# 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

______________________

J UANITA R OSE B ROOKS , Fish & Richardson, P.C., San Diego, CA

, argued for plaintiff -appellee. Also represented by C RAIG E. C OUNTRYMAN ; J ONATHAN E LLIOT S INGER , D EANNA J EAN R EICHEL , Minneapolis, MN; D OUGLAS E. M C C ANN , S US AN M. C OLETTI , Wilmington, DE

.

D EANNE M AYNARD , Morrison & Foerster LLP, Was hington, DC

, argued for defendant

- appellant Sandoz Inc

. Also represented by B RIAN R OBERT M ATSUI ; D AVIDALLERGAN , INC

. v. SANDOZ INC

. 2

C LARENCE D OYLE , A NDERS T. A ANNESTAD , J AMES C EKOLA , San Diego, CA.

W ILLIAM A. R AKOCZY , Rakoczy Molino Mazzochi, Siwik LLP, Chicago, IL

, argued for defendants

- appellants Lupin Ltd.

, Lupin Pharmaceuticals, Inc

. Also represented by P AUL J. M OLINO , D EANNE M. M AZZOCHI , T HEODORE J OSEPH C HIACCHIO , J OHN P OLIVICK

.

S TEVEN D. R OTH , Locke Lord, LLP, New York, NY

, a rgued for defendant

- appellant Hi

- Tech Pharmacal Co., Inc

. Also represented by T HOMAS J. V ETTER , Lucas & Me rcanti, LLP, New York, NY.

______________________
Before L OURIE , L INN , and H UGHES , Circuit Judges

. L OURIE , Circuit Judge

. Sandoz Inc. (“Sandoz”), Lupin Ltd. and Lupin Pha rmaceuticals, Inc. ( collectively, “Lupin”), and Hi

- Tech Pharmacal Co., Inc. (“Hi

- Tech”) (collectively, “the Appe llants ”) 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 p atent”), 8,299,118 ( the “ ’118 patent”), 8,309,605 ( the “ ’605 patent”), and 8,338,479 ( the “ ’479 patent”)

, asserted by Allergan, Inc. (“Allergan”)

, we re not shown to be invalid for obviousness under 35 U.S.C. § 103 , and that the

1 Watson Laboratories, Inc., Watson Pharmaceut icals, 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 adequa te written descrip tion 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 Alle rgan’s patents were not shown to be inval id for lack of enablement under § 112, ¶ 1. Id

. at 80

– 81. Hi

- Tech also challenges the district court’s finding that it in fringed the claims of the ’504, ’605, and ’479 patents literally and under the doctr ine of equivalents

. Id

. at 64

– 66. For the

reasons that follow , we affirm in all respects.

B ACKGROUND

I

G lauco m a is a n eye disease associated with elevate d intraocular pressure (“IOP”) . T reatments that effectively reduce IOP can slow the progres sion of the disease

. I f 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 bimato prost and 50 parts per million (“ppm”) benzalkonium chloride (“BAK”)

, among other ingredients

. Bimatoprost , t he active ingredient in Lumigan 0.03%, is a prostaglandin analog that effectively lowers IOP, but

can cause hyperem ia, 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 v e rsion of 35 U.S.C. § 103 and § 112.ALLERGAN , INC

. v. SANDOZ INC

. 4

the ocular surface

. One structural difference between b imatoprost 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 understoo d that both latanoprost and travoprost

, but not bimatoprost, act as prodrug s of the corresponding acid s. Id.

BAK is a preserva tive for inhibit ing bacterial growth in ophthalmic solutions

. I t was known , however, that BAK is cyto toxic and that it can damage the cell s on the ocular surface and cause undesirable side effects

. Although Lumigan 0.03% was effective at lowering IOP, it also cause d frequent and severe hyperemia

. M any pa tients 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 increase d the corneal perm eability of bimatoprost

. Id. at 12

– 13. After further research

, Allergan developed Lumigan ® 0.01% (“Lumigan 0.01%”)

. Lumigan 0.01% is a topical solution con taining 0.01% bimatoprost and 200 ppm BAK ; otherwise, it has the same ingredients as Lumigan 0.03%

. Thus, a s compared with Lumigan 0.03%, Lumigan 0.01% has a three

- fold lower bimatoprost concentration and a four

- fold higher BAK concentration

. C linical studies showed that Lum igan 0.01% has similar efficacy to Lumigan 0.03%

, viz.

, IOP -lowering within 0. 5 mmHg of that of Lumigan 0.03%

, b ut it causes less frequent and severe hypere mia than Lumigan 0.03%

. Id. at 20

– 21. In 2010, the FDA a pproved 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 p atent s, 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 Abbrevi ated New Drug Application (“ ANDA ”) to the FDA, seeking approval to engage in the commercial manufacture, use, import ation, sale , or offer for sale of generic version s of Lumi gan 0.01% prior to the expiration of the ’504, ’353, ’118, ’605, and ’479 patents

. In response, Allergan sued each of the ANDA applicant s in the United States District Court for the Eastern District of Texas, asserting that their ANDA filings inf ringed th ose patents

. The district court consol idat ed those actions into one case

. T he asserted patents all derive from an application filed on March 16, 2005 and share a common specific ation . The patents are entitled “Enhanced Bimatoprost Ophthalmic Solution ,” ’504 patent col. 1 ll. 1 –2, 3 and refer
to what is L umigan 0.03% in the background section, i d. col. 1 ll. 34

– 36. The specification s of the patents describe a composition comprising 0.005% to 0.02% bima toprost and 100 ppm to 250 ppm BAK, which is an aqueous liquid “formulated for ophthalmic administration” and “useful in treating glaucoma or ocular hypertension .” I d. col. 1 l l. 61

– 67. The specification s 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 p atents.ALLERGAN , INC

. v. SANDOZ INC

. 6

Additionally, the specification s disclose in vitro and in vivo experimental data in rabbits, showing that increa sing 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 specification s 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% bimatop rost and 50 ppm BAK,]” and “[l]owered intraocular pressure persists for as long as the treatment continues.” Id. col. 6 ll. 7

– 14

. A llergan asserted the following claims against each of the ANDA applicants : claim 2 of the ’504 patent; claim 15 of the ’479 pate nt; claims 1, 6, 10, and 12 of the ’605
pa tent; claims 1, 7, and 8 of the ’353 patent; and claims 1, 7, and 8 of the ’118 patent (collective l y, “the asserted claims”). Th ose claims collectively are directed to comp ositions comprising bimatoprost and BAK and methods of using them to treat glaucoma or to lower IOP

. Each of t he asserted claims requires a composition comprising 0.01% bimatoprost and 200 ppm BAK

. C laim 2 of the ’ 504 patent, claim 15 of the ’479 patent, and clai ms 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.” C laims 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
compo sition as compared to a composition comprising 0.03% bimatoprost and 50 ppm BAK

. C laim 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 monoh ydrate, a phosphate buffer, and NaCl wherein said composition is an aqueous liquid which is form ulated 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 co mprised of: about 0.01% w/v bimatoprost ; about 200 ppm benzalkonium chloride ; the solution having a pH of about 7.3 ; a phosphate buffer; a nd
water. ’605 patent col. 5 ll. 47

– 55 (emphases added)

. As indicated, the Group II cla ims all contain clinical
pro file limi tation s

. Claims 1, 7, and 8 of the ’353 paten t are directed to compositions and read as follows:

1. A first composition administered o nce daily for lowering intraocular pressure in a person with glaucoma or ocular hypertension, the first comp osition 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 co mpared 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 comp o-ALLERGAN , INC

. v. SANDOZ INC

. 8

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 i ntraocular pressure lowering benefit provided by the once daily administration of a second comp os ition comprising 0.03% w/v bimatoprost and 0.005% w/v benzalkonium chloride

. 8. The composition of claim 7 wherein the once daily adm inistration of the first composition r esults 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 C laims 1, 7, and 8 of the ’118 patent are di rected 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 c ol. 5 ll. 48

– 56, col. 6 ll. 3

– 16.

III

T he district court held a five

- day bench trial in July 2013 on the issues of obviousness and infringement

. T he defendants also argued that the claims were invalid for lack of written description and enablement in pre - and post

- trial briefings

. I n Ja nuary 2014, the court rendered its find ings of fact and conclusions of law on all of those issues.

a.
The district court concluded that the asserted claims would not have be en obvious in view of the cited prior art, which includ ed: (1) U.S. Patent 5,688,819 (“Woodward”); (2) U.S. Patent 6,933,289 (“Lyons”); (3) Laibovitz et al.

, Compari son 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 F 2α 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. Pharmace utics 165 (1996) (“Higaki”); and (8) Keller et al.

, Increased Corneal Permeability Induced by the Dual Effects of Transient Tear Film Acidification and Exposure to Be nzal konium Chloride , 30 Experimental Eye Res. 2 03 (1980) (“Keller”). Specifically, with respect to the scope and content of the prior art, t he district court found that : (1) ophthalmic formula tion was unpredictable, and it was not a field with a finite number of identified and predictable solutions

, Opinion at 29

– 31; (2) Laibovitz and Lyon s 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, Cam ber, Lee, Keller, and Abelson, as wel l as Xalatan ® (latanoprost), which contains 200 ppm BAK, did not teach that high concentrations of BAK would enhance the corneal permeability of bimat oprost , a neutral prostaglandin amide analog ; instead, the prior art suggested that BAK would decrease the perme ability of a neutral prostaglandin analog

, id. at 35 , 38

– 47 ; and (5) the prior art taught that BAK should be min imized in ophthalmic formulations due to its toxicity

, and

, in particular

, taught away from using 200 ppm BAK in a bimatoprost formula tion because BAK was known toALLERGAN , INC

. v. SANDOZ INC

. 10

cause side effects, including increased IOP, hyperemia, and dry eye, making it unsuitable for chronic use at high concentration s , id. at 47

– 54.

T he 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

. T he court also found evidence of long

- felt need, unexpected results, and commercial success supporting a conclusion of nonobviousness

. Id. at 56

– 59. T he court specifically found that it was unexpected that Lumigan 0.01% would reduce the incidence and severity of hyper emia

, as compared to Lumigan 0.03%

, while maintaining IOP

- lowering efficacy

, and that it was also unexpected that 200 ppm BAK would enh ance 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 claim s would not have been obvious. Id. at 74. In reaching that conclusion, t he court emphasized that t he 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.

T he district court also re jected the def endants’ arg ument 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 di sclosed a formulation comprising 0.001%

– 1% bi matoprost and 0

– 1000 ppm BAK for treat ing glaucoma, and that the amounts of bimatoprost and BAK in the claimed formul ation fall within those prior art ranges, thus render ing theALLERGAN , INC

. v. SANDOZ INC

. 11

claims obvious. The district court rea soned 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 conside rations. ’” Opinion at 75 (quoting Ga lderma , 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

. I

d. at 75

– 76. T he court also emphasized that the une xpected result s were “ of a different kind , not just of diffe rent degree .” Id. at 76 (emphases in origi nal).

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 r ejected the defendants’ inv alidity challenges based on the writ ten 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, t he 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 d escribe 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 additio nal support in the title s 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 descriptionALLERGAN , INC

. v. SANDOZ INC

. 12

sup port
, “especially given the expre ss disclosure that Lumigan 0.01% is an example of the best mode of the invention.” Id. T he court additionally reasoned that the inventors had possession of the claimed invention because a clinical protocol pre pared in November 2004 , before the March 2005 applicatio n filing date, describes the formul ation of Lumigan 0.01% and the later- claimed clinical profile

. Id

. at 79. Lupin also alleged that the asserted claims were inv alid for lack of enablement. The district court rejected that argument, reasoning that Allergan’s patents disclose the formulation of Lumigan 0.01% and that t he 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.
T he district court also found that each of the ANDA products infringed each of the asserted claims. Relevant to this appeal, the court found that H i- 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 approxi mately 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 speci fied 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 , t he court found that Hi

- Tech’s ANDA product literally i nfringed the Group I claims. Id. at 64. The court a lso found, in the alternative, that Hi

- Tech ’s ANDA product infringed the Group I claims under the doctrine of equiv alents. Id. at 64

– 66. Accordingly, the district court entered final judgment of infringement and no invalidity . The Appellants timelyALLERGAN , INC

. v. SANDOZ INC

. 13

ap pea led to this court ; w e have jurisdiction under 28 U.S.C. § 1295(a)(1).

D ISCUSSION 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. Robe rt 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 convin cing 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’ argument s conten ding 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 i nfringer proves th at 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 u ltimately 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) obj ective evidence

, such as commercial su ccess, 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 Kni t-ALLERGAN , INC

. v. SANDOZ INC

. 14

ting Mach. Corp. v. Sulzer Morat Gmb H , 139 F.3d 877, 881 (Fed. Cir. 1998)

. T he 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 modify ing Lumi gan 0.03% and a reasonable expectation of success in doing so

. According to the Appellants, b ecause the claimed amounts of bimatoprost and BAK fall within prior art ranges, the
proper obviousness in quiry should focus only on teaching
away, unex pected results, and other objective indicia

. T he Appellants also asse rt that the district court appl ied

an incorrect stand ard for teaching away because it merely found that the prior art taught that the claimed formul ation would be inferior, rathe r than that it would not work

. And t he y argue that the prior art does not teach away from 0.01% bimato prost or 200 ppm BAK. The y assert
, moreover, that there are no unexpected results because the observed results of similar efficacy and less hypere mia

are only a differ ence in degree, not a differ ence in kind

. T hey also argue that those re sults are the inherent pro pe rties of an otherwise obvious formulation. Finally, they argue that the district court erred in finding other obje ctive indicia as support ing nonobvi ousness.
Alle r gan responds that this appea l 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 dec rease the permeability of bima toprost ; a nd (3) 200 ppm BAK would be un safe for chronic use with bimatoprost. Allergan contends that the Appellants should not , on appeal, fault the district court for a pproac hing the issue of obviousness in the way they argued it during trial. Alle rgan 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 artALLERGAN , INC

. v. SANDOZ INC

. 15

rang es

. Allergan also responds th at , in any event, the district court did not err in finding teaching away, une xpected results, and other objective indicia, which fully support ed the court’s conclusion of nonobvious ness. We agree with Allergan that the district court did not err in conclu ding 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 , t he district court did not clearly err in finding that the prior art taught away from a formul ation comprising 0.01% bimatoprost and 200 ppm BAK

, and that such a formulation exhibited unexpected re sults

. It is undisputed that t he asserted claims all require a formulation comprising 0.01% bimatoprost and 200 ppm B AK. Although th e prior art does not teach th at partic ular combination of amounts of bimatoprost and BAK,
t hose amounts do fall within the ranges disclosed in a single reference: Woodward discloses a composition co mprising 0.001%

– 1% bimatoprost and 0– 1000 ppm of a
pres ervative, including BAK

. Th ose disclosed ranges also encompass Lumigan 0.03%, a prior art commercial e mbodi ment, 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 co mposition from the prior art range s

. Galderma

, 737 F.3d at 737 –38 ( prior art disclosing 0.01%

– 1% adapalene enco mpass ing the claimed composition comprising 0.3% adapalene )

. I n those circumstances, “t he burden of production falls upon the patentee to come forward with evi dence that (1) the prior art taught away from the claimed inve ntion; (2) there were new and unexpected results relative to the prior art; or (3) there are other pertinent secondary considerations .” Id. at 738.ALLERGAN , INC

. v. SANDOZ INC

. 16

Here i n 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 als o 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 teach ing away, unexpected results

, and other pertinent secondary considerations did not shift to Allergan. But w e need not decide that issue, as it would not affect our affirmance of the district court’s conclusion of nonobviousnes s, 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 support s a conclusion of non obviousness. “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 re ading the reference, would be discouraged from following the path set out in the refe rence, 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 fi nding that the prior art taught away from using 200 ppm BAK in a bimatoprost formulation. As the district court found, t he prior art taught that BAK should be minimized in op hthalmic 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, a s the district court found in great detail, BAK was known to cause increased IOP, hyperemia, dry eye, and damage to corneal cells, and to exacerbat e other eye disorders. Id. at 40

– 54. It is not clearly erroneous to find that t hose known side effects would have discouraged

a person of ordinary skill from using high er concentr ations of BAK in a bimatoprost formulation

, especially when 50 ppm BAK was known to be an adequate preser va tive in Lumigan 0.03%.

While it is true that the prior art , such as Abelson, a lso disclosed ophthalmic formulations containing 200 ppm BAK, the district court correctly found that those form ulations, with the except ion of Xala tan ® 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 lat ano prost
, a prostaglandin ester analog, the district court found that “the majority of BAK in solution complexed with lat ano prost and was not free in solutio n to inte ract with the epithelial cells,” id. at 40, 53

– 54; and , moreover, that Xalatan ® “ showed a d ecr ease in cell membrane integrity and a si gnificant i ncrease in apoptosis ” as compared to a formulation with less BAK, which would have discour aged the ski lled artisan from increasing the amount of BAK in a bimat oprost formulation

, id. at 52

. Those factual findings are not clearly errone ous. Moreover, t he district court did not clearly err in fin ding that the prior art taught that BAK would not increase the permeability of bimatoprost

, but might instead decrease it. Id. at 35, 38

– 47. T he district court found that Higaki and Camber taught that BAK reduced the perm eability of uncharged prostaglan din analogs that are similar to bimato prost
, i d. a t 38

– 40, and that the other cited references, including Lee, Keller, and Abelson, d id
not teach that BAK would enhance the permeability ofALLERGAN , INC

. v. SANDOZ INC

. 18

bimatoprost because those references studied large, charged, or hydrophilic molecules that are dissimilar to bimatopr ost
, id. at 41

– 47. In view of those factual fin dings, there would not have been a reason to use 200 ppm BAK in a bimatoprost formulation. See DeP uy Spine, Inc. v. Medtronic Sofamor Danek, Inc.

, 567 F.3d 1314, 1326 (Fed. Cir. 2009) (“An inference of nonobvi ousness is especially strong where the prior art’s teachings unde rmine the very reason being proffered as to why a person of ordinary skill would have combined the known el ements.” ). The record thus shows that the prior art “criti cize [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 t he A ppellants ’ additional argument that the dis trict court erred in find ing that Laibovitz and Lyons taught away from 0.01% bimat oprost

. T he Appellants do not argue, and there is no evidence to suggest
, that Laibovitz and Lyons favored using 200 ppm BAK in a bimatoprost formulation

. A ccordingly, 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 cl aimed formulation exhibited

“ unexpected r esults, ” 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 bimato prost

or decrease it. Allergan’s inventors surprisingly determined that the opposite was true, namely, that 200 ppm BAK enhanced the permeability of bimatoprost

. That is an unexpected difference in kind that supports nonobv iousness. In re Applied Materials, Inc. , 692 F.3d 1289, 1298 (Fed. Cir. 2012) (“Evidence that the variables inte r-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 La ibovitz 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. T he claimed formul ation , 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

. Th ose re sults exhibited by the claimed formulation thus consti tute an unexpected differ ence 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 t he Appellants’ argument that the unexpected results do not support nonobviousness because they are merely the inherent proper ties of an ot herwise obvious formulation

. As indicated, t he prior art did not disclose, either explicitly or implicitly, t he claimed formulation; rather , it taught aw ay from such a formul ation . 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 Lumi gan 0.03% to arrive at the claimed formulation

. T he unexpected properties of the claimed formulation , even if inherent in that formul ation, dif fer 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.”)

.ALLERGAN , INC

. v. SANDOZ INC

. 20

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 admi nistering it to a p atient and claiming the resulting serum concentrations

. ”); In re Kao , 639 F.3d 1057, 1070 (Fed. Cir. 2011) (“Mal oney’s express teachings render the claimed controlled release oxymorphone formulation obvious, and the claimed ‘ food effect ’ adds nothing of patentable cons equence.”). Here, t he 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’ argument s cont en ding that the district court erred in finding that the Group II claims are not invalid for lack of an adequate written descrip tion, and Lupin’s arguments contending that the court erred in holding that the asserted claims are not invalid for lack of enab lement. Section 112 of the patent statute provides in relevant part that: The specification shall contain a written descri ption of the invention, and of the manner and pr ocess of making and using it, in such full, clear, concise, and exact terms as to en able any person skilled in the art to which it pertains, or with which it is most nearly connect ed, 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. C ir. 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 r equirement 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 re quirement 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 (Fe d. Cir. 2002). There is no rigid requir ement that the disclosure contain “either examples or an actual reduction to practice”; the proper inquiry is whet her the patentee has provided a n adequate description that “in a definite way identifies the claimed i nvention” in sufficient detail such that a person of ordinary skill would under stand that t he inventor had made the invention at the time of filing. Ariad

, 598 F.3d at 1352

. That asses sment “requires an objective inquiry into the four corners of the spec ifica tion, ” as “the hallmark of written descri ption 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 do es not disclose any effica cy or hyperemia data of a formul ation comprising 0.01% bimatoprost and 200 ppm BAK

. The Appellants assert that the district court erred by relying on the permeability d ata of test formulationsALLERGAN , INC

. v. SANDOZ INC

. 22

(which are not efficacy or hyperemia data ), the constructive example (which relate s to a formula tion comprising 0.015% bimatoprost and 125 ppm BAK ), and the clinical protocol (which i s not part of the specification s ). Hi

- Tech addi tionally argues that there are no “ blaze marks ” in the specification s to allow the skilled artisan to immediately discern the clinical profile claim limitations. Allergan responds that the district court did not clea rly err in finding that the Appellants f ailed 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 mo de of the inven tion and Lumigan 0.01% exhibited the claimed clinical results. Allergan also responds tha t the district court referenced the clinical protocol simply to corroborate what the specification s show

. Allergan also maintains that the disclosed permeability data and the constructive example are relevant to the written descri ption inquiry as they would allow the skilled artisan to predict the clinical performance of Lumigan 0.01%.
We agree with Allergan that the specification s of the asserted pate nts provide an adequate wr itten de scription of the invention claimed by the Group II claims

. T he specification s specifically descr ibe a formulation compri sing 0.01% bimatoprost and 200 ppm BAK as one of the best mode s 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 specification s thus disclose the claimed formulation as characterized by those ingr edients , and t he skilled artisan would immediately discern the cl aimed formulation in that disclosure.

I t is true that the Group II claims also recite clinical profile limitations and the specification s do not explicitly describe the clinical efficacy and hyperemia profile of the claimed formulation . But the Appellan ts have emph a-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 clinica l 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 (incorpo rating Sandoz’s opening brief by reference ) ; Hi

- Tech’s Opening Br. 24 (same)

. A claim that r ecites 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 descri ption by clear and convincing evidence. See Enzo Biochem

, 323 F.3d at 963 ( “Compliance with the written description requirement is esse ntially 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 it s writ ten description determination . As we have explained,

“ [i] t is the disclosure s of the application s that count .” Lockwood v. Am. Airlines, Inc. , 107 F.3d 1565, 1571 (Fed. Cir. 1997). The clinical protocol is not part of the specification s of the asse rted patents

. I t should not form the basis of the written description inquiry , even if it shows that the inventor s had i nvented the claimed invention before the time of filing

. The written description r equirement requires possession as shown in the specification , not as shown by prior experimental work. Nevertheless, as indicated, because the specification s contain an adequate disclosu re of the claimed formul ation, the district court’s erroneous reliance on the clinical protocol does not affect the out come of this case

.ALLERGAN , INC

. v. SANDOZ INC

. 24

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 convinci ng evidence that the Group II claims are invalid for lack of an adequate written description.

b. Whether a claim satisfies the enablement requir ement is a question of law that we review without defe rence. Alcon , 745 F.3d at 1188. W e 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 exper imentation.” 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 specification s contain no actual efficac y and hyperemia data; rather, they merely provide a research proposal. According to Lupin, the skilled artisan would not accept without doubt the asser ted utility of the claimed formulation

, i.e.

, comparable efficacy as Lumigan 0.03% and less hypere mia

. Lupin

a rgues that if the claims are held to be nonobvious, then they must fail the ena blement requirement because the district court found that ophthalmic formulation is unpr edictable 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 specification s 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. AllerganALLERGAN , 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 gene rally 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 pr ophetic examples actually work.” Id. at 1189

– 90.
Here, the asserted claims require a formulation co mprising specific amounts of bimatoprost and BAK. T he patents refer to what is Lumigan 0.03%, which was a known drug for treating g laucoma. ’504 patent col. 1 ll. 34

– 36. The specification s disclose actual in vitro and in vivo data

, showing that increasing the amount of BAK unexpectedly increas ed the permeability of bimato pr ost across ocular membranes

. Id. col. 4 ll. 10

– 58, col. 5 l. 19

– col. 6 l. 5, Figs. 1 & 2. In a constructive example, t he specifica tion s teach that a formulation containing 0.015% bimatop r ost and 125 ppm BA K would effectively reduce IOP and also exhibit less hyperemia than Lumigan 0.03%

. Id. col. 6 ll. 7

– 14. I n view of those disclosure s , 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 claime d invention without undue experimentation.
Lupin argues that “if the asserted claims are non

obvious, they cannot possibly be ena bled. ” Lupin’s Ope ning Br. 28. We disagree. The obviousness inquiry turns on what the prior art would have taught a person o f ordinary skill in the art and whether the claimed inve n-ALLERGAN , INC

. v. SANDOZ INC

. 26

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 pe rmeability 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. W e 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 d etermination of infringement, whether literal or under the doctrine of equivalents, is a question of fact and is r eviewed for clear error following a bench trial

. Biovail Corp. Int’l v. Andrx Pharm ., Inc.

, 239 F.3d 1297, 130 0 (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 co nstruing a “pH of about 7.3.” Hi

- Tech also argues that the district court erred in finding that Hi

- Tech literally i n-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 t hat the district court did not clearly err in finding both literal infring ement 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 c laims. 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 construct i on 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 pro duct’s shelf life. The district court thus correctly evaluated infringement based on the proposed product. Sunovion Pha rm., 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, i f “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 infringem ent,

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 cou rt’s finding that Hi -Tec h i nfringed the Group I claims.ALLERGAN , INC

. v. SANDOZ INC

. 28

C ONCLUSION Accordingly, we affirm the district court’s determin ation that the asserted claims are not invalid for obviou sness 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