Allergan, Inc. v. Sandoz Inc.

United States Court of Appeals
for the Federal Circuit
______________________
ALLERGAN, INC.,
Plaintiff-Appellee
v.
SANDOZ INC., LUPIN LTD., LUPIN
PHARMACEUTICALS, INC., HI-TECH
PHARMACAL CO., INC.,
Defendants-Appellants
______________________
2014-1275
______________________
Appeal from the United States District Court for the
Eastern District of Texas in No. 6:11-cv-00441-MHS,
Judge Michael H. Schneider.
______________________
Decided: August 4, 2015
______________________
JUANITA ROSE BROOKS, Fish & Richardson, P.C., San
Diego, CA, argued for plaintiff-appellee. Also represented
by CRAIG E. COUNTRYMAN; JONATHAN ELLIOT SINGER,
DEANNA JEAN REICHEL, Minneapolis, MN; DOUGLAS E.
MCCANN, SUSAN M. COLETTI, Wilmington, DE.
DEANNE MAYNARD, Morrison & Foerster LLP, Wash-
ington, DC, argued for defendant-appellant Sandoz Inc.
Also represented by BRIAN ROBERT MATSUI; DAVID
2 ALLERGAN, INC. v. SANDOZ INC.
CLARENCE DOYLE, ANDERS T. AANNESTAD, JAMES CEKOLA,
San Diego, CA.
WILLIAM A. RAKOCZY, Rakoczy Molino Mazzochi,
Siwik LLP, Chicago, IL, argued for defendants-appellants
Lupin Ltd., Lupin Pharmaceuticals, Inc. Also represented
by PAUL J. MOLINO, DEANNE M. MAZZOCHI, THEODORE
JOSEPH CHIACCHIO, JOHN POLIVICK.
STEVEN D. ROTH, Locke Lord, LLP, New York, NY, ar-
gued for defendant-appellant Hi-Tech Pharmacal Co., Inc.
Also represented by THOMAS J. VETTER, Lucas & Mer-
canti, LLP, New York, NY.
______________________
Before LOURIE, LINN, and HUGHES, Circuit Judges.
LOURIE, Circuit Judge.
Sandoz Inc. (“Sandoz”), Lupin Ltd. and Lupin Phar-
maceuticals, Inc. (collectively, “Lupin”), and Hi-Tech
Pharmacal Co., Inc. (“Hi-Tech”) (collectively, “the Appel-
lants”) 1 appeal from the decision of the United States
District Court for the Eastern District of Texas, following
a bench trial, which held that the claims of U.S. Patents
7,851,504 (the “ ’504 patent”), 8,278,353 (the “ ’353 pa-
tent”), 8,299,118 (the “ ’118 patent”), 8,309,605 (the “ ’605
patent”), and 8,338,479 (the “ ’479 patent”), asserted by
Allergan, Inc. (“Allergan”), were not shown to be invalid
for obviousness under 35 U.S.C. § 103, and that the
1 Watson Laboratories, Inc., Watson Pharmaceuti-
cals, Inc., and Watson Pharm, Inc. (collectively, “Watson”)
were also defendants-appellants initially. But Watson
has since been dismissed from this appeal on a joint
motion filed by Watson and Allergan. See Allergan, Inc. v.
Sandoz Inc., No. 14-1275, ECF No. 121 (Fed. Cir. Apr. 17,
2015).
ALLERGAN, INC. v. SANDOZ INC. 3
claims of the ’353 and ’118 patents were not shown to be
invalid for lack of an adequate written description under
35 U.S.C. § 112, ¶ 1. 2 Allergan, Inc. v. Sandoz Inc., No.
6:11-cv-00441, ECF No. 303, slip op. at 77, 79 (E.D. Tex.
Jan. 13, 2014) (“Opinion”). Additionally, Lupin challenges
the district court’s determination that the claims of Aller-
gan’s patents were not shown to be invalid for lack of
enablement under § 112, ¶ 1. Id. at 80–81. Hi-Tech also
challenges the district court’s finding that it infringed the
claims of the ’504, ’605, and ’479 patents literally and
under the doctrine of equivalents. Id. at 64–66. For the
reasons that follow, we affirm in all respects.
BACKGROUND
I
Glaucoma is an eye disease associated with elevated
intraocular pressure (“IOP”). Treatments that effectively
reduce IOP can slow the progression of the disease. If left
untreated, however, elevated IOP can damage the optic
nerve and lead to permanent vision loss and blindness. In
2001, the U.S. Food and Drug Administration (the “FDA”)
approved Lumigan® 0.03% (“Lumigan 0.03%”), a once-
daily topical solution developed by Allergan, for treating
open angle glaucoma and ocular hypertension. Lumigan
0.03% contains 0.03% by weight of bimatoprost and 50
parts per million (“ppm”) benzalkonium chloride (“BAK”),
among other ingredients.
Bimatoprost, the active ingredient in Lumigan 0.03%,
is a prostaglandin analog that effectively lowers IOP, but
can cause hyperemia, i.e., red eye, when administered to
2 Because the applications resulting in the patents
asserted in this case were filed before the enactment of
the Leahy-Smith America Invents Act (“AIA”), Pub. L. No.
112-29, 125 Stat. 284 (2011), we apply the pre-AIA ver-
sion of 35 U.S.C. § 103 and § 112.
4 ALLERGAN, INC. v. SANDOZ INC.
the ocular surface. One structural difference between
bimatoprost and two other prostaglandin analogs that
were approved for treating glaucoma at the time of its
approval, Xalatan® (latanoprost) and Travatan®
(travoprost), is that bimatoprost contains an amide,
instead of an ester as in latanoprost and travoprost.
Opinion at 7–8. It was understood that both latanoprost
and travoprost, but not bimatoprost, act as prodrugs of
the corresponding acids. Id.
BAK is a preservative for inhibiting bacterial growth
in ophthalmic solutions. It was known, however, that
BAK is cytotoxic and that it can damage the cells on the
ocular surface and cause undesirable side effects.
Although Lumigan 0.03% was effective at lowering
IOP, it also caused frequent and severe hyperemia. Many
patients thus stopped using it without consulting their
physicians, which led to gradual vision loss. To address
that problem, Allergan explored a number of alternative
formulations of bimatoprost and surprisingly discovered
that increasing the concentration of BAK from 50 ppm to
200 ppm significantly increased the corneal permeability
of bimatoprost. Id. at 12–13. After further research,
Allergan developed Lumigan® 0.01% (“Lumigan 0.01%”).
Lumigan 0.01% is a topical solution containing 0.01%
bimatoprost and 200 ppm BAK; otherwise, it has the
same ingredients as Lumigan 0.03%. Thus, as compared
with Lumigan 0.03%, Lumigan 0.01% has a three-fold
lower bimatoprost concentration and a four-fold higher
BAK concentration. Clinical studies showed that Lumi-
gan 0.01% has similar efficacy to Lumigan 0.03%, viz.,
IOP-lowering within 0.5 mmHg of that of Lumigan 0.03%,
but it causes less frequent and severe hyperemia than
Lumigan 0.03%. Id. at 20–21. In 2010, the FDA ap-
proved Allergan’s New Drug Application for Lumigan
0.01% for the same approved uses as Lumigan 0.03%.
ALLERGAN, INC. v. SANDOZ INC. 5
II
Allergan owns the ’504, ’353, ’118, ’605, and ’479 pa-
tents, which are all listed in the FDA’s Approved Drug
Products with Therapeutic Equivalence Evaluations
(commonly known as the “Orange Book”) as claiming
Lumigan 0.01% and its approved uses. After Allergan
received FDA-approval of Lumigan 0.01%, Sandoz, Lupin,
Hi-Tech, and Watson each submitted an Abbreviated New
Drug Application (“ANDA”) to the FDA, seeking approval
to engage in the commercial manufacture, use, importa-
tion, sale, or offer for sale of generic versions of Lumigan
0.01% prior to the expiration of the ’504, ’353, ’118, ’605,
and ’479 patents. In response, Allergan sued each of the
ANDA applicants in the United States District Court for
the Eastern District of Texas, asserting that their ANDA
filings infringed those patents. The district court consoli-
dated those actions into one case.
The asserted patents all derive from an application
filed on March 16, 2005 and share a common specifica-
tion. The patents are entitled “Enhanced Bimatoprost
Ophthalmic Solution,” ’504 patent col. 1 ll. 1–2, 3 and refer
to what is Lumigan 0.03% in the background section, id.
col. 1 ll. 34–36. The specifications of the patents describe
a composition comprising 0.005% to 0.02% bimatoprost
and 100 ppm to 250 ppm BAK, which is an aqueous liquid
“formulated for ophthalmic administration” and “useful in
treating glaucoma or ocular hypertension.” Id. col. 1
ll. 61–67. The specifications also specifically describe a
formulation comprising 0.01% bimatoprost and 200 ppm
BAK, among other formulations, as a “best mode” of the
invention. Id. col. 2 ll. 59, 64–67.
3 Because the asserted patents share an identical
specification in relevant part, we refer only to the ’504
patent when discussing the specifications of those pa-
tents.
6 ALLERGAN, INC. v. SANDOZ INC.
Additionally, the specifications disclose in vitro and in
vivo experimental data in rabbits, showing that increas-
ing the concentration of BAK from 50 ppm to 200 ppm
significantly increased the permeability of bimatoprost
across ocular membranes. Id. col. 4 ll. 10–58, col. 5 l. 19–
col. 6 l. 5, Figs. 1 & 2. Finally, in a constructive example,
the specifications describe the once-daily ophthalmic
administration to a glaucoma patient of a formulation
containing 0.015% bimatoprost, 125 ppm BAK, and
0.015% EDTA, stating that “intraocular pressure drops
more and less hyperemia is observed than would be
observed for [a formulation containing 0.03% bimatoprost
and 50 ppm BAK,]” and “[l]owered intraocular pressure
persists for as long as the treatment continues.” Id. col. 6
ll. 7–14.
Allergan asserted the following claims against each of
the ANDA applicants: claim 2 of the ’504 patent; claim 15
of the ’479 patent; claims 1, 6, 10, and 12 of the ’605
patent; claims 1, 7, and 8 of the ’353 patent; and claims 1,
7, and 8 of the ’118 patent (collectively, “the asserted
claims”). Those claims collectively are directed to compo-
sitions comprising bimatoprost and BAK and methods of
using them to treat glaucoma or to lower IOP.
Each of the asserted claims requires a composition
comprising 0.01% bimatoprost and 200 ppm BAK. Claim
2 of the ’504 patent, claim 15 of the ’479 patent, and
claims 1, 6, 10, and 12 of the ’605 patent (collectively, “the
Group I claims”) further require the composition to have a
pH of “about 7.3.” Claims 1, 7, and 8 of the ’353 patent
and claims 1, 7, and 8 of the ’118 patent (collectively, “the
Group II claims”) do not contain such a pH limitation, but
they require a particular clinical profile of the claimed
composition as compared to a composition comprising
0.03% bimatoprost and 50 ppm BAK.
Claim 2 of the ’504 patent is representative of the
Group I composition claims and reads as follows:
ALLERGAN, INC. v. SANDOZ INC. 7
2. A composition having a pH of about 7.3 which
comprises about 0.01% bimatoprost, about 200
ppm benzalkonium chloride, citric acid monohy-
drate, a phosphate buffer, and NaCl wherein said
composition is an aqueous liquid which is formu-
lated for ophthalmic administration.
Id. col. 6 ll. 21–25 (emphases added).
Claim 1 of the ’605 patent is representative of the
Group I method claims and reads as follows:
1. A method of lowering elevated intraocular
pressure in a patient with open-angle glaucoma or
ocular hypertension which comprises applying to
the eyes of the patient an aqueous solution com-
prised of: about 0.01% w/v bimatoprost; about 200
ppm benzalkonium chloride; the solution
having a pH of about 7.3; a phosphate buffer; and
water.
’605 patent col. 5 ll. 47–55 (emphases added).
As indicated, the Group II claims all contain clinical
profile limitations. Claims 1, 7, and 8 of the ’353 patent
are directed to compositions and read as follows:
1. A first composition administered once daily for
lowering intraocular pressure in a person with
glaucoma or ocular hypertension, the first compo-
sition comprising about 0.01% w/v bimatoprost
and about 0.02% w/v benzalkonium chloride,
wherein the first composition lowers intraocular
pressure and results in less hyperemia as com-
pared to the once daily administration of a second
composition comprising 0.03% w/v bimatoprost
and 0.005% w/v benzalkonium chloride.
7. A first composition administered once daily for
lowering intraocular pressure in a person with
glaucoma or ocular hypertension, the first compo-
8 ALLERGAN, INC. v. SANDOZ INC.
sition comprising about 0.01% w/v bimatoprost
and about 0.02% w/v benzalkonium chloride,
wherein the first composition lowers intraocular
pressure without a substantial reduction in the in-
traocular pressure lowering benefit provided by
the once daily administration of a second composi-
tion comprising 0.03% w/v bimatoprost and
0.005% w/v benzalkonium chloride.
8. The composition of claim 7 wherein the once
daily administration of the first composition re-
sults in less hyperemia as compared to the once
daily administration of the second composition.
’353 patent col. 5 ll. 48–56, col. 6 ll. 3–15 (emphases
added). 4 Claims 1, 7, and 8 of the ’118 patent are directed
to methods of treatment; they contain the same clinical
profile limitations as those in claims 1, 7, and 8 of the ’353
patent. ’118 patent col. 5 ll. 48–56, col. 6 ll. 3–16.
III
The district court held a five-day bench trial in July
2013 on the issues of obviousness and infringement. The
defendants also argued that the claims were invalid for
lack of written description and enablement in pre- and
post-trial briefings. In January 2014, the court rendered
its findings of fact and conclusions of law on all of those
issues.
a.
The district court concluded that the asserted claims
would not have been obvious in view of the cited prior art,
which included: (1) U.S. Patent 5,688,819 (“Woodward”);
(2) U.S. Patent 6,933,289 (“Lyons”); (3) Laibovitz et al.,
Comparison of the Ocular Hypotensive Lipid AGN 192024
4 The parties agree that 0.02% w/v corresponds to
200 ppm, and 0.005% w/v corresponds to 50 ppm.
ALLERGAN, INC. v. SANDOZ INC. 9
with Timolol, 119 Archives of Ophthalmology 994 (2001)
(“Laibovitz”); (4) Abelson et al., How to Handle BAK Talk,
Rev. of Ophthalmology, Dec. 2002, at 52–54 (“Abelson”);
(5) Lee et al., Review: Topical Ocular Drug Delivery:
Recent Developments and Future Challenges, 2 J. Ocular
Pharmacology 67 (1986) (“Lee”); (6) Camber et al., Factors
Influencing the Corneal Permeability of Prostaglandin F2α
and Its Isopropyl Ester In Vitro, 37 Int’l J. Pharmaceutics
27 (1987) (“Camber”); (7) Higaki et al., Estimation and
Enhancement of In Vitro Corneal Transport of S-1033, a
Novel Antiglaucoma Medication, 132 Int’l J. Pharmaceu-
tics 165 (1996) (“Higaki”); and (8) Keller et al., Increased
Corneal Permeability Induced by the Dual Effects of
Transient Tear Film Acidification and Exposure to Ben-
zalkonium Chloride, 30 Experimental Eye Res. 203 (1980)
(“Keller”).
Specifically, with respect to the scope and content of
the prior art, the district court found that: (1) ophthalmic
formulation was unpredictable, and it was not a field with
a finite number of identified and predictable solutions,
Opinion at 29–31; (2) Laibovitz and Lyons both taught
that reducing bimatoprost from 0.03% to 0.01% would
result in less IOP-lowering efficacy, id. at 31–34;
(3) Laibovitz also taught that reducing bimatoprost from
0.03% to 0.01% would not result in less hyperemia, and
Lyons did not suggest the contrary, id. at 34–35; (4) the
cited prior art, including Higaki, Camber, Lee, Keller, and
Abelson, as well as Xalatan® (latanoprost), which contains
200 ppm BAK, did not teach that high concentrations of
BAK would enhance the corneal permeability of bimato-
prost, a neutral prostaglandin amide analog; instead, the
prior art suggested that BAK would decrease the permea-
bility of a neutral prostaglandin analog, id. at 35, 38–47;
and (5) the prior art taught that BAK should be mini-
mized in ophthalmic formulations due to its toxicity, and,
in particular, taught away from using 200 ppm BAK in a
bimatoprost formulation because BAK was known to
10 ALLERGAN, INC. v. SANDOZ INC.
cause side effects, including increased IOP, hyperemia,
and dry eye, making it unsuitable for chronic use at high
concentrations, id. at 47–54.
The district court then found that there would not
have been a reason to pursue the claimed invention or a
reasonable expectation of success if it were pursued. Id.
at 55–56. The court also found evidence of long-felt need,
unexpected results, and commercial success supporting a
conclusion of nonobviousness. Id. at 56–59. The court
specifically found that it was unexpected that Lumigan
0.01% would reduce the incidence and severity of hypere-
mia, as compared to Lumigan 0.03%, while maintaining
IOP-lowering efficacy, and that it was also unexpected
that 200 ppm BAK would enhance the permeability of
bimatoprost to such an extent so as to allow the reduction
of the bimatoprost concentration from 0.03% to 0.01%
without loss of efficacy. Id. at 57–58.
In view of those factual findings, the district court
concluded that the asserted claims would not have been
obvious. Id. at 74. In reaching that conclusion, the court
emphasized that the prior art taught away from the
claimed invention because it taught “(1) that bimatoprost
lost efficacy as its concentration decreased; (2) that BAK
had no impact on bimatoprost’s permeability; and (3) that
BAK was cytotoxic and could cause corneal disorders,
therefore encouraging the elimination or reduction in the
concentration of BAK.” Id. at 74–75.
The district court also rejected the defendants’ argu-
ment raised in post-trial briefings that our decision in
Galderma Laboratories, L.P. v. Tolmar, Inc., 737 F.3d 731(Fed. Cir. 2013), compels a conclusion of obviousness in
this case. The defendants argued that Woodward dis-
closed a formulation comprising 0.001%–1% bimatoprost
and 0–1000 ppm BAK for treating glaucoma, and that the
amounts of bimatoprost and BAK in the claimed formula-
tion fall within those prior art ranges, thus rendering the
ALLERGAN, INC. v. SANDOZ INC. 11
claims obvious. The district court reasoned that “Allergan
has met its burden of producing rebuttal evidence, i.e.,
‘that (1) the prior art taught away from the claimed
invention; (2) there were new and unexpected results
relative to the prior art; or (3) there are other pertinent
secondary considerations.’” Opinion at 75 (quoting Gal-
derma, 737 F.3d at 738). The court again emphasized
that the prior art taught away from 200 ppm BAK, noting
that the defendants’ own expert, Dr. Samples, had serious
concerns about BAK and strongly warned against its use.
Id. at 75–76. The court also emphasized that the unex-
pected results were “of a different kind, not just of differ-
ent degree.” Id. at 76 (emphases in original).
The district court thus concluded that the defendants
failed to prove by clear and convincing evidence that the
asserted claims would have been obvious. Id. at 77.
b.
The district court also rejected the defendants’ inva-
lidity challenges based on the written description and
enablement requirements, which they raised only in pre-
and post-trial briefings. Id. at 77–81. The court noted
that the defendants “did not present any evidence or
argument” on those issues at trial. Id. at 77, 79.
Specifically, the defendants alleged that the Group II
claims, which recite clinical profile limitations, were
invalid for lack of an adequate written description. The
district court found, however, that the patents explicitly
describe the formulation of Lumigan 0.01%, and that
Lumigan 0.01% has the clinical profile recited in the
Group II claims. Id. at 78. The court also found addition-
al support in the titles of the patents, the disclosed in
vitro and in vivo permeability data of bimatoprost, as well
as the constructive example comparing the IOP-lowering
efficacy and hyperemia profile of a test formulation to
that of Lumigan 0.03%. The court therefore found that
the Group II claims have adequate written description
12 ALLERGAN, INC. v. SANDOZ INC.
support, “especially given the express disclosure that
Lumigan 0.01% is an example of the best mode of the
invention.” Id. The court additionally reasoned that the
inventors had possession of the claimed invention because
a clinical protocol prepared in November 2004, before the
March 2005 application filing date, describes the formula-
tion of Lumigan 0.01% and the later-claimed clinical
profile. Id. at 79.
Lupin also alleged that the asserted claims were inva-
lid for lack of enablement. The district court rejected that
argument, reasoning that Allergan’s patents disclose the
formulation of Lumigan 0.01% and that the patents’
disclosure would enable one of ordinary skill in the art to
make and use the claimed invention without undue
experimentation. Id. at 80–81.
c.
The district court also found that each of the ANDA
products infringed each of the asserted claims. Relevant
to this appeal, the court found that Hi-Tech’s ANDA
product infringed the Group I claims, which require the
claimed composition to have a pH of “about 7.3.” Before
trial, the parties agreed to construe a “pH of about 7.3” as
a “pH of approximately 7.3,” and the court adopted that
construction. Allergan, Inc. v. Sandoz Inc., No. 6:11-cv-
00441, 2013 WL 139350, at *9 (E.D. Tex. Jan. 10, 2013).
Hi-Tech’s ANDA specified that its proposed product has a
pH of 6.8–7.2 during the product’s shelf life. Opinion at
27. After considering the evidence presented at trial, the
court found that Hi-Tech’s ANDA product literally in-
fringed the Group I claims. Id. at 64. The court also
found, in the alternative, that Hi-Tech’s ANDA product
infringed the Group I claims under the doctrine of equiva-
lents. Id. at 64–66.
Accordingly, the district court entered final judgment
of infringement and no invalidity. The Appellants timely
ALLERGAN, INC. v. SANDOZ INC. 13
appealed to this court; we have jurisdiction under 28
U.S.C. § 1295(a)(1).
DISCUSSION
Following a bench trial, we review a district court’s
conclusions of law de novo and its findings of fact for clear
error. Golden Blount, Inc. v. Robert H. Peterson Co., 365
F.3d 1054, 1058 (Fed. Cir. 2004). A factual finding is
clearly erroneous if, despite some supporting evidence, we
are left with a definite and firm conviction that a mistake
has been made. United States v. U.S. Gypsum Co., 333
U.S. 364, 395 (1948); Alza Corp. v. Mylan Labs., Inc., 464
F.3d 1286, 1289 (Fed. Cir. 2006).
Furthermore, patents are presumed to be valid and
overcoming that presumption requires clear and convinc-
ing evidence. 35 U.S.C. § 282; Microsoft Corp. v. i4i Ltd.
P’ship, 564 U.S. __, 131 S. Ct. 2238, 2242 (2011).
I
We first consider the Appellants’ arguments contend-
ing that the district court erred in concluding that the
asserted claims would not have been obvious.
A patent claim is invalid as obvious if an alleged in-
fringer proves that the differences between the claimed
subject matter and the prior art are such that the subject
matter as a whole would have been obvious at the time of
invention to a person having ordinary skill in the art. 35
U.S.C. § 103(a) (2006). Obviousness is ultimately a
question of law premised on underlying issues of fact,
including: (1) the scope and content of the prior art;
(2) the level of ordinary skill in the pertinent art; (3) the
differences between the claimed invention and the prior
art; and (4) objective evidence, such as commercial suc-
cess, long-felt need, and the failure of others. KSR Int’l
Co. v. Teleflex Inc., 550 U.S. 398, 427 (2007); Graham v.
John Deere Co., 383 U.S. 1, 17–18 (1966); Monarch Knit-
14 ALLERGAN, INC. v. SANDOZ INC.
ting Mach. Corp. v. Sulzer Morat GmbH, 139 F.3d 877,
881 (Fed. Cir. 1998).
The Appellants argue that the district court erred as a
matter of law by requiring them to establish a motivation
to pursue the claimed formulation by modifying Lumigan
0.03% and a reasonable expectation of success in doing so.
According to the Appellants, because the claimed amounts
of bimatoprost and BAK fall within prior art ranges, the
proper obviousness inquiry should focus only on teaching
away, unexpected results, and other objective indicia.
The Appellants also assert that the district court applied
an incorrect standard for teaching away because it merely
found that the prior art taught that the claimed formula-
tion would be inferior, rather than that it would not work.
And they argue that the prior art does not teach away
from 0.01% bimatoprost or 200 ppm BAK. They assert,
moreover, that there are no unexpected results because
the observed results of similar efficacy and less hyperemia
are only a difference in degree, not a difference in kind.
They also argue that those results are the inherent prop-
erties of an otherwise obvious formulation. Finally, they
argue that the district court erred in finding other objec-
tive indicia as supporting nonobviousness.
Allergan responds that this appeal turns on disputed
facts and that the district court did not clearly err in
finding those facts in Allergan’s favor, including finding
that the prior art taught that (1) 0.01% bimatoprost
would be less efficacious than 0.03% bimatoprost; (2) BAK
would decrease the permeability of bimatoprost; and
(3) 200 ppm BAK would be unsafe for chronic use with
bimatoprost. Allergan contends that the Appellants
should not, on appeal, fault the district court for ap-
proaching the issue of obviousness in the way they argued
it during trial. Allergan maintains that it would not have
been obvious to modify Lumigan 0.03% to make the
claimed formulation or to select the claimed amounts of
bimatoprost and BAK from two very broad prior art
ALLERGAN, INC. v. SANDOZ INC. 15
ranges. Allergan also responds that, in any event, the
district court did not err in finding teaching away, unex-
pected results, and other objective indicia, which fully
supported the court’s conclusion of nonobviousness.
We agree with Allergan that the district court did not
err in concluding that the asserted claims would not have
been obvious. That conclusion is supported by underlying
factual findings, which are not clearly erroneous on this
record. In particular, the district court did not clearly err
in finding that the prior art taught away from a formula-
tion comprising 0.01% bimatoprost and 200 ppm BAK,
and that such a formulation exhibited unexpected results.
It is undisputed that the asserted claims all require a
formulation comprising 0.01% bimatoprost and 200 ppm
BAK. Although the prior art does not teach that particu-
lar combination of amounts of bimatoprost and BAK,
those amounts do fall within the ranges disclosed in a
single reference: Woodward discloses a composition com-
prising 0.001%–1% bimatoprost and 0–1000 ppm of a
preservative, including BAK. Those disclosed ranges also
encompass Lumigan 0.03%, a prior art commercial em-
bodiment, which contains 0.03% bimatoprost and 50 ppm
BAK.
As we explained in Galderma, where there is a range
disclosed in the prior art, and the claimed invention falls
within that range, a relevant inquiry is whether there
would have been a motivation to select the claimed com-
position from the prior art ranges. Galderma, 737 F.3d at
737–38 (prior art disclosing 0.01%–1% adapalene encom-
passing the claimed composition comprising 0.3% adapa-
lene). In those circumstances, “the burden of production
falls upon the patentee to come forward with evidence
that (1) the prior art taught away from the claimed inven-
tion; (2) there were new and unexpected results relative to
the prior art; or (3) there are other pertinent secondary
considerations.” Id. at 738.
16 ALLERGAN, INC. v. SANDOZ INC.
Here in this case, the prior art ranges are broader
than the range in Galderma, and the record shows that
the claimed amounts of the two different ingredients
could and did materially and unpredictably alter the
property of the claimed formulation. Thus, Galderma
does not compel a conclusion of obviousness in this case.
It may also be true here that “the disclosed range[s are] so
broad as to encompass a very large number of possible
distinct compositions,” In re Peterson, 315 F.3d 1325, 1330
n.1 (Fed. Cir. 2003), such that they do not teach any
specific amounts or combinations and that the burden of
producing evidence of teaching away, unexpected results,
and other pertinent secondary considerations did not shift
to Allergan. But we need not decide that issue, as it
would not affect our affirmance of the district court’s
conclusion of nonobviousness, because, as indicated infra,
we conclude that the district court did not clearly err in
finding that Allergan had produced ample evidence of
teaching away and unexpected results, and that such
evidence fully supports a conclusion of nonobviousness.
“Whether the prior art teaches away from the claimed
invention is a question of fact.” Spectralytics, Inc. v.
Cordis Corp., 649 F.3d 1336, 1343 (Fed. Cir. 2011). “A
reference may be said to teach away when a person of
ordinary skill, upon reading the reference, would be
discouraged from following the path set out in the refer-
ence, or would be led in a direction divergent from the
path that was taken by the applicant.” In re Gurley, 27
F.3d 551, 553 (Fed. Cir. 1994).
The district court did not clearly err in finding that
the prior art taught away from using 200 ppm BAK in a
bimatoprost formulation. As the district court found, the
prior art taught that BAK should be minimized in oph-
thalmic formulations to avoid safety problems. Opinion
at 49. Indeed, the Appellants’ own expert summarized
the prior art’s widespread concern by describing BAK as
“a natural-born killer” that was “from Satan.” Id. at 75–
ALLERGAN, INC. v. SANDOZ INC. 17
76. Specifically, as the district court found in great detail,
BAK was known to cause increased IOP, hyperemia, dry
eye, and damage to corneal cells, and to exacerbate other
eye disorders. Id. at 40–54. It is not clearly erroneous to
find that those known side effects would have discouraged
a person of ordinary skill from using higher concentra-
tions of BAK in a bimatoprost formulation, especially
when 50 ppm BAK was known to be an adequate preserv-
ative in Lumigan 0.03%.
While it is true that the prior art, such as Abelson, al-
so disclosed ophthalmic formulations containing 200 ppm
BAK, the district court correctly found that those formu-
lations, with the exception of Xalatan® and Xalacom, were
“not for chronic long-term use” and “would teach nothing
about whether it was safe to use 200 ppm BAK with a
lifelong glaucoma drug.” Id. at 53 (emphasis added).
With respect to Xalatan® and Xalacom, both of which
contain 200 ppm BAK and latanoprost, a prostaglandin
ester analog, the district court found that “the majority of
BAK in solution complexed with latanoprost and was not
free in solution to interact with the epithelial cells,” id. at
40, 53–54; and, moreover, that Xalatan® “showed a de-
crease in cell membrane integrity and a significant in-
crease in apoptosis” as compared to a formulation with
less BAK, which would have discouraged the skilled
artisan from increasing the amount of BAK in a bimato-
prost formulation, id. at 52. Those factual findings are
not clearly erroneous.
Moreover, the district court did not clearly err in find-
ing that the prior art taught that BAK would not increase
the permeability of bimatoprost, but might instead de-
crease it. Id. at 35, 38–47. The district court found that
Higaki and Camber taught that BAK reduced the perme-
ability of uncharged prostaglandin analogs that are
similar to bimatoprost, id. at 38–40, and that the other
cited references, including Lee, Keller, and Abelson, did
not teach that BAK would enhance the permeability of
18 ALLERGAN, INC. v. SANDOZ INC.
bimatoprost because those references studied large,
charged, or hydrophilic molecules that are dissimilar to
bimatoprost, id. at 41–47. In view of those factual find-
ings, there would not have been a reason to use 200 ppm
BAK in a bimatoprost formulation. See DePuy Spine, Inc.
v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1326
(Fed. Cir. 2009) (“An inference of nonobviousness is
especially strong where the prior art’s teachings under-
mine the very reason being proffered as to why a person of
ordinary skill would have combined the known ele-
ments.”).
The record thus shows that the prior art “criticize[d],
discredit[ed], or otherwise discourage[d]” the use of
200 ppm BAK in a bimatoprost formulation. In re
Mouttet, 686 F.3d 1322, 1334 (Fed. Cir. 2012) (quoting In
re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004)). We
therefore need not address the Appellants’ additional
argument that the district court erred in finding that
Laibovitz and Lyons taught away from 0.01% bimato-
prost. The Appellants do not argue, and there is no
evidence to suggest, that Laibovitz and Lyons favored
using 200 ppm BAK in a bimatoprost formulation. Ac-
cordingly, we conclude that the district court did not
clearly err in finding that the prior art taught away from
the claimed formulation.
We also conclude that the district court did not clearly
err in finding that the claimed formulation exhibited
“unexpected results,” which differed in kind, not just in
degree, from the prior art. Opinion at 57–58, 76. As
indicated, the prior art taught that 200 ppm BAK would
either have no impact on the permeability of bimatoprost
or decrease it. Allergan’s inventors surprisingly deter-
mined that the opposite was true, namely, that 200 ppm
BAK enhanced the permeability of bimatoprost. That is
an unexpected difference in kind that supports nonobvi-
ousness. In re Applied Materials, Inc., 692 F.3d 1289,
1298 (Fed. Cir. 2012) (“Evidence that the variables inter-
ALLERGAN, INC. v. SANDOZ INC. 19
acted in an unpredictable or unexpected way could render
the combination nonobvious.”) (citing KSR, 550 U.S. at
421).
Moreover, the district court properly found that Lai-
bovitz taught that reducing bimatoprost from 0.03% to
0.01% resulted in significantly reduced efficacy, Opinion
at 31–33, but that such a reduction in bimatoprost did not
result in less hyperemia, id. at 34. The claimed formula-
tion, which comprises 0.01% bimatoprost and 200 ppm
BAK, unexpectedly maintained the IOP-lowering efficacy
of Lumigan 0.03%, while exhibiting reduced incidence and
severity of hyperemia, even though the prior art taught
that BAK could cause hyperemia at high concentrations.
Those results exhibited by the claimed formulation thus
constitute an unexpected difference in kind, viz., the
difference between an effective and safe drug and one
with significant side effects that caused many patients to
discontinue treatment.
Finally, we reject the Appellants’ argument that the
unexpected results do not support nonobviousness be-
cause they are merely the inherent properties of an oth-
erwise obvious formulation. As indicated, the prior art
did not disclose, either explicitly or implicitly, the claimed
formulation; rather, it taught away from such a formula-
tion. A person of ordinary skill in the art thus would not
have had a reason to select the claimed formulation from
the prior art ranges or to modify Lumigan 0.03% to arrive
at the claimed formulation. The unexpected properties of
the claimed formulation, even if inherent in that formula-
tion, differ in kind from the prior art, thereby supporting
a conclusion of nonobviousness. See W.L. Gore & Assocs.,
Inc. v. Garlock, Inc., 721 F.2d 1540, 1555 (Fed. Cir. 1983)
(“Inherency and obviousness are distinct concepts.”); In re
Spormann, 363 F.2d 444, 448 (CCPA 1966) (“That which
may be inherent is not necessarily known. Obviousness
cannot be predicated on what is unknown.”).
20 ALLERGAN, INC. v. SANDOZ INC.
This is not a case where the claims merely recite the
unknown properties of an otherwise obvious formulation.
E.g., Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344,
1354 (Fed. Cir. 2012) (“[A]n obvious formulation cannot
become nonobvious simply by administering it to a pa-
tient and claiming the resulting serum concentrations.”);
In re Kao, 639 F.3d 1057, 1070 (Fed. Cir. 2011) (“Malo-
ney’s express teachings render the claimed controlled
release oxymorphone formulation obvious, and the
claimed ‘food effect’ adds nothing of patentable conse-
quence.”). Here, the previously unknown and unexpected
properties of a new and nonobvious formulation constitute
additional, objective evidence of nonobviousness.
We have considered the remaining arguments on the
issue of obviousness but find them unpersuasive. For the
foregoing reasons, we affirm the district court’s holding
that the asserted claims would not have been obvious in
view of the cited references.
II
We next consider the Appellants’ arguments contend-
ing that the district court erred in finding that the Group
II claims are not invalid for lack of an adequate written
description, and Lupin’s arguments contending that the
court erred in holding that the asserted claims are not
invalid for lack of enablement.
Section 112 of the patent statute provides in relevant
part that:
The specification shall contain a written descrip-
tion of the invention, and of the manner and pro-
cess of making and using it, in such full, clear,
concise, and exact terms as to enable any person
skilled in the art to which it pertains, or with
which it is most nearly connected, to make and
use the same . . . .
ALLERGAN, INC. v. SANDOZ INC. 21
35 U.S.C. § 112, ¶ 1 (2006). “[T]his statutory language
mandates satisfaction of two separate and independent
requirements: an applicant must both describe the
claimed invention adequately and enable its production
and use.” Alcon Research Ltd. v. Barr Labs., Inc., 745
F.3d 1180, 1188 (Fed. Cir. 2014) (citing Ariad Pharm.,
Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1344 (Fed. Cir.
2010) (en banc); Vas-Cath Inc. v. Mahurkar, 935 F.2d
1555, 1562–63 (Fed. Cir. 1991)).
a.
“Whether a claim satisfies the written description re-
quirement is a question of fact that, on appeal from a
bench trial, we review for clear error.” Alcon, 745 F.3d at
1190. The written description requirement is met when
the disclosure “allow[s] one skilled in the art to visualize
or recognize the identity of the subject matter purportedly
described.” Enzo Biochem, Inc. v. Gen-Probe Inc., 323
F.3d 956, 968 (Fed. Cir. 2002). There is no rigid require-
ment that the disclosure contain “either examples or an
actual reduction to practice”; the proper inquiry is wheth-
er the patentee has provided an adequate description that
“in a definite way identifies the claimed invention” in
sufficient detail such that a person of ordinary skill would
understand that the inventor had made the invention at
the time of filing. Ariad, 598 F.3d at 1352. That assess-
ment “requires an objective inquiry into the four corners
of the specification,” as “the hallmark of written descrip-
tion is disclosure.” Id. at 1351.
The Appellants argue that the claims of the ’353 and
’118 patents (the Group II claims), which recite clinical
profile limitations, are not adequately supported by the
written description because the written description does
not disclose any efficacy or hyperemia data of a formula-
tion comprising 0.01% bimatoprost and 200 ppm BAK.
The Appellants assert that the district court erred by
relying on the permeability data of test formulations
22 ALLERGAN, INC. v. SANDOZ INC.
(which are not efficacy or hyperemia data), the construc-
tive example (which relates to a formulation comprising
0.015% bimatoprost and 125 ppm BAK), and the clinical
protocol (which is not part of the specifications). Hi-Tech
additionally argues that there are no “blaze marks” in the
specifications to allow the skilled artisan to immediately
discern the clinical profile claim limitations.
Allergan responds that the district court did not clear-
ly err in finding that the Appellants failed to prove lack of
an adequate written description by clear and convincing
evidence. Allergan argues that the written description
here adequately describes the claimed invention because
it identifies the exact formulation of Lumigan 0.01% as a
best mode of the invention and Lumigan 0.01% exhibited
the claimed clinical results. Allergan also responds that
the district court referenced the clinical protocol simply to
corroborate what the specifications show. Allergan also
maintains that the disclosed permeability data and the
constructive example are relevant to the written descrip-
tion inquiry as they would allow the skilled artisan to
predict the clinical performance of Lumigan 0.01%.
We agree with Allergan that the specifications of the
asserted patents provide an adequate written description
of the invention claimed by the Group II claims. The
specifications specifically describe a formulation compris-
ing 0.01% bimatoprost and 200 ppm BAK as one of the
best modes of the invention. ’504 patent col. 2 ll. 59, 64–
67. The Group II claims all require the same amounts of
bimatoprost and BAK. The specifications thus disclose
the claimed formulation as characterized by those ingre-
dients, and the skilled artisan would immediately discern
the claimed formulation in that disclosure.
It is true that the Group II claims also recite clinical
profile limitations and the specifications do not explicitly
describe the clinical efficacy and hyperemia profile of the
claimed formulation. But the Appellants have empha-
ALLERGAN, INC. v. SANDOZ INC. 23
sized, in connection with their obviousness challenge, that
the inherent properties of a formulation comprising 0.01%
bimatoprost and 200 ppm BAK produce the claimed
clinical profile. Sandoz’s Opening Br. 51 (stating that
“the claimed clinical effects necessarily result from using
0.01% bimatoprost and 200 ppm BAK” (emphasis in
original) (citing J.A. 5537–41, 5764–66)); Lupin’s Opening
Br. 23 (incorporating Sandoz’s opening brief by reference);
Hi-Tech’s Opening Br. 24 (same). A claim that recites a
property that is necessarily inherent in a formulation that
is adequately described is not invalid as lacking written
description merely because the property itself is not
explicitly described. On this particular record, we agree
with the district court that the Appellants have failed to
prove invalidity for lack of an adequate written descrip-
tion by clear and convincing evidence. See Enzo Biochem,
323 F.3d at 963 (“Compliance with the written description
requirement is essentially a fact-based inquiry that will
necessarily vary depending on the nature of the invention
claimed.” (internal quotation marks omitted)).
We do find, however, that the district court erred by
relying on the undisclosed clinical protocol to support its
written description determination. As we have explained,
“[i]t is the disclosures of the applications that count.”
Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 1571 (Fed.
Cir. 1997). The clinical protocol is not part of the specifi-
cations of the asserted patents. It should not form the
basis of the written description inquiry, even if it shows
that the inventors had invented the claimed invention
before the time of filing. The written description re-
quirement requires possession as shown in the specifica-
tion, not as shown by prior experimental work.
Nevertheless, as indicated, because the specifications
contain an adequate disclosure of the claimed formula-
tion, the district court’s erroneous reliance on the clinical
protocol does not affect the outcome of this case.
24 ALLERGAN, INC. v. SANDOZ INC.
We have considered the remaining arguments on the
issue of written description but find them unpersuasive.
We therefore conclude that the district court did not err in
finding that the Appellants failed to prove by clear and
convincing evidence that the Group II claims are invalid
for lack of an adequate written description.
b.
Whether a claim satisfies the enablement require-
ment is a question of law that we review without defer-
ence. Alcon, 745 F.3d at 1188. We review the factual
issues underlying enablement for clear error. Id. To
prove that a claim is invalid for lack of enablement, a
challenger must show by clear and convincing evidence
that a person of ordinary skill in the art would not be able
to practice the claimed invention without “undue experi-
mentation.” Id. (quoting In re Wands, 858 F.2d 731, 736–
37 (Fed. Cir. 1988)).
Lupin argues that the asserted claims are invalid for
lack of enablement because the specifications contain no
actual efficacy and hyperemia data; rather, they merely
provide a research proposal. According to Lupin, the
skilled artisan would not accept without doubt the assert-
ed utility of the claimed formulation, i.e., comparable
efficacy as Lumigan 0.03% and less hyperemia. Lupin
argues that if the claims are held to be nonobvious, then
they must fail the enablement requirement because the
district court found that ophthalmic formulation is unpre-
dictable and that the prior art taught away from the
claimed invention.
Allergan responds that there is no inconsistency in
the district court’s decision that the asserted claims would
not have been obvious and that they are also enabled.
Allergan argues that the specifications disclose the exact
formulation of Lumigan 0.01% and the permeability data
of test formulations, which would enable the skilled
artisan to make and use the claimed invention. Allergan
ALLERGAN, INC. v. SANDOZ INC. 25
also responds that, in view of the patents’ disclosure, the
skilled artisan would not have questioned the utility of
the claimed formulation.
We agree with Allergan that the asserted claims are
not invalid for lack of enablement. “[A] patent does not
need to guarantee that the invention works for a claim to
be enabled.” Alcon, 745 F.3d at 1189. And efficacy data
are generally not required in a patent application. Only a
sufficient description enabling a person of ordinary skill
in the art to carry out an invention is needed. “Similarly,
a patentee is not required to provide actual working
examples; we have rejected enablement challenges based
on the theory that there can be no guarantee that pro-
phetic examples actually work.” Id. at 1189–90.
Here, the asserted claims require a formulation com-
prising specific amounts of bimatoprost and BAK. The
patents refer to what is Lumigan 0.03%, which was a
known drug for treating glaucoma. ’504 patent col. 1
ll. 34–36. The specifications disclose actual in vitro and in
vivo data, showing that increasing the amount of BAK
unexpectedly increased the permeability of bimatoprost
across ocular membranes. Id. col. 4 ll. 10–58, col. 5 l. 19–
col. 6 l. 5, Figs. 1 & 2. In a constructive example, the
specifications teach that a formulation containing 0.015%
bimatoprost and 125 ppm BAK would effectively reduce
IOP and also exhibit less hyperemia than Lumigan 0.03%.
Id. col. 6 ll. 7–14. In view of those disclosures, we agree
with the district court that the skilled artisan would not
have questioned the utility of the claimed formulation and
would be able to make and use the claimed invention
without undue experimentation.
Lupin argues that “if the asserted claims are non-
obvious, they cannot possibly be enabled.” Lupin’s Open-
ing Br. 28. We disagree. The obviousness inquiry turns
on what the prior art would have taught a person of
ordinary skill in the art and whether the claimed inven-
26 ALLERGAN, INC. v. SANDOZ INC.
tion would have been obvious in view of the prior art. As
indicated, the claims here would not have been obvious
because, among other reasons, the prior art taught that
BAK would not increase the permeability of bimatoprost.
In contrast, the enablement inquiry turns on whether the
skilled artisan, after reading the specification, would be
able to make and use the claimed invention without
undue experimentation, based on the ordinary skill in the
art. Because the specifications here provide sufficient
guidance to the skilled artisan, there is no tension in the
district court’s decision that the asserted claims would not
have been obvious and also are not invalid for lack of
enablement.
We have considered the remaining arguments on the
issue of enablement but find them unpersuasive. We
therefore affirm the district court’s holding that Lupin
failed to prove by clear and convincing evidence that the
asserted claims are invalid for lack of enablement.
III
Finally, we address Hi-Tech’s arguments contending
that the district court erred in finding that its ANDA
product infringed, both literally and under the doctrine of
equivalents, the Group I claims, which require the
claimed composition to have a “pH of about 7.3.” A de-
termination of infringement, whether literal or under the
doctrine of equivalents, is a question of fact and is re-
viewed for clear error following a bench trial. Biovail
Corp. Int’l v. Andrx Pharm., Inc., 239 F.3d 1297, 1300
(Fed. Cir. 2001). “Prosecution history estoppel operates
as a legal limitation on a patentee’s ability to invoke the
doctrine of equivalents, and we review its application de
novo.” Trading Techs. Int’l, Inc. v. Open E Cry, LLC, 728
F.3d 1309, 1318 (Fed. Cir. 2013).
Hi-Tech argues that the district court erred in con-
struing a “pH of about 7.3.” Hi-Tech also argues that the
district court erred in finding that Hi-Tech literally in-
ALLERGAN, INC. v. SANDOZ INC. 27
fringed the Group I claims and that prosecution history
estoppel did not bar Allergan from relying on the doctrine
of equivalents to prove infringement. Allergan responds
that Hi-Tech stipulated to the claim construction in the
district court and cannot now allege error for the first
time on appeal. Allergan also responds that the district
court did not clearly err in finding both literal infringe-
ment and infringement under the doctrine of equivalents.
We agree with Allergan that the district court did not
clearly err in finding that Hi-Tech literally infringed the
Group I claims. In the district court, the parties agreed to
construe a “pH of about 7.3” as a “pH of approximately
7.3,” and the district court adopted that construction. Hi-
Tech did not argue for further construction in the district
court. That construction thus controls in this case.
It is undisputed that Hi-Tech’s ANDA specifies that
its proposed product has a pH of 6.8–7.2 during the prod-
uct’s shelf life. The district court thus correctly evaluated
infringement based on the proposed product. Sunovion
Pharm., Inc. v. Teva Pharm. USA, Inc., 731 F.3d 1271,
1278–80 (Fed. Cir. 2013). After considering the expert
testimony proffered by both sides, the district court found
that Hi-Tech’s product would infringe the Group I claims
literally. We find no clear err in that determination.
Moreover, if “about 7.3” is to mean anything other than
7.3, it is not clearly erroneous for it to include a value that
differs from it by only one decimal place. Because we
affirm the district court’s finding of literal infringement,
we do not need to address whether the district court erred
in finding infringement under the doctrine of equivalents.
We have considered Hi-Tech’s remaining arguments
but find them unpersuasive. For the foregoing reasons,
we affirm the district court’s finding that Hi-Tech in-
fringed the Group I claims.
28 ALLERGAN, INC. v. SANDOZ INC.
CONCLUSION
Accordingly, we affirm the district court’s determina-
tion that the asserted claims are not invalid for obvious-
ness or for lack of an adequate written description and
enablement, and that Hi-Tech infringed the claims of the
’504, ’605, and ’479 patents.
AFFIRMED