SENJU EXHIBIT 2134
`LUPIN v SENJU
`IPR2015-01105
`
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`

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`2
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`ALLERGAN, INC. V. SANDOZ INC.
`
`CLARENCE DOYLE, ANDERS '1‘. 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 defendantappellant Hi-Tech Pharmacal C0,, Inc.
`Also represented by THOMAS J. VE'1“I‘ER, 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 Pharrn, Inc. (coilectively, “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 Allergen, Ino. 0.
`Sandoz Inc., No. 14-1275, ECF No. 121 (Fed. Cir. Apr. 17,
`2015)
`
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`ALLERGAbLINC.V.SANDOZINC.
`
`3
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`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] 1.3 Allergen, Inc. 0. 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[ 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 US. 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
`
`Because the applications resulting in the patents
`2
`asserted in this case were filed before the enactment of
`
`the Leahy-Smith America Invents Act (“AIA”), Pub. L. No.
`11229, 125 Stat. 284 (2011), we apply the pre-AIA ver-
`sion of 35 U.S.C. § 103 and § 112.
`
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`ALLERGAN, INC. V. SANDOZ INC.
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`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%.
`
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`ALLERGAN, INC. V. SANDOZ INC.
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`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, ‘I18, ‘E305,
`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 these 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.
`(:01.
`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 I1. 59, 64-67.
`
`Because the asserted patents share an identical
`3
`specification in relevant part, we refer only to the ’504
`patent when discussing the specifications of those pa-
`tents.
`
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`ALLERGAN, INC. V. SANDOZ INC.
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`Additionally, the specifications disclose in vitro and in
`viva 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
`11. 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 ’l18 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:
`
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`ALLERGAN, INC. V. SANDOZ INC.
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`7
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`2. A composition having a pH of about 7.3 which
`comprises about 0.01% bimutoprost, about 200
`ppm benzalkonium chloride, citric acid rnonohy-
`drate, a phosphate buffer, and NaCl wherein said
`composition is an aqueous liquid which is formu-
`lated for ophthalmic administration.
`
`Id. col. 6 11. 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% wiv bimatoprost
`and about 0.02% wfv 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% wfv bimatoprost
`and 0.005% wlv benzalkonium chloride.
`
`7. A first composition administered once daily for
`lowering intraocular pressure in a person with
`glaucoma or ocular hypertension, the first compo-
`
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`8
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`ALLERGAN, INC. V. SANDOZ INC.
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`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.-
`trctocular pressure lowering benefit provided by
`the once daily administration of a second composi-
`tion comprising 0.03% wlv bimatoprost and
`0.005% wfv 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 11. 48-56, col. 6 11. 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.
`
`8..
`
`The district court concluded that the asserted claims
`
`would not have been obvious in View of the cited prior art,
`which included: (1) US. Patent 5,688,819 (“Woodward”);
`(2) US. Patent 6,933,289 (“Lyons”); (3) Laibovitz et 4:11.,
`Comparison of the Ocular I-Iypotensive Lipid AGN 1.92024
`
`The parties agree that 0.02% wlv corresponds to
`4
`200 ppm, and 0.005% w.-‘V corresponds to 50 ppm.
`
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`ALLERGAN, INC. V. SANDOZ INC.
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`9
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`with Timolol, 119 Archives of Ophthalmology 994 (2001)
`(“Laibovitz”); (4) Abelson et ai., How to Handle BAX 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 6'? (1986) (“Lee”); (6) Camber et al., Factors
`Influencing the Corneal Permeability of Prostaglandin Fax
`and Its Isopropyl Ester In Vitro, 37 Int’1 J. Pharmaceutics
`27 (1987) (“Camber”); (7) Higaki et al., Estimation and
`Enhancement of In Vitro Corneal Transport of S-I033, a
`Novel Antiglaucoma Medication, 132 Int’1 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 birnatoprost 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
`
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`10
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`ALLERGAN, INC. V. SANDOZ INC.
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`including increased IOP, hyperemia,
`cause side effects,
`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 hyperc-
`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
`
`In reaching that conclusion, the court
`obvious. Id. at 74.
`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. U. Tolmer, 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 birnatoprost and BAK in the claimed formula-
`tion fall within those prior art ranges, thus rendering the
`
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`ALLERGAN, INC. V. SANDOZ INC.
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`11
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`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-
`derrna, 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 viva 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
`
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`12
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`ALLERGAN, INC. V. SANDOZ INC.
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`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 I-Ii-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. Allergen, Inc.
`I). Sandoz Inc., No. 6:11~cv-
`00441, 2013 WL 139350, at *9 (ED. Tex. Jan. 10, 2013).
`I-Ii-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
`
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`ALLERGAN, INC. v. SANDOZ INC.
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`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 nova 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. US. Gypsum. Co., 333
`U.S. 364, 395 (1948); Alzo. Corp. v. Mylcm La.bs., 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. 1). Mi 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, Iong-felt need, and the failure of others. KSR Int’!
`_C0. 0. Teleflex Inc., 550 US. 398, 427 (2007); Graham 1}.
`John, Deere Co-, 383 U.S. 1, 17-18 (1966); Monarch Knit-
`
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`14
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`ALLERGAN, INC. V. SANDOZ INC.
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`ting Mach. Corp. v. Sulzer Marat 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
`
`PAGE 14 OF 28
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`

`
`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 001% 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 0.00l%—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 Galderrnos, 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.
`
`PAGE 15 OF 28
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`

`
`16
`
`ALLERGAN, INC. V. SANDOZ INC.
`
`Here in this case, the prior art ranges are broader
`than the range in Gnlderma, 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, Go‘.lder.rna
`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.
`I).
`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—
`
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`ALLERGAN, INC. V. SANDOZ INC.
`
`'
`
`I7
`
`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
`
`PAGE 17 OF 28
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`

`
`18
`
`ALLERGAN, INC. v. SANDOZ INC.
`
`studied large,
`bimatoprost because those references
`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 DePu.y 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 “criticizc[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% biInato-
`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. Allergarfs 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 nonohvi-
`ousness.
`In re Applied Materials, Inc., 692 F.3d 1289,
`1298 (Fed. Cir. 2012) (“Evidence