Grunenthal Gmbh v. Alkem Laboratories Limited

United States Court of Appeals
for the Federal Circuit
______________________
GRUNENTHAL GMBH, ASSERTIO
THERAPEUTICS, INC.,
Plaintiffs-Cross-Appellants
v.
ALKEM LABORATORIES LIMITED, HIKMA
PHARMACEUTICALS INTERNATIONAL LIMITED,
HIKMA PHARMACEUTICALS USA INC.,
Defendants-Appellants
ACTAVIS ELIZABETH LLC,
Defendant-Appellee
ACTAVIS LABORATORIES UT, INC.,
Defendant
______________________
2017-1153, 2017-2048, 2017-2049, 2017-2050
______________________
Appeals from the United States District Court for the
District of New Jersey in Nos. 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
______________________
2 GRUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED
MICHAEL SITZMAN, Gibson, Dunn & Crutcher LLP, San
Francisco, CA, argued for all plaintiffs-cross-appellants.
Plaintiff-cross-appellant Assertio Therapeutics, Inc. also
represented by JAYSEN CHUNG; CHRISTINE RANNEY, Den-
ver, CO; TIMOTHY P. BEST, Los Angeles, CA.
LINDA A. WADLER, Finnegan, Henderson, Farabow,
Garrett & Dunner, LLP, Washington, DC, for plaintiff-
cross-appellant Grunenthal GmbH. Also represented by
KRISTA E. BIANCO.
MICHAEL E. JOFFRE, Sterne Kessler Goldstein & Fox,
PLLC, Washington, DC, argued for defendant-appellee.
Also represented by WILLIAM H. MILLIKEN.
ROBERT J. GAJARSA, Latham & Watkins LLP, Washing-
ton, DC, argued for defendants-appellants Hikma Pharma-
ceuticals International Limited, Hikma Pharmaceuticals
USA Inc. Also represented by KENNETH G. SCHULER, Chi-
cago, IL; GREGORY SOBOLSKI, San Francisco, CA.
IMRON T. ALY, Schiff Hardin, Chicago, IL, argued for
defendant-appellant Alkem Laboratories Limited. Also
represented by CINDY AHN, JASON HARP, NEIL LLOYD;
AHMED M.T. RIAZ, New York, NY.
______________________
Before REYNA, TARANTO, and CHEN, Circuit Judges.
REYNA, Circuit Judge.
Alkem Laboratories Limited, Hikma Pharmaceuticals
International Limited, and Hikma Pharmaceuticals USA
Inc. appeal the judgment of the district court that U.S. Pa-
tent No. 7,994,364 is not invalid for obviousness or lack of
utility. Grünenthal 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 do
GRUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 3
not infringe U.S. Patent No. 8,536,130. Because the dis-
trict court did not err in its conclusions, we affirm.
BACKGROUND
A. Patents at Issue
Grünenthal GmbH (“Grünenthal”) 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 licen-
see of both patents. Each patent is listed in the U.S. Food
and Drug Administration’s (“FDA”) Approved Drug Prod-
ucts with Therapeutic Equivalence Evaluations (the “Or-
ange Book”) for NUCYNTA® ER (extended release), a
tapentadol hydrochloride tablet. J.A. 52853, 52856. The
’364 patent is directed to the Form A polymorph 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 ’364
patent states that Form A “is very stable at ambient condi-
tions and therefore 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-rays
scattered by a polycrystalline sample as a function of scat-
tering angle. Each polymorph has a unique XRPD.
The ’130 patent describes a method of using tapentadol
and tapentadol hydrochloride for the treatment of polyneu-
ropathic pain. Polyneuropathic pain is a type of pain
1 A polymorph is a chemical compound that can pre-
sent in different three-dimensional crystalline structures.
2 The patent claims “(–)-(1R,2R)-3-(3-dimethyla-
mino-1-ethyl-2-methylpropyl)-phenol hydrochloride,”
which is tapentadol hydrochloride. ’364 patent, col. 18 ll.
66–67; see also Grünenthal Br. 8.
4 GRUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED
caused by damage to multiple nerves. In contrast, mo-
noneuropathic 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 phar-
maceutically acceptable salt thereof,” i.e., tapentadol hy-
drochloride. ’130 patent, col. 18 ll. 2–7. Claim 2 is directed
to the method of treating polyneuropathic pain using “a hy-
drochloric salt” of tapentadol, i.e., tapentadol hydrochlo-
ride. Id. col. 18 ll. 8–10.
B. Prior Art References
There are two different polymorphs of tapentadol hy-
drochloride: Form A and Form B. Form B of tapentadol
hydrochloride was known in the art and previously dis-
closed in U.S. Patent No. 6,248,737 (“the ’737 patent”), also
assigned to Grünenthal. See ’364 patent, col. 1 ll. 58–63.
The ’737 patent discloses a number of compounds, includ-
ing tapentadol hydrochloride, intended to have an analge-
sic 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 crys-
tallized, but it does not describe the resulting crystal struc-
ture, nor does it discuss polymorphs.
Also known in the art at the time of filing was the con-
cept of polymorph screening, which is the practice of char-
acterizing all crystal forms of a chemical compound. A
3 Example 25 incorporates by reference the synthe-
sis steps of Example 24 and the synthesis preparation pro-
cess of Example 2 of the ’737 patent. ’737 patent, col. 20 ll.
18–20.
GRUNENTHAL 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 de-
termine 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 tree
outlining, among other things, different ways to gain addi-
tional information about whether polymorphs exist for a
particular chemical compound 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 the
substance in question. The listed solvents are water, meth-
anol, 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 and
limits of what the disclosure in Byrn teaches about discov-
ering polymorphs, if any, of a known compound, and ulti-
mately, whether a skilled artisan would reasonably expect
the recrystallization of tapentadol hydrochloride to result
in any polymorph, let alone one with the physical proper-
ties of Form A.
C. Proceedings in District Court
Grünenthal and Depomed (collectively, “Cross-Appel-
lants”) brought suit against Alkem Laboratories Limited
4 Stephen Byrn et al., Pharmaceutical Solids: A
Strategic Approach to Regulatory Considerations, 12 Phar-
maceutical Res. 945 (1995).
5 Polymorphism is the ability of a compound to crys-
tallize in more than one crystal arrangement but retain the
same chemical structure. J.A. 8528 (228:11–14); J.A.
57373.
6 GRUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED
(“Alkem”), Hikma Pharmaceuticals International Lim-
ited, 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 seeking to market generic versions of im-
mediate and extended release tapentadol hydrochloride
tablets. 8 All defendants subsequently stipulated to in-
fringement of the ’364 patent. Alkem and Hikma chal-
lenged the validity of the ’364 and ’130 patents.
After 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 Inter-
national Limited. During pendency of this appeal, defend-
ant Roxane Laboratories, Inc. (“Roxane”) transferred
ownership of its ANDA applications, which are at issue in
the instant appeal, to West-Ward Pharmaceuticals Inter-
national Limited. ECF No. 65. As a result, West-Ward
Pharmaceuticals International Limited was substituted for
Roxane in this appeal. ECF No. 66.
7 Grünenthal 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.GRUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 7
patent is not invalid due to obviousness-type double pa-
tenting in light of U.S. Patent No. RE39,593. Id.Alkem and Hikma each appeal different aspects of the
district court’s invalidity rulings. Grünenthal 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).
DISCUSSION
Much of Hikma’s argument on appeal is made in the
alternative and many of its arguments become moot should
we hold Hikma does not infringe the ’130 patent. There-
fore, we will first address Cross-Appellants’ arguments re-
garding noninfringement. We will then 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 Grünenthal and
Depomed’s cross-appeal. Because neither Hikma’s nor Ac-
tavis’s proposed label is indicated to treat polyneuropathic
pain, and the case made by Grünenthal and Depomed for
indirect infringement depended on the proposed label indi-
cations, we agree with the trial court that Hikma and Ac-
tavis 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 adults
8 GRUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED
• neuropathic pain associated with diabetic
peripheral neuropathy (DPN) in adults
when a continuous, around-the-clock opioid analge-
sic 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,” but 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 ex-
tended 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 quotation marks omitted); Alcon
Research Ltd. v. Barr Labs., Inc., 745 F.3d 1180, 1186 (Fed.
Cir. 2014). A finding is clearly erroneous when “the review-
ing 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 pain. See Takeda Pharm. U.S.A., Inc. v.
GRUNENTHAL 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 encour-
ages, recommends, or promotes infringement. Id.Depomed argues that because the Hikma and Actavis la-
bels contain an indication for severe chronic pain, the la-
bels will cause at least some users to infringe the ’130
patent because polyneuropathic pain is a common form of
“severe chronic pain.” Depomed Br. 61–62.
“The pertinent question is whether the proposed label
instructs users to perform the patented method.” Astra-
Zeneca, 633 F.3d at 1060. In this case, we ask whether the
Hikma and Actavis labels instruct users to treat polyneu-
ropathic pain with tapentadol 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 pro-
posed ANDA product has a similar indication, designated
for “[m]oderate to severe chronic pain in adults when a con-
tinuous, 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 Ac-
tavis proposed labels cite chronic 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 nocicep-
tive pain. E.g., J.A. 9190 (169:9–17); J.A. 9388 (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 polyneu-
ropathic pain, it also includes mononeuropathic pain and
nociceptive pain. Therefore, the proposed ANDA labels do
9 Nociceptive pain is pain associated with damage to
non-neural tissue, or non-nerve tissue.
10 GRUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED
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
associated with DPN. Nor do they mention any DPN clin-
ical studies, which served as the basis for FDA approval of
NUCYNTA® ER’s indication for the treatment of neuro-
pathic pain. In fact, both Hikma and Actavis filed “Section
viii” statements with FDA specifically carving out the neu-
ropathic pain indication. Accordingly, we agree with the
district court that these labels do not encourage infringe-
ment of the ’130 patent. See Takeda, 785 F.3d at 631 (“The
label must encourage, recommend, or promote infringe-
ment.”).
Cross-Appellants rely heavily on the holding in Astra-
Zeneca 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 1059–60. But AstraZeneca is inapposite to our
facts. We held that specific intent could be inferred be-
cause the defendant proceeded with a plan to distribute the
generic drug knowing that its label posed infringement
problems. Id. In addition, the instructions in the DOSAGE
AND ADMINISTRATION section of the label “would inev-
itably 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, Grünen-
thal and Depomed point only to the indications of the pro-
posed labels as grounds for inducement, which, as
explained above, do not implicitly or explicitly encourage
or instruct users to take action that would inevitably lead
to use of tapentadol hydrochloride for treatment of poly-
neuropathic pain. Therefore, we discern no clear error and
uphold the district court’s finding of no induced infringe-
ment.
GRUNENTHAL 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 sub-
stantial noninfringing uses for the accused product.
35 U.S.C. § 271(c). A noninfringing use is substantial
when it is “not unusual, far-fetched, illusory, impractical,
occasional, aberrant, or experimental.” Toshiba Corp. v.
Imation Corp., 681 F.3d 1358, 1362 (Fed. Cir. 2012) (quot-
ing Vita-Mix Corp. v. Basic Holding, Inc., 581 F.3d 1317,
1327 (Fed. Cir. 2009)). In a pharmaceutical case, the non-
infringing use must be in accordance with the use for which
the product is indicated. Eli Lilly and Co. v. Actavis Eliz-
abeth LLC, 435 F. App’x 917, 927 (Fed. Cir. 2011) (“[U]nau-
thorized activity does not avoid infringement by a product
that 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-in-
fringing uses for the proposed ANDA products are “rare”
and not substantial. Depomed Response Br. 74. We disa-
gree 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 testimony of all experts
in this case, giving due consideration to both Cross-Appel-
lants’ and Appellants’ experts. Cross-Appellants’ experts
opined that most of the uses of the proposed ANDA prod-
ucts would be directed to chronic, polyneuropathic pain.
Appellants’ experts, some of whom included practicing phy-
sicians, provided testimony about the use of tapentadol hy-
drochloride in their respective practices, including
statements that they have prescribed opioids to treat se-
vere chronic pain conditions that are nociceptive or not pol-
yneuropathic. They testified that treating nociceptive or
mononeuropathic conditions with tapentadol hydrochlo-
ride would not be unusual. Although there appears to be
12 GRUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED
evidence supporting both positions, the court made credi-
bility determinations 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 fac-
tual findings related to, among other things, the scope 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 FDA
guidance suggesting the undertaking of polymorph screen-
ings 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, relatedly, it would have been obvious
to try to find a polymorph of Form B of tapentadol hydro-
chloride. Based on the district court’s findings of fact, we
conclude that Alkem has not met those standards. Conse-
quently, we reject the challenge to the district court’s hold-
ing that Alkem failed to prove obviousness.
GRUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 13
Reasonable Expectation of Success
The district court did not clearly err in finding that a
POSA would not have had a reasonable expectation of suc-
cessfully producing Form A, as claimed in the ’364 patent,
by using the methods outlined in Byrn on the compound
disclosed in the ’737 patent (Form 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 the polymorph decision tree is . . . to attempt
to answer the question: Are polymorphs possible?”).
The Byrn article presents a flow chart that outlines a
number of variables that may be adjusted during the re-
crystallization process to determine whether polymor-
phism occurs in a compound. Figure 1 below is the
polymorphs tree presented in Byrn.
14 GRUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED
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 should include
those used in the final recrystallization steps and those
used during formulation and processing and may also in-
clude water, methanol, ethanol, propanol, isopropanol, ac-
etone, acetonitrile, ethyl acetate, hexane and mixtures if
appropriate.” Id. Byrn does not disclose when it would be
appropriate to use particular solvents or a particular mix-
ture of solvents for recrystallization.
Byrn also instructs a POSA to “vary temperature, con-
centration, agitation, pH.” Id., Figure 1. Dr. Bernstein,
Cross-Appellants’ expert, testified that when it comes to so-
lution 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 pro-
vide guidelines regarding which temperature, concentra-
tion, agitation, or pH levels are likely to result in
polymorphs of particular compounds. It only notes that
GRUNENTHAL 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). In-
deed, 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 pol-
ymorph investigations require varying parameters like
temperature and solvents to “extend as broad as possible
[the] range of investigations.”); see also Pfizer, Inc. v. Apo-
tex, Inc., 480 F.3d 1348, 1365 (Fed. Cir. 2007) (“To be sure,
‘to have a reasonable expectation of success, one must be
motivated to do more than merely vary all parameters or
try each of numerous possible choices until one possibly ar-
rived at a successful result, where the prior art gave either
no indication of which parameters were critical or no direc-
tion as to which of many possible choices is likely to be suc-
cessful.’” (quoting Medichem, S.A. v. Rolabo, S.L., 437 F.3d
1157, 1165 (Fed. Cir. 2006)). Consequently, we hold that
the district court did not clearly err in crediting Dr. Bern-
stein’s testimony or concluding that Byrn provides insuffi-
cient guidance in discussing the wide array of conditions
that could affect recrystallization, and therefore, the crys-
tal structure of a resulting compound. See Depomed Liti-
gation, 2016 WL 7163647, at *52–53.
Despite the lack of disclosure in Byrn, Alkem argues
that any polymorph screening of a sample of tapentadol hy-
drochloride 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 Form A if following the
synthesis steps of Example 25. The record, however, does
not support Alkem’s argument.
16 GRUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED
Alkem advanced this same argument before the dis-
trict court to allege that the ’737 patent inherently antici-
pates the ’364 patent, an issue that is not before us. The
district court rejected Alkem’s inherent anticipation theory
because the method of synthesis that Alkem used, for pur-
poses of this litigation, to produce a sample of tapentadol
hydrochloride that comprised a mixture of Form A and
Form B was not performed in accordance with the three
steps outlined in Example 25 of the ’737 patent. Depomed
Litigation, 2016 WL 7163647, at *45–50. Instead, the mix-
ture of Form A and Form B that Alkem relied on at trial
was a result of performing only one of the three steps de-
scribed in Example 25, whereas testimony showed that
fully performing each of the three steps outlined in Exam-
ple 25 results in only Form B. Id. at *46, *48, *50; see also
J.A. 8557–60 (257:10–260:3) (stating resynthesis of Exam-
ple 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 reproduc-
tions of Example 25 result in only Form B, not Form A);
J.A. 9729–30 (7:16–8:18) (same). Given the weight of evi-
dence, 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
would 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). See
J.A. 9773 (51:6–14) (stating there is no way to predict the
most stable form without testing). Because the record in-
dicates that there was (1) no known or expected polymor-
phism 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 rates,
etc., were likely to result in Form A, Alkem failed to prove
that a POSA would have reasonably expected a polymorph
screening of the Form B disclosed in the ’737 patent to re-
sult in Form A.
GRUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 17
Alkem also argues that the district court applied the
wrong legal standard in its obviousness inquiry, requiring
“absolute predictability,” as opposed to a reasonable expec-
tation of success. Indeed, in each of the cases Alkem cites,
we did not require “absolute predictability,” but acknowl-
edged 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. Cir. 2015).
However, each of these cases is inapposite to the facts at
hand.
For example, in Pfizer, Inc. v. Apotex, Inc., we deter-
mined that a POSA would have had a reasonable expecta-
tion of success to make amlodipine besylate based on the
disclosure of amlodipine and a list of “53 FDA-approved,
commercially marketed anions.” 480 F.3d at 1355, 1361–
69. Under the “particularized facts of [Pfizer],” such expec-
tation was reasonable because a POSA would have nar-
rowed the list of 53 anions “to a few” due to known
characteristics of the anions. Id. at 1363, 1366–67. In
other words, it was reasonable to expect that the combina-
tion of amlodipine and benzene sulphonate—one of the 53
anions disclosed the prior art—would likely result in am-
lodipine besylate because of the known acid strength, solu-
bility, and other chemical characteristics of the benzene
sulphonate. Id. at 1363.
In AstraZeneca LP v. Breath Ltd., we concluded that a
POSA would have had a reasonable expectation of success
of producing the claimed sterile budesonide composition
using known sterilization techniques even if the level of pu-
rity resulting from the methods was not actually known.
603 F. App’x at 1001–02. We did not require “actual suc-
cess” in creating the claimed invention because the record
abundantly supported the conclusion that four out of five
known sterilization techniques would result in a sterile
18 GRUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED
budesonide product that met the purity limitations 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 tech-
niques to produce a daptomycin-related substance having
the recited purity levels. 805 F.3d at 1127, 1129. The as-
serted purity claims in Cubist recited each of the purifica-
tion techniques that were described in the prior art. Id. at
1127–29. Using these purification techniques, the purity
levels disclosed in each of these claims could be achieved.
Id. at 1128 (“The purity patents do not point to any addi-
tional techniques that are necessary to obtain the recited
purity levels in each of the claims.”). Therefore, we con-
cluded 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 Breath 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 realm
of possible anions could be reduced to a manageable num-
ber based on known properties of the anions, thus provid-
ing a POSA with a reasonable expectation of success. Here,
a POSA did not know, or have reason to know, that tapen-
tadol hydrochloride is polymorphic. Nor could a POSA
know, or have reason to know, how the multiple 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
used 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) (“If a per-
son of ordinary skill can implement a predictable variation,
GRUNENTHAL 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 obvious-
ness”). This lack of knowledge in the field shows there was
little to no basis from which a POSA could expect a proba-
bility of success in producing Form A.
Our decision today does not rule out the possibility that
polymorph patents could be found obvious. But on the rec-
ord 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 district
court did not commit legal error in concluding the ’364 pa-
tent is not invalid as obvious.
Obvious to 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 show (1) a design or market need
to solve a particular problem, and (2) that “there are a fi-
nite 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, 550
U.S. at 421. Rather, Byrn simply provides “a general ap-
proach” to polymorph screening, only giving “general guid-
ance,” without providing “detailed enabling methodology.”
In re Kubin, 561 F.3d 1351, 1359–60 (Fed. Cir. 2009) (quot-
ing 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 or
20 GRUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED
try[ing] each of numerous possible choices until one possi-
bly 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
clearly err in finding that a POSA would not have had a
reasonable expectation of producing Form A using the dis-
closure of the ’737 patent and Byrn. Therefore, for the rea-
sons 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 util-
ity 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. Watta-
nasin, 93 F.3d 1559, 1563 (Fed. Cir. 1996)). The substan-
tial 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 ben-
efit to the public.” Id. In other words, a patent has utility
if the alleged invention is capable of providing some iden-
tifiable benefit presently available to the public. Id. A pa-
tent 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 De-
vices, Inc., 977 F.2d 1555, 1571 (Fed. Cir. 1992). For phar-
maceutical patents, practical utility may be shown by
evidence of “any pharmacological activity.” Fujikawa, 93
F.3d at 1564.
GRUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 21
Hikma contends that the ’364 patent lacks specific util-
ity because the specification vaguely states that “Crystal-
line 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-de-
fined 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 in-
vention is used for the treatment of pain or the treatment
of urinary incontinence.” ’364 patent, col. 4 ll. 63–65; see
also id., Abstract. The prior art confirms that tapentadol
hydrochloride was known as an analgesic at the time of fil-
ing of the ’364 patent, 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 hydrochloride
as an analgesic.
Hikma next argues that to show substantial utility,
Form A’s superior stability over Form B at room tempera-
ture must not only be proven, but must be proven by test
data. Hikma attempts to set too high a bar for purposes of
finding a sufficient disclosure of utility. While test results
often support claims of utility in patents concerning phar-
macological arts, such testing is not always required. Ras-
musson v. SmithKline Beecham 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 claimed utility. E.g.,
Fujikawa, 93 F.3d at 1564 (“[T]est results need not abso-
lutely prove that the compound is pharmacologically ac-
tive. All that is required is that the tests be reasonably
indicative of the desired [pharmacological] response.”
22 GRUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED
(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 be-
lieved that, at the time of filing the ’364 patent, Form A
was more 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 tem-
perature. ’364 patent, col. 18 ll. 53–57. This effect is “re-
versible with Form B changing over into Form A at lower
temperature.” Id. col. 18 ll. 56–57. Expert testimony con-
firmed the results of Example 16, namely that Form A is
stable at room temperature and Form B is stable above
50º C. J.A. 10471–72 (124:9–125:6); see also J.A. 9694–96
(57:14–59:7); J.A. 9800–02 (78:25–80:20). There is suffi-
cient proof that the disclosure of Example 16 is reasonably
indicative of the stability of Form A at room temperature.
There is also sufficient evidence that thermodynamic sta-
bility 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
prove 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 pa-
tentable invention be superior to all prior devices.”). It is
sufficient that Form A is shown to be stable at room tem-
perature and useful for pain relief.
For these reasons, we hold that the district court’s find-
ing of utility was not clearly erroneous.
Hikma makes additional arguments regarding the va-
lidity of the ’130 patent to be considered only if this court
reverses the district court’s findings of noninfringement of
GRUNENTHAL GMBH v. ALKEM LABORATORIES LIMITED 23
the ’130 patent. Because we affirm the findings of nonin-
fringement, we need not reach these issues.
CONCLUSION
For the foregoing reasons, we affirm the judgment of
the district court.
AFFIRMED
COSTS
No costs.