release oxymorphone, which when tak-
en under fed conditions produces total blood con-
centration (AUC) of 20%. If the food effect of
oxymorphone was merely a result of natural pro-
cesses, then one would expect the same total blood
18 ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS
USA, INC.
concentration (AUC) after eating for both the im-
mediate release and controlled release formula-
tions.
J.A. 109–10 (citations omitted).
The district court also relied on secondary considera-
tions, which “strongly indicate[d]” the non-obviousness of
the invention. J.A. 129. Endo’s expert on commercial
success established that OPANA®ER achieved tremen-
dous sales growth since its launch. J.A. 120–21. The
expert also demonstrated a clear nexus between the
asserted claims of the two patents and the market success
of OPANA®ER. See, e.g., J.A. 2438–39. It was undisputed
that OPANA®ER embodied the asserted claims.
Endo’s expert on long-felt need separately testified
that the medical community had long sought to effectively
combat chronic pain, but the numerous immediate release
opioids on the market had a short duration of effective-
ness and often involved inconvenient routes of admin-
istration. J.A. 121, 1354–55, 1369. Moreover, after Endo
demonstrated significant growth in sales and prescrip-
tions, other companies decided to develop their own
controlled release oxymorphone products. J.A. 2419.
On balance, Appellants fail to carry their burden to
show, by clear and convincing evidence, that claims
reciting the dissolution and pharmacokinetic limitations
are fairly suggested by any prior art of record or combina-
tion thereof. The district court therefore did not err by
concluding that the asserted claims of the ’122 and ’216
patents are not invalid as obvious.
B
Appellants next argue that the district court erred by
concluding that the asserted claims of the ’122 and ’216
patents that recite the dissolution limitations are not
invalid for lack of written description in the specification.
Because the specification provides adequate support for
ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS 19
USA, INC.
the dissolution or release rate limitations recited in the
relevant claims, we disagree.
The written description requirement provides that a
patentee’s application for a patent must “clearly allow
persons of ordinary skill in the art to recognize that [he]
invented what is claimed.” Ariad Pharm., Inc. v. Eli Lilly
& Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc)
(quoting Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563
(Fed. Cir. 1991)). “[T]he test for sufficiency is whether the
disclosure of the application relied upon reasonably
conveys to those skilled in the art that the inventor had
possession of the claimed subject matter as of the filing
date.” Id.
Actavis argues that the asserted claims reciting the
dissolution limitations claim a much broader range of
release rates (15–50% of the drug after one hour, 45–80%
after four hours, and more than 80% after ten hours), but
the specification discloses much narrower ranges of
release rates (27.8–32.3% at one hour, 58.1–66.9% at four
hours, and 85.3–95.8% at ten hours) for formulations
having 12 hours of analgesic efficacy. The allegedly
expansive claims Actavis refers to in its argument—claim
1 of the ’122 patent, for instance—recite “[a]n analgesical-
ly effective controlled release pharmaceutical composition
with a twelve hour dosing interval in the form of a tablet,
comprising oxymorphone or a pharmaceutically accepta-
ble salt thereof as the sole active ingredient in the tablet .
. . .” ’122 patent, col. 26 ll. 59–63. Actavis contends that
nothing in the specification explains or supports the
dramatic extrapolation from the narrow range tested by
the inventors during the clinical trials.
Actavis, however, plucks the release rates out of the
cabined context in which the rates are disclosed: those
specific release rates reflect the results from the admin-
istration of a 20 mg oxymorphone hydrochloride dosage.
Id. at col. 10 ll. 21–64. As the district court noted, the
20 ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS
USA, INC.
specification is replete with additional examples of dosag-
es satisfying each of the claimed limitations. J.A. 126–27.
The specification clearly explains that an analgesically
effective dosage could contain as low as about 5 mg to as
high as about 80 mg of oxymorphone hydrochloride. ’122
patent, col. 4 ll. 37–39. Accordingly, Endo is entitled to
claim not just the narrower range based on a 20 mg
dosage, but a broader range based on 5 mg to 80 mg
dosage—and that is exactly what it did in the claims
reciting the dissolution limitations.
The specification also discloses several different tech-
niques for producing the oxymorphone controlled release
oral solid dosage form of Endo’s invention. See id. at
col. 5 l. 44–col. 9 l. 28. The district court found, for in-
stance, that the specification gives detailed descriptions of
the in vitro and in vivo testing methods employed by Endo
in developing the controlled release tablets. J.A. 127.
Based on such disclosures, a person of ordinary skill in
the art would recognize that Endo possessed the invention
claimed. Nothing in our controlling precedent requires
patent owners to test release rates for each dosage level
before claiming such rates in the patents. Accordingly,
the inventors chose ranges encompassing the invention
while allowing for variations, as the court correctly noted.
The district court therefore did not err by concluding
that the asserted claims of the ’122 and ’216 patents that
recite the dissolution limitations are not invalid for inad-
equate written description.
C
Appellants next argue that the district court erred in
concluding that the asserted claims that recite the multi-
ple peaks limitations are not invalid for indefiniteness.
Because the specification sufficiently describes the mean-
ing and scope of the multiple peaks limitations, we disa-
gree.
ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS 21
USA, INC.
Claims are indefinite when “read in light of the speci-
fication delineating the patent, and the prosecution
history,” they “fail to inform, with reasonable certainty,
those skilled in the art about the scope of the invention.”
Nautilus, Inc. v. Biosig Instruments, Inc., 134 S. Ct. 2120,
2124 (2014). “Even if a claim term’s definition can be
reduced to words, the claim is still indefinite if a person of
ordinary skill in the art cannot translate the definition
into meaningfully precise claim scope.” Halliburton
Energy Servs., Inc. v. M-I LLC, 514 F.3d 1244, 1251 (Fed.
Cir. 2008).
Amneal argues that claims 1, 71, and 78 of the ’216
patent are invalid for indefiniteness because the claims
recite the term “peaks,” contending that the patents
contain no explanation of how peaks should be measured
or what constitutes peaks. That argument lacks merit.
The district court noted that the specification refers to
peaks of curves drawn on charts. J.A. 29 (referencing ’216
patent, col. 12 ll. 58–67). Upon looking at the charts in
the specification, the court found a skilled artisan would
recognize a peak as occurring where blood concentration
of oxymorphone reaches a high-point before declining.
J.A. 29–30 (referencing ’216 patent, fig. 5). In fact, the
court’s definition of the term peaks is no different from
that offered by Appellants’ own expert at trial. See J.A.
1997. Amneal cannot turn their back on that simple
meaning and claim now that “‘peak’ as used in the patent
had some special meaning representing a level of some
particular sufficient magnitude,” Amneal’s Br. 68, not
apparent from the specification, which renders the term
indefinite.
Indeed, peaks are readily ascertainable as plotted in
Figure 5 of the ’216 patent based on a plain inspection.
First, that chart is plotted on the basis of specific set of
data tabulated in the specification, see ’216 patent, tbl. 5,
so each peak on the chart is tied to a numerical value of
the plasma concentration of oxymorphone specified in
22 ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS
USA, INC.
Table 5. Second, each peak is easily identifiable contex-
tually from the set of lower values adjacent to it as shown
on the chart in Figure 5. Accordingly, Appellants merely
fish for far more precision than “reasonable certainty”
requires under our precedent. See Nautilus, 134 S. Ct. at
2124; see also id. at 2123 (“[S]ome modicum of uncertainty
is the ‘price of ensuring the appropriate incentives for
innovation’ . . . .” (citation omitted)).
In sum, the district court did not err by concluding
that the asserted claims that recite the multiple peaks
limitations are not invalid for indefiniteness.
D
Appellants also argue that the district court erred in
finding that Endo showed infringement of all but two
asserted claims of the ’122 and ’216 patents. Because the
court properly credited the testimony of Endo’s expert
who relied on information on package inserts of the pro-
posed generics, we disagree.
“[T]he infringement inquiry called for by § 271(e)(2) is
‘whether, if a particular drug were put on the market, it
would infringe the relevant patent’ in the usual, non-
artificial sense.” Acorda Therapeutics Inc. v. Mylan
Pharm. Inc., 817 F.3d 755, 760 (Fed. Cir. 2016) (citations
omitted), cert. denied sub nom. Mylan Pharm. v. Acorda
Therapeutics, 137 S. Ct. 625 (2017). The inquiry therefore
focuses on a comparison of the asserted patent claims
against the ANDA product that is likely to be sold follow-
ing FDA approval. Warner-Lambert Co. v. Apotex Corp.,
316 F.3d 1348, 1365–66 (Fed. Cir. 2003) (citing Glaxo, Inc.
v. Novopharm, Ltd., 110 F.3d 1562, 1567–68 (Fed. Cir.
1997)). Infringement exists if the defendants’ product, as
described in their ANDAs, meets each and every element
of the asserted claims. Sunovion Pharm., Inc. v. Teva
Pharm. USA, Inc., 731 F.3d 1271, 1278 (Fed. Cir. 2013).
ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS 23
USA, INC.
Amneal argues that the district court erred in finding
infringement because the ANDA products do not infringe
the “food effect” limitations. But the court found that
“[d]efendants’ package inserts expressly state that their
products satisfy the AUC and Cmax limitations of the ’122
and ’216 patents.” J.A. 64–65 (citing to the package
inserts). There is no basis to disregard the information
contained on the package inserts, which are representa-
tions made to the FDA to establish that the proposed
generics possess the same characteristics, including the
food effect limitations, present in Endo’s approved prod-
ucts. Thus, the court did not clearly err by finding in-
fringement of all but two of the asserted claims of the
patents.
E
Actavis finally argues that the district court abused
its discretion by entering a permanent injunction against
the manufacture, use, offer to sell, or sale of its generic
version of OPANA®ER prior to the expiration of the ’122
and ’216 patents. Because Endo presented evidence of
irreparable harm as well as other factors supporting an
injunction, we conclude that the district court did not
abuse its discretion by enjoining Actavis.
35 U.S.C. § 283 provides that a district court may
grant an injunction “to prevent the violation of any right
secured by patent, on such terms as the court deems
reasonable.” A plaintiff seeking a permanent injunction
“must demonstrate: (1) that it has suffered an irreparable
injury; (2) that remedies available at law, such as mone-
tary damages, are inadequate to compensate for that
injury; (3) that, considering the balance of hardships
between the plaintiff and defendant, a remedy in equity is
warranted; and (4) that the public interest would not be
disserved by a permanent injunction.” eBay, 547 U.S. at
391.
24 ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS
USA, INC.
Actavis mainly argues that the district court abused
its discretion in enjoining Actavis’s original formulation of
controlled release oxymorphone because Endo presented
no evidence at trial of irreparable harm. That is inaccu-
rate. The district court found that Endo will likely suffer
irreparable harm relying on, among other things, its
subsidiary findings that: (1) Actavis’s generic version of
OPANA®ER infringed Endo’s patents; (2) Endo and
Actavis are direct competitors in the oxymorphone mar-
ket; and (3) the introduction of additional generics into
the market has led Endo to suffer past harms (losing its
market share, cutting its sales force, reducing its promo-
tional expenses, and changing its research and develop-
ment strategies)—which would continue unabated in the
absence of an injunction—and, relatedly, that Endo is also
at risk of intangible harms such as “reputational, organi-
zational, and administrative.” J.A. 178–79. Among other
evidence, the court credited trial testimony to that end.
See J.A. 1272–73; see also J.A. 1306. Indeed, “[i]t was
proper for the district court to consider evidence of past
harm” to assess irreparable injury to Endo. i4i Ltd.
P’ship v. Microsoft Corp., 598 F.3d 831, 861 (Fed. Cir.
2010), aff’d, 564 U.S. 91 (2011); see also Broadcom Corp.
v. Emulex Corp., 732 F.3d 1325, 1338 (Fed. Cir. 2013)
(“The district court determined that Broadcom and
Emulex were competitors and that Broadcom lost market
share while Emulex gained it—thus Broadcom estab-
lished irreparable harm.” (citation omitted)).
Endo relatedly demonstrated, mainly through trial
testimony, that it had to lay off its sales force, which may
damage its reputation in the market segment and make
the company less attractive to potential new hires. The
court found that such irreparable harm cannot be ade-
quately addressed without an injunction. J.A. 179–80.
Actavis, on the other hand, made no affirmative argument
that it would suffer hardship from an injunction to coun-
ter Endo’s likely hardship. J.A. 180–81. Finally, the
ENDO PHARMACEUTICALS INC. v. TEVA PHARMACEUTICALS 25
USA, INC.
court also found that public interest favors Endo’s right to
exclude others as the rightful patent owner. J.A. 181–82.
On balance, it cannot be said that the district court
abused its discretion in weighing these factors in Endo’s
favor and granting permanent injunctive relief.
III
We have considered the remaining arguments and
find them unpersuasive. Accordingly, we affirm the
district court’s final judgment on invalidity, infringement,
and permanent injunction.
AFFIRMED