# United States **Court of Appeals**  **for the Federal Circuit**

______________________ GRUNENTHAL GMBH, ASSERTIO THERAPEUTICS, INC., Plaintiffs

- Cross

- Appellants

v.

ALKEM LABORATORIES L IMITED, HIKMA PHARMACEUTICALS INTE RNATIONAL LIMITED, HIKMA PHARMACEUTICA LS USA INC., Defendants

- Appellants

ACTAVIS ELIZABETH LL C, Defendant

- Appellee

ACTAVIS LABORATORIES UT, INC., Defendant

______________________

2017

- 1153, 2017

- 204 8, 2017

- 2049, 2017

- 2050

______________________ Appeals from the United States District Court for the District of New Jersey in No s . 2:13

- cv

- 04507

- CCC

- MF, 2:13

- cv

- 06929

- CCC

- MF, 2:13

- cv

- 07803

- CCC

- MF, 2:14

- cv

03941

- CCC

- MF, 2:14

- cv

- 04617

- CCC

- MF, 2:15

- cv

- 06797

- CCC

- MF, Judge Claire C. Cecchi.

______________________
Decided: March 28, 2019

______________________G RUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 2

M ICHAEL S ITZMAN , Gibson, Dunn & Crutcher LLP, San Francisco, CA, argued for all plaintiffs

- cross

- appellants. Plaintiff

- cross

- appellant Assertio Therapeutics, Inc. also represented by J AYSEN C HUNG ; C HRISTINE R ANNEY , Denver, CO; T IMOTHY P. B EST , Los Angeles, CA.

L INDA A. W ADLER , Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, Washington, DC, for plaintiff

cross

- appellant Grunenthal GmbH. Also represented by K RISTA E. B IANCO

.

M ICHAEL E. J OFFRE , Sterne Kessler Goldstein & Fox, PLLC, Washington, DC, argued for defendant

- appellee. Also represented by W ILLIAM H. M ILLIKEN

.

R OBERT J. G AJARSA , Latham & Watkins LLP, Washington, DC, argued for defendants

- appellants Hikma Pharmaceuticals International Limited, Hikma Pharmaceuticals USA Inc. Also represented by K ENNETH G. S CHULER , Chicago, IL; G REGORY S OBOLSKI , San Francisco, CA.

I MRON T. A LY , Schiff Hardin, Chicago, IL, argued for defendant

- appellant Alkem Laboratories Limited. Also represented by C INDY A HN , J ASON H ARP , N EIL L LOYD ; A HMED M.T. R IAZ , New York, NY.

______________________
Before R EY NA , T ARANTO , and C HEN , Circuit Judges.

R EYNA , Circuit Judge

. Alkem Laboratories Limited, Hikma Pharmaceuticals International Limited, and Hikma Pharmaceuticals USA Inc. appeal the judgment of the district court that U.S. Patent No. 7,994,364 is not invalid for obviousness or lack of utility. Gr ü nenthal GmbH and Assertio Therapeutics, Inc., formerly Depomed, Inc., cross

- appeal the finding that Hikma Pharmaceuticals International Limited, Hikma Pharmaceuticals USA Inc., and Actavis Elizabeth LLC doG RUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 3

not infri nge U.S. Patent No. 8,536,130. Because the district court did not err in its conclusions, we affirm.

B ACKGROUND

A. Patents at Issue

Gr ü nenthal GmbH (“Gr ü nenthal ”) is the assignee of U.S. Patent Nos. 7,994,364 (“the ’364 patent”) and 8,536,130 (“the ’130 patent”). Assertio Therapeutics, Inc.,formerly Depomed, Inc. (“Depomed”), is an exclusive licensee of both patents. Each patent is listed in the U.S. Food and Drug Administration ’s (“FDA”) Approved Drug Products with Therapeutic Equivalence Evaluations ( the “ Orange Book ”) for NUCYNTA ® ER (extended release), a tapentadol hydrochloride tablet. J.A. 52853, 52856. The ’364 patent is directed to the Form A polymorp h 1 of the chemical compound tapentadol hydrochloride and a method of treating pain and/or urinary incontinence

. 2 See ’364 patent, Abstract; id. col. 18 l. 66

– col. 19 l. 4. The ’364patent states that Form A “is very stable at ambient conditions and there fore useful for producing a pharmaceutical composition.” Id. col. 1 ll. 63

– 67. The asserted claims of the ’364 patent, claims 1, 2, 3, and 25, recite various X

- ray powder diffraction (XRPD) patterns. See, e.g.

, id. col. 18 l. 65

– col. 19 l. 4. XRPD is a method for measuring the X

- raysscattered by a polycrystalline sample as a function of scattering angle. Each polymorph has a unique XRPD.
The ’130 patent describes a method of using tapentadoland tapentadol hydrochloride for the treatment of polyneuro pathic pain. Polyneuropathic pain is a type of pain

1 A polymorph is a chemical compound that can present in different three

- dimensional crystalline structures.

2 The patent claims “ (

– )

- (1R,2R)

- 3

- (3

- dimethylamino

- 1

- ethyl

- 2

- methylpropyl)

- phenol hydrochloride

, ” which is tapentadol hydrochloride. ’364 patent, co l. 18 ll. 66

– 67; see also Gr ü nenthal Br. 8.G RUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 4

caused by damage to multiple nerves. In contrast, mononeuropathic pain is pain associated with damage to a single nerve.
Claim 1 of the ’130 patent is directed to the method of treating “polyneuropathic pain” with tapentadol or “a pharmaceutically acceptable salt thereof,” i.e., tapentadol hydrochloride. ’130 patent, col. 18 ll. 2

– 7. Claim 2 is directedto the method of treating polyneuropathic pain using “a hydrochloric salt” of tapentadol, i.e., tape ntadol hydrochloride. Id. col. 18 ll. 8

– 10.

B. Prior Art References
There are two different polymorphs of tapentadol hydrochloride: Form A and Form B. Form B of tapentadolhydrochloride was known in the art and previously disclosed in U.S. Patent No. 6,24 8,737 (“the ’737 patent”), also assigned to Gr ü nenthal. See ’364 patent, col. 1 ll. 58

– 63.The ’737 patent discloses a number of compounds, including tapentadol hydrochloride, intended to have an analgesic effect suitable for the treatment of pain. See, e.g. , ’737 patent, col. 1 l. 52

– col. 2 l. 36; id. , Example 25, col. 20 ll. 1

– 20. 3 Specifically, Example 25 of the ’737 patent discloses the steps for synthesizing tapentadol hydrochloride

. The ’737 patent states that tapentadol hydrochloride was crystallized, but it does not describe the resulting crystal structure, nor does it discuss polymorphs.
Also known in the art at the time of filing was the concept of polymorph screening, which is the practice of characterizing all crystal forms of a chemi cal compound. A

3 Example 25 incorporates by reference the synthesis steps of Example 24 and the synthesis preparation process of Example 2 of the ’737 patent. ’737 patent

, col. 20 ll. 18

– 20.G RUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 5

1995 article by Byrn et al. 4 (“Byrn”) “describes a conceptual approach to the characterization of pharmaceutical solids,”including a flow chart describing investigative steps to determine whether polymorphs are possible. J.A. 57372

– 73. Byrn does not outline a particular method to definitively test for polymorphism. 5 Instead, it provides a decision treeoutlining, among other things, different ways to gain additional information about whether polymorphs exist for a particular chemical co mpound and lists various analytical tests to identify polymorphs. J.A. 57373.
To determine whether polymorphs are possible, Byrn lists a number of solvents to be used in recrystallizing thesubstance in question. The listed solvents are water, methanol , ethanol, propanol, isopropanol, acetone, acetonitrile, ethyl acetate, and hexane. Id. Other variables such as temperature, concentration, agitation, and pH could affect the solids produced by recrystallization with these various solvents. Id. , Figure 1. This case focuses on the extent andlimits of what the disclosure in Byrn teaches about discovering polymorphs, if any, of a known compound, and ultimately, whether a skilled artisan would reasonably expect the recrystallization of tapentadol hydrochlo ride to resultin any polymorph, let alone one with the physical properties of Form A.

C. Proceedings in District Court

Gr ü nenthal and Depomed (collectively, “Cross

- Appellants”) brought suit against Alkem Laboratories Limited

4 Stephen Byrn et al., Pharmac eutical Solids: A Strategic Approach to Regulatory Considerations , 12 Pharmaceutical Res. 945 (1995).

5 Polymorphism is the ability of a compound to crystallize in more than one crystal arrangement but retain the same chemical structure. J.A. 8528 ( 228:11

– 14 ) ; J.A. 57373

.G RUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 6

(“Alkem”), Hikma Pharmaceutica ls International Limited, 6 Hikma Pharmaceuticals USA Inc. (collectively, “Hikma”), and Actavis Elizabeth LLC (“Actavis”), 7 alleging infringement of the ’364 and ’130 patents stemming from their respective Abbreviated New Drug Application (“ANDA”) filings s eeking to market generic versions of immediate and extended release tapentadol hydrochloride tablets. 8 All defendants subsequently stipulated to infringement of the ’364 patent. Alkem and Hikma challenged the validity of the ’364 and ’130 patents.

Afte r a bench trial, the district court concluded that Alkem infringes the ’130 patent, but that Actavis and Hikma do not. In re Depomed Patent Litig. , No. 13

- cv

- 4507

- CCC

- MF, 2016 WL 7163647, at *2 (D.N.J. Sept. 30, 2016) (“ Depomed Litigation ”). The district court also determined that the ’364 patent is not invalid as obvious, that the ’130 patent is not invalid as anticipated, and that the ’130

6 Hikma Pharmaceuticals International Limited was formerly known as West

- Ward Pharmaceuticals International Limited. During pendency of this appeal, defendant Roxane Laboratories, Inc. (“Roxane”) transferred ownership of its ANDA applications, which are at issue in the instant appeal, to West

- Ward Pharmaceuticals International Limited. ECF No. 65. As a result, West

- Ward Pharmaceuticals International Limited was substituted for Roxane in this appeal. ECF No. 66.

7 Gr ü nenthal and Depomed also brought suit against Actavis Laboratories UT, Inc., Actavis LLC, and Actavis, Inc. These defendants did not participate in this appeal.

8 U.S. Patent Nos. RE39,593 and 8,309,060 were also asserted. J.A. 33. U.S. Patent No. RE39,593 is not directly at issue in this appeal, but Hikma relies on it for purposes of its invalidity arguments. The proceedings involving U.S. Patent No. 8,309,060 were stayed by the district court. Id.G RUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 7

patent is not invalid due to obviousness

- type double patenting in light of U.S. Patent No. RE39,593. Id.

Alkem an d Hikma each appeal different aspects of the district court’s invalidity rulings. Gr ü nenthal and Depomed collectively appeal the district court’s finding of noninfringement of the ’130 patent. We have jurisdiction under 28 U.S.C. § 1295(a)(1).

D ISCUSSION Much of Hikma’s argument on appeal is made in the alternative and many of its arguments become moot shouldwe hold Hikma does not infringe the ’130 patent. Therefore, we will first address Cross

- Appellants’ arguments regarding noninfringement. We will t hen address Alkem’s appeal of the finding that the ’364 patent is not invalid as obvious and Hikma’s challenge to the utility and validity of the ’130 patent.

A. Infringement
We begin with a discussion of Gr ü nenthal and Depomed’s cross

- appeal. Because neither Hikma’s nor Actavis’s proposed label is indicated to treat polyneuropathic pain, and the case made by Gr ü nenthal and Depomed forindirect infringement depended on the proposed label indications, we agree with the trial court that Hikma and Actavis do not induce infringement of or contributorily infringe claims 1 and 2 of the ’130 patent.
Depomed has several NUCYNTA ® products used “for the management of moderate to severe acute pain in adults.” See J.A. 70

– 73. One of Depomed’s products, NUCYNTA ® ER (extended release), is a tablet approved for the following indications:

NUCYNTA ® ER is an opioid agonist indicated for the management of:

• moderate to severe chronic pain in adultsG RUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 8

• neuropathic pain associated with diabetic

pe ripheral neuropathy (DPN) in adults
when a continuous, around

- the

- clock opioid analgesic is needed for an extended period of time.
J.A. 50091 (emphasis added , reference numerals omitted ). The label makes no explicit reference to “polyneuropathic pain,” bu t DPN is a type of polyneuropathic pain. Depomed Br. 18, 20. The original label for NUCYNTA ® ER did not include the second indication to treat neuropathic pain. J.A. 50310.
Hikma and Actavis each filed ANDAs seeking approval to market a generic version of tapentadol hydrochloride extended release tablets. Both parties filed “Section viii” statements under 21 U.S.C. § 355(j)(2)(A)(viii), whereby Hikma and Actavis told FDA that they will not seek FDA approval for an indication directed to the treatment of DPN. J.A. 7290

– 91; see also J.A. 52858.
Induced Infringement
After a bench trial, this court reviews a district court’s judgment for legal error or clearly erroneous findings of fact. SmithKline Beecham Corp. v. Apotex Corp. , 403 F.3d 1331, 1337 (Fed. Cir. 2005). Infringement is a question of fact reviewed for clear error. AstraZeneca LP v. Apotex, Inc. , 633 F.3d 1042, 1056 (Fed. Cir. 2010) ( quoting Golden Blount, Inc. v. Robert H. Peterson Co. , 438 F.3d 1354, 1361 (Fed. Cir. 2006)) (internal quotati on mark s omitted); Alcon Research Ltd. v. Barr Labs., Inc. , 745 F.3d 1180, 1186 (Fed.Cir. 2014). A finding is clearly erroneous when “the reviewing court is left with the definite and firm conviction that a mistake has been made.” AstraZeneca , 633 F.3d at 1056.
In this case, the question of induced infringement turns on whether Hikma and Actavis have the specific intent, based on the contents of their proposed labels, to encourage physicians to use their proposed ANDA products to treat polyneuropathic p ain. See Takeda Pharm. U.S.A., Inc. v.G RUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 9

West

- Ward Pharm. Corp. , 785 F.3d 625, 631 (Fed. Cir. 2015). In other words, we ask whether the label encourages, recommends, or promotes infringement. Id. Depomed argues that because the Hikma and Actavis labels contain an indication for severe chronic pain, the labels will cause at least some users to infringe the ’130 patent because polyneuropathic pain is a common form of “severe chronic pain.” Depomed Br. 61

– 6 2.
“The pertinent question is whether the proposed label instructs users to perform the patented method.” AstraZeneca , 633 F.3d at 1060. In this case, we ask whether theHikma and Actavis labels instruct users to treat polyneuropathic pain with tapenta dol hydrochloride. They do not.
Actavis’s proposed ANDA product is indicated for “[p]ain severe enough to require daily, around

- the

- clock, long

- term opioid treatment.” J.A. 52679. Hikma’s proposed ANDA product has a similar indication, designated for “ [m]oderate to severe chronic pain in adults when a continuous, around

- the

- clock opioid analgesic is needed for an extended period of time.” J.A. 56864

– 65 ; see also Hikma Br. 23 . To support these indications, the Hikma and Actavis proposed labels cite chr onic lower back pain studies, a type of pain that both Cross

- Appellants and FDA defined as nociceptive. 9 At trial, experts on both sides testified that severe chronic pain could be neuropathic pain or nociceptive pain. E.g. , J.A. 9190 (169:9

– 17); J.A. 93 88 (40:15

– 22); J.A. 9389 (41:19

– 23); J.A. 9399 (51:20

– 22); J.A. 10630 (54:2

– 8); J.A. 11161 (12:4

– 14); J.A. 11208 (59:13

– 20)

. In other words , even if severe chronic pain includes polyneuropathic pain, it also includes mononeuropathic pain and nociceptive p ain. Therefore, the proposed ANDA labels do

9 Nociceptive pain is pain associated with damage to

non

- neura l tissue, or non

- nerve tissue.G RUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 10

not specifically encourage use of tapentadol hydrochloride for treatment of polyneuropathic pain.
Further, it is undisputed that neither of the accused ANDA labels list an indication for the management of pain

a ssociated with DPN. Nor do they mention any DPN clinical studies, which served as the basis for FDA approval of NUCYNTA ® ER’s indication for the treatment of neuropathic pain. In fact, both Hikma and Actavis filed “Section viii” statements with FDA speci fically carving out the neuropathic pain indication. Accordingly, we agree with thedistrict court that these labels do not encourage infringement of the ’130 patent. See Takeda , 785 F.3d at 631 (“Thelabel must encourage, recommend, or promote infringem ent.”).

Cross

- Appellants rely heavily on the holding in AstraZeneca LP v. Apotex, Inc. , where we held that if the label instructs “at least some users” to infringe the patent, then specific intent to induce infringement may be inferred. 633 F.3d at 1059

– 6 0

. But AstraZeneca is inapposite to ourfacts. We held that specific intent could be inferred because the defendant proceeded with a plan to distribute the generic drug knowing that its label posed infringement problems. Id. In addition, the instructio ns in the DOSAGEAND ADMINISTRATION section of the label “would inevitably lead some consumers to practice the claimed method” of once

- daily dosing by encouraging users to taper downward to the “lowest effective dose” and showing the lowest effective dose to be the lowest available strength, administered daily. Id. at 1057, 1059

– 60. Here, Gr ü nenthal and Depomed point only to the indications of the proposed labels as grounds for inducement, which, as explained above, do not implicitly or explicitly encoura ge or instruct users to take action that would inevitably leadto use of tapentadol hydrochloride for treatment of polyneuropathic pain. Therefore, we discern no clear error anduphold the district court’s finding of no induced infringement.G RUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 11

Contributory Infringement
To establish liability for contributory infringement, a patent owner must show, inter alia , that there are no substantial noninfringing uses for the accused product. 35 U.S.C. § 271(c). A noninfringing use is substantial when it is “not unus ual, far

- fetched, illusory, impractical, occasional, aberrant, or experimental.” Toshiba Corp. v. Imation Corp. , 681 F.3d 1358, 1362 (Fed. Cir. 2012) (quoting Vita

- Mix Corp. v. Basic Holding, Inc. , 581 F.3d 1317, 1327 (Fed. Cir. 2009)). In a pharmaceutic al case, the non

infringing use must be in accordance with the use for which the product is indicated. Eli Lilly and Co. v. Actavis Elizabeth LLC , 435 F. App’x 917, 927 (Fed. Cir. 2011) (“[U]nauthorized activity does not avoid infringement by a product th at is authorized to be sold solely for the infringing use.”).
The question before us is whether the noninfringing uses Hikma and Actavis identified for the district court are “substantial.” Cross

- Appellants argue that any non

- infringing uses for the propo sed ANDA products are “rare” and not substantial. Depomed Response Br. 74. We disagree and find no clear error in the district court’s finding that Hikma and Actavis do not contributorily infringe the ’130 patent.
The district court weighed the testimo ny of all experts in this case, giving due consideration to both Cross

- Appellants’ and Appellants’ experts. Cross

- Appellants’ expertsopined that most of the uses of the proposed ANDA products would be directed to chronic, polyneuropathic pain. Appellant s’ experts, some of whom included practicing physicians, provided testimony about the use of tapentadol hydrochloride in their respective practices, includingstatements that they have prescribed opioids to treat severe chronic pain conditions that are noc iceptive or not polyneuropathic. They testified that treating nociceptive ormononeuropathic conditions with tapentadol hydrochloride would not be unusual. Although there appears to beG RUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 12

evidence supporting both positions, the court made credibility determ inations that supported Hikma and Actavis’s theory of noninfringement. We see no reason to disturb those findings. See Nilssen v. Osram Sylvania, Inc. , 504 F.3d 1223, 1231

– 32 (Fed. Cir. 2007) (“While an opposite conclusion could have been reached, it is not the function of a court of appeals to override district court judgments on close issues, where credibility findings have been made.”); Agfa Corp. v. Creo Prods. Inc. , 451 F.3d 1366, 1379 (Fed. Cir. 2006) (“This court must defer heavily to the trial court’s credibility determinations.”).

B. Obviousness
Obviousness is a question of law with underlying factual findings related to, among other things, the sc ope and content of the prior art, whether a person of ordinary skill in the art (“POSA”) would have had reason to combine or modify the prior art to arrive at the claimed invention, and in so doing, would have had a reasonable expectation of

success

. IXI IP, LLC v. Samsung Elecs. Co., Ltd. , 903 F.3d 1257, 1262 (Fed. Cir. 2018); ZUP, LLC v. Nash Mfg., Inc.

, 896 F.3d 1365, 1371 (Fed. Cir. 2018).
On appeal, Alkem argues that , at least because of FDAguidance suggesting the undertaking of polymorph screenings for pharmaceutical solids, the district court clearly erred in finding no motivation to combine. We need not address that challenge because Alkem acknowledges that it also had to prove a reasonable expectation of success in arriving at Form A or, relatedl y, it would have been obviousto try to find a polymorph of Form B of tapentadol hydrochloride. Based on the district court’s findings of fact, weconclude that Alkem has not met those standards. Consequently, we reject the challenge to the district court ’s holding that Alkem failed to prove obviousness.G RUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 13

Reasonable Expectation of Success
The district court did not clearly err in finding that aPOSA would not have had a reasonable expectation of successfully producing Form A, as claimed in the ’364 patent, by using the methods outlined in Byrn on the compound disclosed in the ’737 patent (F orm B). As an initial matter, polymorphism of tapentadol hydrochloride was unknown at the time of filing the ’364 patent. Form B was the only crystal structure of tapentadol hydrochloride known in the art at the time. See J.A. 8567 (267:13

– 21); 9772

– 73 (50:11

– 51:10). As the record reflects, polymorphism does not occur in all compounds. Depomed Litigation , 2016 WL 7163647, at *51 (“Dr. Bernstein testified that about 30 to 35% of all compounds are polymorphic.”); see also J.A. 57373 (“The first step in t he polymorph decision tree is .

. . to attempt to answer the question: Are polymorphs possible?”).
The Byrn article presents a flow chart that outlines anumber of variables that may be adjusted during the recrystallization process to determine whether pol ymorphism occurs in a compound. Figure 1 below is the polymorph s tree presented in Byrn.G RUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 14

J.A. 57373. At the outset, Byrn lists a number of solvents to be used to recrystallize a substance to first determine whether polymorphs are possible. “Solvents s hould include those used in the final recrystallization steps and thoseused during formulation and processing and may also include water, methanol, ethanol, propanol, isopropanol, acetone, acetonitrile, ethyl acetate, hexane and mixtures if appropriate.” Id. Byrn does not disclose when it would beappropriate to use particular solvents or a particular mixture of solvents for recrystallization.
Byrn also instructs a POSA to “vary temperature, concentration, agitation, pH.” Id. , Figure 1. Dr. Bernstein, Cross

- Appellants’ expert, testified that when it comes to solution recrystallization “there’s a huge variety of solvents with temperatures, whether you stir or not, and .

. . the crystallization is generally carried out by cooling. So the cooling rate can be a major factor in determining what you get.” J.A. 10489

– 90 (142:24

– 143:3). But Byrn does not provide guidelines regarding which temperature, concentration, agitation, or pH levels are likely to result in polymorphs of particular compounds. It only n otes thatG RUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 15

these parameters should be varied. This lack of disclosure supports Dr. Bernstein’s testimony that a POSA would have to manipulate the variables to “determine what the crystal form landscape looks like” because “you don’t know what the result’s going to be.” J.A. 10493 (146:11

– 24). Indeed, a POSA could alter any number of variables and still fail to find a polymorph of a particular compound. J.A. 10494 (147:20

– 25); J.A. 8528 (228:15

– 21) (noting that polymorph investigations require varying par ameters like temperature and solvents to “extend as broad as possible [the] range of investigations.”); see also Pfizer, Inc. v. Apotex, Inc. , 480 F.3d 1348, 1365 (Fed. Cir. 2007) (“To be sure, ‘to have a reasonable expectation of success, one must be moti vated to do more than merely vary all parameters ortry each of numerous possible choices until one possibly arrived at a successful result, where the prior art gave eitherno indication of which parameters were critical or no direction as to which of many possible choices is likely to be successful.’” (quoting Medichem, S.A. v. Rolabo, S.L. , 437 F.3d 1157, 1165 (Fed. Cir. 2006)). Consequently, we hold thatthe district court did not clearly err in crediting Dr. Bernstein’s testimony or concluding that Byr n provides insufficient guidance in discussing the wide array of conditionsthat could affect recrystallization, and therefore, the crystal structure of a resulting compound. See Depomed Litigation , 2016 WL 7163647, at *52

– 53.
Despite the lack of disclosu re in Byrn, Alkem argues that any polymorph screening of a sample of tapentadol hydrochloride would result in Form A, either in whole or in part , because Form A is more stable at room temperature

. Alkem contends that it is “not disputed” that the synthesis described in Example 25 of the ’737 patent resulted in at least some Form A. Alkem Br. 34. In other words, Alkem asserts a POSA would have likely performed polymorph screening on a sample with some F orm A if following the synthesis steps of Example 25. The record, however, does not support Alkem’s argument.G RUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 16

Alkem advanced this same argument before the district court to allege that the ’737 patent inherently anticipates the ’364 patent, an issue tha t is not before us. The district court rejected Alkem’s inherent anticipation theorybecause the method of synthesis that Alkem used, for purposes of this litigation, to produce a sample of tapentadol hydrochloride that comprised a mixture of Form A and F orm B was not performed in accordance with the three steps outlined in Example 25 of the ’737 patent. Depomed Litigation , 2016 WL 7163647, at *4 5

– 50. Instead, the mixture of Form A and Form B that Alkem relied on at trial was a result of performing only one of the three steps described in Example 25, whereas testimony showed thatfully performing each of the three steps outlined in Example 25 results in only Form B. Id. at *46, *48, *50; see also J.A. 8557

– 60 (257:10

– 260:3) (stating resynthesis of Examp le 25 resulted in Form B); J.A. 8561 (261:11

– 19) (Example 25 resynthesis resulted in Form B and no Form A); J.A. 10497

– 10503 (150:20

– 156:21) (stating faithful reproductions of Example 25 result in only Form B, not Form A); J.A. 9729

– 30 (7:16

– 8:18) (same). Given the weight of evidence, we do not believe the district court clearly erred in concluding that Alkem failed to prove that synthesizing tapentadol hydrochloride according to Example 25 of the ’737 patent resulted in only Form B. In addition, a POSA

w ould not reasonably expect any polymorph screening of Form B to necessarily result in the “most stable form” of tapentadol hydrochloride (Form A, as Alkem argues). S ee J.A. 9773 (51:6

– 14) (stating there is no way to predict the most stable form without te sting). Because the record indicates that there was (1) no known or expected polymorphism of tapentadol; (2) no evidence that the synthesis of Example 25 results in any Form A; and (3) no guidance as to what particular solvents, temperatures, agitation ra tes, etc., were likely to result in Form A, Alkem failed to prove that a POSA would have reasonably expected a polymorphscreening of the Form B disclosed in the ’737 patent to result in Form A.G RUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 17

Alkem also argues that the district court applied the wrong l egal standard in its obviousness inquiry, requiring“absolute predictability,” as opposed to a reasonable expectation of success. Indeed, in each of the cases Alkem cites, we did not require “absolute predicta bility,” but acknowledged that the combination of prior art disclosures resulted in a predictable outcome. See Pfizer , 480 F.3d at 1364; AstraZeneca LP v. Breath Ltd. , 603 F. App’x 999, 1001

– 02 (Fed. Cir. 2015) (“ Breath ”) ; see also Cubist Pharm., Inc. v. Hospira, Inc.

, 805 F.3d 1112, 1128

– 29 (Fed. Ci r. 2015)

. However, each of these cases is inapposite to the facts at hand.
For example, in Pfizer , Inc. v. Apotex, Inc. , we determined that a POSA would have had a reasonable expectation of success to make amlodipine besylate based on the disclosure of am lodipine and a list of “53 FDA

- approved, commercially marketed anions.” 480 F.3d at 1355, 1361

– 69. Under the “particularized facts of [ Pfizer ],” such expectation was reasonable because a POSA would have narrowed the list of 53 anions “to a few” due to kn own characteristics of the anions. Id. at 1363, 1366

– 67. Inother words, it was reasonable to expect that the combination of amlodipine and benzene sulphonate

— one of the 53 anions disclosed the prior art

— would likely result in amlodipine besylate because of the known acid strength, solubility, and other chemical characteristics of the benzene sulphonate

. Id. at 1363.

In AstraZeneca LP v. Breath Ltd.

, we concl uded that a POSA would have had a reasonable expectation of success of producing the claimed sterile budesonide compositionusing known sterilization techniques even if the level of purity resulting from the methods was not actually known. 603 F. App’x at 1001

– 02. We did not require “actual success” in creating the claimed invention because the record abundantly supported the conclusion that four out of five known sterilization techniques would result in a sterileG RUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 18

budesonide product that met the purity li mitations of the claims. Id. at 1002.

In Cubist Pharmaceuticals, Inc. v. Hospira, Inc. , we agreed with the district court’s determination that it would have been obvious to use well

- known purification techniques to produce a daptomycin

- related substance having the recited purity levels . 805 F.3d at 1127, 1129. The asserted purity claims in Cubist recited each of the purification techniques that were described in the prior art. Id. at 1127

– 29. Using these purification techniques, the purity levels dis closed in each of these claims could be achieved. Id. at 1128 (“The purity patents do not point to any additional techniques that are necessary to obtain the recitedpurity levels in each of the claims.”). Therefore, we concluded a POSA would have had a reasonable expectation of success in achieving the claimed purity levels because the purification techniques claimed in the patents used to achieve said purity levels were already known in the art. Id. at 1129.
The prior art processes described in Brea th and Cubist were each known to purify substances, and therefore it was reasonably predictable that these methods would result in purity levels described in the claims. In Pfizer , the realmof possible anions could be reduced to a manageable number based on known properties of the anions, thus providing a POSA with a reasonable expectation of success. Here, a POSA did not know, or have reason to know, that tapentadol hydrochloride is polymorphic. Nor could a POSA know, or have reason to know, how the mul tiple variables involved in conducting a polymorph screen would affect the recrystallization of tapentadol hydrochloride . Byrn does not provide any guidance as to how the different solvents, varying temperatures, rates of agitation, or other variables

use d in polymorph screenings should be manipulated to even determine whether polymorphism occurs. Cf. KSR Int’l Co. v. Teleflex Inc. , 550 U.S. 398, 417 (2007) ( “ I f a person of ordinary skill can implement a predictable variation,G RUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 19

§ 103 likely bars its patentability.” ); DePuy Spine , Inc. v. Medtronic Sofamor Danek, Inc. , 567 F.3d 1314, 1326 (Fed. Cir. 2009) ( noting “predictability is a touchstone of obviousness”). This lack of knowledge in the field shows there was little to no basis from which a POSA c ould expect a probability of success in producing Form A.
Our decision today does not rule out the possibility thatpolymorph patents could be found obvious. But on the record here, the district court did not clearly err in finding a failure to prove that a POSA would have had a reasonable expectation of success at arriving at the claimed invention based on the prior art. As a result, we hold the districtcourt did not commit legal error in concluding the ’364 patent is not invalid as obvious.

Obvious t o Try
Alkem contends that because Byrn discloses a finite number of solvents to use for recrystallization, it would have been obvious to try to produce Form A of tapentadol hydrochloride. To prove obviousness under an obvious to try theory, Alkem must sho w (1) a design or market need to solve a particular problem, and (2) that “there are a finite number of identified, predictable solutions” that would lead to an expectation of success. KSR , 550 U.S. at 421 (emphasis added).
As stated above, the district court did not clearly err in finding that Byrn identified many variables for screening, i.e., a “huge number of possible choices,” as opposed to a “finite number,” as contemplated in KSR

. See Depomed Litigation , 2016 WL 7163647, at *53; see also KSR , 550U.S. at 421. Rather, Byrn simply provides “a general approach” to polymorph screening, only giving “general guidance,” without providing “detailed enabling methodology.” In re Kubin , 561 F.3d 1351, 1359

– 60 (Fed. Cir. 2009) (quoting In re O’Farrell , 853 F.2d 894, 902

– 03 (Fed. Cir. 1988)). This court has explained that a conclusion of obviousness does not follow from merely “vary[ing] all parameters orG RUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 20

try[ing] each of numerous possible choices until one possibly arrived at a successful result, where the prior art gave either no indication of which parameters were critical or no direction as to which of many possible choices is likely to be successful.” Id. at 1359 (quoting O’Farrell , 853 F.2d at 903) . As already explained, the district court did not cle arly err in finding that a POSA would not have had a reasonable expectation of producing Form A using the disclosure of the ’737 patent and Byrn. Therefore, for the reasons stated above, it would not have been obvious to try to produce Form A based on the prior art in the record.

C. Utility
We now turn to the question of the ’364 patent’s utility. Utility is a question of fact. Stiftung v. Renishaw PLC , 945 F.2d 1173, 1180 (Fed. Cir. 1991); Raytheon Co. v. Roper Corp. , 724 F.2d 951, 956 (Fed. Cir. 1983). The bar for utility is not high. Juicy Whip, Inc. v. Orange Bang, Inc. , 185 F.3d 1364, 1366 (Fed. Cir. 1999). Nonetheless, a patent must have specific and substantial utility. In re Fisher , 421 F.3d 1365, 1371 (Fed . Cir. 2005) (citing Fujikawa v. Wattanasin , 93 F.3d 1559, 1563 (Fed. Cir. 1996)). The s ubstantial requirement , also known as “ practical utility, ” is satisfied when “ the claimed invention has a significant and presently available benefit to the public.” Id. To satisfy the specific prong of utility, the claimed invention must show that it can “ provide a well

- defined and particular benefit to the public.” Id. In other words, a patent has utilityif the alleged invention is capable of providing some ident ifiable benefit presently available to the public. Id. A patent fails to satisfy the utility requirement under 35 U.S.C. § 101 only if the invention is “totally incapable of achieving a useful result.” Brooktree Corp. v. Advanced Micro Devices, Inc. , 97 7 F.2d 1555, 1571 (Fed. Cir. 1992). For pharmaceutical patents, practical utility may be shown by evidence of “any pharmacological activity.” Fujikawa , 93 F.3d at 1564.G RUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 21

Hikma contends that the ’364 patent lacks specific utility because the specificatio n vaguely states that “Crystalline Form A .

. . has the same pharmacological activity as Form B but is more stable under ambient conditions. It can be advantageously used as [an] active ingredient in pharmaceutical compositions.” ’364 patent, col. 4 ll. 13

– 16. Hikma argues this disclosure fails to provide a “well

- defined and particular benefit to the public.” Hikma Br. 32 (citing In re Fisher , 421 F.3d 1365, 1371 (Fed. Cir. 2005)).
Hikma’s arguments are without merit. The ’364 patent teaches that “[t ]he crystalline Form A according to the invention is used for the treatment of pain or the treatment of urinary incontinence.” ’364 patent, col. 4 ll. 63

– 65; s ee also id. , Abstract. The prior art confirms that tapentadol hydrochloride was known as an ana lgesic at the time of filing of the ’364 pat ent, as does the expert testimony given at trial. E.g. , J.A. 58128; J.A. 9843 (121:15

– 17); J.A. 10898 (21:3

– 17). Therefore, the ’364 patent concretely discloses the practical benefit of Form A of tapentadol hyd rochloride as an analgesic.
Hikma next argues that to show substantial utility,Form A’s superior stability over Form B at room temperature must not only be proven, but must be proven by test data. Hikma attempts to set too high a bar for purposes of find ing a sufficient disclosure of utility. While test resultsoften support claims of utility in patents concerning pharmacological arts, such testing is not always required. Rasmusson v. SmithKline Be e cham Corp. , 413 F.3d 1318, 1323 (Fed. Cir. 2005) (“[I]t is proper for the examiner to ask for substantiating evidence unless one with ordinary skill in the art would accept the allegations as obviously correct.” (quoting In re Jolles , 628 F.2d 1322, 1325 (CCPA 1980) ). Nor do said results need to prove the cla imed utility. E.g.

, Fujikawa , 93 F.3d at 1564 (“[T]est results need not absolutely prove that the compound is pharmacologically active. All that is required is that the tests be reasonably indicative of the desired [pharmacological] response.”G RUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 22

(internal quotations and citations omitted)). All that is necessary is evidence that a POSA would accept the claimed utility as correct.

The district court found that a POSA would have believed that, at the time of filing the ’364 patent, Form A

was mor e stable than Form B at room temperature, i.e., “ambient conditions.” Example 16 describes a variable temperature XRPD experiment that produced Form B from Form A at temperatures (40

– 50o C) higher than room temperature. ’364 patent, col. 18 ll. 53

– 57. T his effect is “reversible with Form B changing over into Form A at lower temperature.” Id. col. 18 ll. 56

– 57. Expert testimony confirmed the results of Example 16, namely that Form A is stable at room temperature and Form B is stable above 50o C. J.A. 10 471

– 72 (124:9

– 125:6); see also J.A. 9694

– 96 (57:14

– 59:7) ; J.A. 9800

– 02 (78:25

– 80:20). There is sufficient proof that the disclosure of Example 16 is reasonably indicative of the stability of Form A at room temperature. There is also sufficient evidence t hat thermodynamic stability is considered beneficial for purposes of storage and consistency in manufacturing, which can be beneficial characteristics for pharmaceutical compositions. J.A. 9107 (86:18

– 23), J.A. 9798 (76:9

– 12). Cross

- appellants need not

p rove that Form A has superior stability over Form B for purposes of determining utility. See Demaco Corp. v. F. Von Langsdorff Licensing, Ltd. , 851 F.2d 1387, 1390 (Fed.Cir. 1988) (“The patent statute does not require that a patentable invention be super ior to all prior devices.”). It issufficient that Form A is shown to be stable at room temperature and useful for pain relief.
For these reasons, we hold that the district court’s finding of utility was not clearly erroneous.
Hikma makes additional arguments regarding the validity of the ’130 patent to be considered only if this court

reverses the district court’s findings of noninfringement ofG RUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 23

the ’130 patent. Because we affirm the findings of noninfringement, we need not rea ch these issues.

C ONCLUSION

For the foregoing reasons, we affirm the judgment of the district court.

AFFIRMED

COSTS

No costs

.