United States Court of Appeals
for the Federal Circuit
______________________
PERSION PHARMACEUTICALS LLC,
Plaintiff-Appellant
v.
ALVOGEN MALTA OPERATIONS LTD.,
Defendant-Appellee
______________________
2018-2361
______________________
Appeal from the United States District Court for the
District of Delaware in No. 1:16-cv-00139-WCB, Circuit
Judge William C. Bryson.
______________________
Decided: December 27, 2019
______________________
DOMINICK A. CONDE, Venable LLP, New York, NY, ar-
gued for plaintiff-appellant. Also represented by
CHRISTOPHER P. BORELLO, JOSHUA DANIEL CALABRO,
ZACHARY GARRETT.
CHAD A. LANDMON, Axinn Veltrop Harkrider, LLP,
Hartford, CT, argued for defendant-appellee. Also repre-
sented by MATTHEW BECKER, THOMAS K. HEDEMANN,
DAVID KEELER LUDWIG, EDWARD M. MATHIAS;
CHRISTOPHER MICHAEL GALLO, Washington, DC.
______________________
2 PERSION PHARMACEUTICALS LLC v. ALVOGEN MALTA
OPERATIONS LTD.
Before O’MALLEY, REYNA, and CHEN, Circuit Judges.
REYNA, Circuit Judge.
Persion Pharmaceuticals LLC appeals from a decision
of the U.S. District Court for the District of Delaware find-
ing the asserted claims of U.S. Patent Nos. 9,265,760 and
9,339,499 invalid as obvious and lacking adequate written
description. Because we find no reversible error in the dis-
trict court’s obviousness determination, we affirm on that
basis and do not reach the written description issue.
BACKGROUND
I. The Asserted Patents
Persion Pharmaceuticals LLC (“Persion”) 1 owns U.S.
Patent Nos. 9,265,760 (“the ’760 patent”) and 9,339,499
(“the ’499 patent”), both entitled “Treating Pain in Patients
with Hepatic Impairment.” Both patents share a common
written description 2 and priority date and are directed to
methods of treating pain in patients with mild or moderate
hepatic impairment using extended-release hydrocodone-
only formulations. Hepatic impairment is compromised
liver functionality.
1 Pernix Ireland Pain DAC and Pernix Therapeutics,
LLC (collectively, “Pernix”) were the named plaintiffs be-
fore the district court and the original appellants in this
case. During the pendency of this appeal, Persion acquired
the patents at issue from Pernix, and we granted leave for
Persion to be substituted as a party. See Order, Persion
Pharm. LLC v. Alvogen Malta Operations LTD, No. 2018-
2361 (Fed. Cir. May 23, 2019), ECF No. 63. For conven-
ience, we refer to Persion as the plaintiff and appellant in
this opinion.
2 For convenience, this opinion cites to the written
description of the ’760 patent.
PERSION PHARMACEUTICALS LLC v. ALVOGEN MALTA 3
OPERATIONS LTD.
Hydrocodone is an opioid that is widely used to treat
pain and has been FDA approved since 1943. It is mar-
keted in both extended-release and immediate-release for-
mulations and is often combined with other active
ingredients. Like many opioids, hydrocodone is primarily
metabolized in the human liver. If liver function is im-
paired, metabolism of opioids is slowed. Thus, the same
dose of hydrocodone may pose a higher risk of overdose in
a patient with hepatic impairment than in a healthy pa-
tient due to potential build-up of the drug in the patient’s
bloodstream.
The ’760 and ’499 patents cover the formulation for Zo-
hydro ER, Persion’s extended-release hydrocodone-only
drug product. When Zohydro ER’s prior owner sought ap-
proval to market the drug from the U.S. Food and Drug
Administration (“FDA”), the FDA required the owner to
conduct a clinical study to determine the potential effect of
the drug on patients with hepatic impairment. The study
showed that use of Zohydro ER did not result in substan-
tially higher concentrations of hydrocodone in the blood-
stream of subjects with mild and moderate hepatic
impairment than in subjects without hepatic impairment.
Following this study, the researchers filed patent ap-
plications directed to their discovery, which later issued as
the ’760 and ’499 patents. Example 8 of the patents de-
scribes the Zohydro ER clinical study and its results.
Id.
col. 22 l. 52–col. 23 l. 48. However, the patent claims are
not limited to the use of the Zohydro ER formulation but
instead cover methods of using any extended-release for-
mulation with “hydrocodone bitartrate as the only active
ingredient” to treat pain in patients with mild or moderate
4 PERSION PHARMACEUTICALS LLC v. ALVOGEN MALTA
OPERATIONS LTD.
hepatic impairment. 3 ’760 patent col. 24 ll. 1–5, col. 25
ll. 13–17, ’499 patent col. 24 ll. 1–5, col. 26 ll. 9–13.
The relevant claims of the ’760 and ’499 patents can
generally be grouped into two sets: the “non-adjustment”
claims and the “pharmacokinetic” claims. The non-adjust-
ment claims are directed to administering a starting dose
of hydrocodone to a patient having mild or moderate he-
patic impairment without adjusting the dose relative to a
patient with a healthy liver. Independent claim 1 of the
’760 patent is representative of the non-adjustment claims,
and recites:
1. A method of treating pain in a patient having
mild or moderate hepatic impairment, the method
comprising:
administering to the patient having mild or
moderate hepatic impairment a starting
dose of an oral dosage unit having hydroco-
done bitartrate as the only active ingredi-
ent, wherein the dosage unit comprises an
extended release formulation of hydroco-
done bitartrate, and wherein the starting
dose is not adjusted relative to a patient
without hepatic impairment.
’760 patent col. 23 l. 66–col. 24 l. 7.
The pharmacokinetic claims recite pharmacokinetic
parameters either as absolute values or in relation to val-
ues in a healthy patient. Independent claim 12 of the ’760
3 Hydrocodone bitartrate is a salt of hydrocodone
used to deliver hydrocodone to the human body. Pernix Ire-
land Pain DAC v. Alvogen Malta Operations Ltd.,
323
F. Supp. 3d 566, 575 (D. Del. 2018) (citing ’760 patent col. 13
ll. 13–15).
PERSION PHARMACEUTICALS LLC v. ALVOGEN MALTA 5
OPERATIONS LTD.
patent is representative of the pharmacokinetic claims,
and recites:
12. A method of treating pain in a patient having
mild or moderate hepatic impairment, the method
comprising:
administering to the patient having mild or
moderate hepatic impairment an oral dos-
age unit having hydrocodone bitartrate as
the only active ingredient, wherein the dos-
age unit comprises an extended release for-
mulation of hydrocodone bitartrate,
wherein the dosage unit provides a release
profile of hydrocodone that:
(1) does not increase average hy-
drocodone AUC0–inf in subjects suf-
fering from mild hepatic
impairment relative to subjects not
suffering from renal or hepatic im-
pairment in an amount of more
than 14%;
(2) does not increase average hy-
drocodone AUC0–inf in subjects suf-
fering from moderate hepatic
impairment relative to subjects not
suffering from renal or hepatic im-
pairment in an amount of more
than 30%;
(3) does not increase average hy-
drocodone Cmax in subjects suffer-
ing from mild hepatic impairment
relative to subjects not suffering
from renal or hepatic impairment
in an amount of more than 9%; and
6 PERSION PHARMACEUTICALS LLC v. ALVOGEN MALTA
OPERATIONS LTD.
(4) does not increase average hy-
drocodone Cmax in subjects suffer-
ing from moderate hepatic
impairment relative to subjects not
suffering from renal or hepatic im-
pairment in an amount of more
than 14%.
’760 patent col. 25 ll. 11–35.
II. Prior Art
A. Devane
U.S. Patent Publication No. 2006/0240105 (“Devane”)
is entitled “Multiparticulate Modified Release Composi-
tion” and was published on October 26, 2006. Devane is
directed to a controlled-release composition that provides
both immediate and extended release of one or more active
ingredients. J.A. 3616 (Devane, ¶¶ 26–27). Devane
teaches that one active ingredient that can be used with
these compositions is hydrocodone. J.A. 3615 (Devane,
¶ 17); J.A. 3620 (Devane, ¶ 70). As an example, Devane
discloses the Zohydro ER formulation and describes an in
vivo study in which the formulation is used to treat pain.
J.A. 3625–26 (Devane, ¶¶ 103–06); J.A. 6, 490; Appellee’s
Br. 4.
B. Jain
U.S. Patent Publication No. 2010/0010030 (“Jain”) is
entitled “Extended Release Hydrocodone Acetaminophen
and Related Methods and Uses Thereof” and was published
on January 14, 2010. Jain is directed to methods of treat-
ing pain using an extended-release formulation containing
about 15 milligrams of hydrocodone and about 500 milli-
grams of acetaminophen. J.A. 3631 (Jain, Abstract). This
formulation is known as Vicodin CR. J.A. 3647 (Jain, ¶ 34).
Jain describes several clinical studies involving Vicodin
CR, including a study conducted to determine the effects of
hepatic insufficiency on the pharmacokinetics of Vicodin
PERSION PHARMACEUTICALS LLC v. ALVOGEN MALTA 7
OPERATIONS LTD.
CR. J.A. 3649 (Jain, ¶ 64). The results of the study demon-
strated that pharmacokinetic parameters for hydrocodone
“were similar in normal subjects and subjects with mild
and moderate hepatic impairment.”
Id. The results fur-
ther demonstrated that the pharmacokinetic parameters
for acetaminophen “were similar in normal subjects and
subjects with mild hepatic impairment, and 34 to 42%
higher in subjects with moderate hepatic impairment.”
Id.
C. Vicodin and Lortab Labels
Vicodin and Lortab are both immediate-release formu-
lations of hydrocodone and acetaminophen that are used to
treat pain. J.A. 3121, 3230. The 2011 labels for these prod-
ucts provide safety information and instructions for use.
J.A. 3121, 3230–33. Although both labels state that these
drugs “should be used with caution in . . . those [patients]
with severe impairment of hepatic . . . function,” neither la-
bel includes any precautions or dosage restrictions for pa-
tients with mild or moderate hepatic impairment. J.A.
3121, 3231.
III. District Court Proceedings
On March 4, 2016, Persion sued Alvogen Malta Opera-
tions Ltd. (“Alvogen”) for infringement of claims 1–4, 11–
12, 17, and 19 of the ’760 patent. After the ’499 patent is-
sued, Persion filed an amended complaint additionally as-
serting infringement of claim 1 of that patent. Persion
alleged that Alvogen infringed these claims by filing an Ab-
breviated New Drug Application (“ANDA”) seeking to mar-
ket a generic version of Zohydro ER. 4
4 Alvogen filed its ANDA with the FDA prior to the
issuance of the ’760 and ’499 patents. Other patents at is-
sue in this case, however, were listed in FDA’s “Approved
Drug Products with Therapeutic Equivalence Evaluations”
8 PERSION PHARMACEUTICALS LLC v. ALVOGEN MALTA
OPERATIONS LTD.
After a bench trial, the district court concluded that Al-
vogen would indirectly infringe the asserted claims be-
cause its product label would induce doctors and patients
to administer Alvogen’s product in an infringing manner.
Pernix Ireland Pain DAC v. Alvogen Malta Operations Ltd.,
323 F. Supp. 3d 566, 579 (D. Del. 2018). The district court
also concluded that the asserted claims are not invalid as
anticipated by Devane.
Id. at 594. These rulings are not
at issue on appeal.
The district court next determined that the asserted
claims are invalid as obvious over Devane in view of Jain,
the state of the prior art at the time of invention, and the
Vicodin and Lortab labels.
Id. at 595–96, 610. Specifically,
the district court found that in light of the teachings of Jain
and the Vicodin and Lortab labels, a person of ordinary
skill in the art would have been motivated to administer
the extended-release hydrocodone bitartrate formulation
disclosed in Devane to patients with mild or moderate he-
patic impairment at an unadjusted dose and would have
had a reasonable expectation of success in so doing.
Id. at
609–10, 615. The district court further found that the
pharmacokinetic limitations in the pharmacokinetic claims
are “inherent in any obviousness combination that contains
the Devane formulation” because the recited pharmacoki-
netic parameters were “necessarily present” in the Zohydro
ER formulation described in both Devane and the asserted
patents.
Id. at 607. Finally, the district court found that
the objective factors of unexpected results, long-felt but un-
met need, and failure of others did not weigh in favor of
finding nonobviousness.
In addition, the district court determined that the as-
serted claims of the ’760 and ’499 patents are invalid under
35 U.S.C. § 112(a) for lack of adequate written description
publication, otherwise known as the “Orange Book,” for Zo-
hydro ER at the time Alvogen filed its ANDA.
PERSION PHARMACEUTICALS LLC v. ALVOGEN MALTA 9
OPERATIONS LTD.
support.
Id. at 624–25. The district court found that the
written description discloses only the formulation de-
scribed in Example 8, which is the same as both the Zohy-
dro ER and the Devane formulations.
Id. at 575, 619. The
district court explained that, by contrast, the claims of the
’760 and ’499 patents “are broadly cast in generic form,”
and “are not limited to that single disclosed formulation.”
Id. at 618–19. The district court concluded that because
“[t]he pharmacokinetic data and dissolution profile for the
Devane formulation provide no guidance as to whether
other formulations would satisfy the functional limitations
of the claims,” the asserted claims of the ’760 and ’499 pa-
tents were not supported by the written description as re-
quired by § 112(a).
Id. at 623, 625.
Persion timely appeals. We have jurisdiction under 28
U.S.C. § 1295(a)(1).
DISCUSSION
Obviousness is a question of law with underlying fac-
tual findings relating to the scope and content of the prior
art; differences between the prior art and the claims at is-
sue; the level of ordinary skill in the pertinent art; the pres-
ence or absence of a motivation to combine or modify with
a reasonable expectation of success; and any objective indi-
cia of non-obviousness. Acorda Therapeutics, Inc. v. Rox-
ane Labs., Inc.,
903 F.3d 1310, 1328 (Fed. Cir. 2018) (citing
KSR Int’l Co. v. Teleflex Inc.,
550 U.S. 398, 406 (2007)); Ari-
osa Diagnostics v. Verinata Health, Inc.,
805 F.3d 1359,
1364 (Fed. Cir. 2015). “The inherent teaching of a prior art
reference is a question of fact.” PAR Pharm., Inc. v. TWI
Pharm., Inc.,
773 F.3d 1186, 1194 (Fed. Cir. 2014) (quoting
In re Napier,
55 F.3d 610, 613 (Fed. Cir. 1995)) (internal
quotation marks omitted).
In an appeal from a bench trial, we review the district
court’s factual findings for clear error and the district
court’s legal conclusion on obviousness de novo. Novo
Nordisk A/S v. Caraco Pharm. Labs., Ltd.,
719 F.3d 1346,
10 PERSION PHARMACEUTICALS LLC v. ALVOGEN MALTA
OPERATIONS LTD.
1354 (Fed. Cir. 2013). Under the clearly erroneous stand-
ard of review, we defer to the district court’s factual find-
ings unless, considering the totality of the evidence, we are
“left with the definite and firm conviction that a mistake
has been committed.” Zenith Radio Corp. v. Hazeltine Re-
search, Inc.,
395 U.S. 100, 123 (1969) (quoting United
States v. U.S. Gypsum Co.,
333 U.S. 364, 395 (1948)).
Persion raises four primary challenges to the district
court’s obviousness conclusion. First, Persion contends
that the district court improperly relied on inherency to
conclude that Devane discloses the pharmacokinetic limi-
tations of the asserted claims. Second, Persion argues that
the district court improperly relied on pharmacokinetic
profiles from drugs other than extended-release single-ac-
tive-ingredient hydrocodone formulations and from pa-
tients other than those with hepatic impairment in
reaching its obviousness conclusion. 5 Third, Persion con-
tends that the district court erred by finding the asserted
claims obvious before considering the objective indicia fac-
tors. Fourth, Persion argues that the district court’s fac-
tual findings concerning obviousness are inconsistent with
its findings concerning the lack of written description sup-
port. We address each argument in turn.
A. Inherency
“[I]nherency may supply a missing claim limitation in
an obviousness analysis.”
PAR, 773 F.3d at 1194–95; see
also Endo Pharm. Sols., Inc. v. Custopharm Inc.,
894 F.3d
1374, 1381 (Fed. Cir. 2018) (“An inherent characteristic of
a formulation can be part of the prior art in an obviousness
5 Persion characterizes several of its arguments as
challenging the district court’s legal errors. See, e.g., Ap-
pellant’s Br. 24, 26, 29. It is clear, however, that Persion’s
arguments are directed to the district court’s factual find-
ings, which we review for clear error.
PERSION PHARMACEUTICALS LLC v. ALVOGEN MALTA 11
OPERATIONS LTD.
analysis even if the inherent characteristic was unrecog-
nized or unappreciated by a skilled artisan.”). It is long
settled that in the context of obviousness, the “mere recita-
tion of a newly discovered function or property, inherently
possessed by things in the prior art, does not distinguish a
claim drawn to those things from the prior art.” In re Oel-
rich,
666 F.2d 578, 581 (C.C.P.A. 1981). The Supreme
Court explained long ago that “[i]t is not invention to per-
ceive that the product which others had discovered had
qualities they failed to detect.” Gen. Elec. Co. v. Jewel In-
candescent Lamp Co.,
326 U.S. 242, 249 (1945).
We too have previously explained that “an obvious for-
mulation cannot become nonobvious simply by administer-
ing it to a patient and claiming the resulting serum
concentrations,” because “[t]o hold otherwise would allow
any formulation—no matter how obvious—to become pa-
tentable merely by testing and claiming an inherent prop-
erty.” Santarus, Inc. v. Par Pharm., Inc.,
694 F.3d 1344,
1354 (Fed. Cir. 2012). In In re Kao, we found that the
claimed controlled-release oxymorphone formulation was
obvious because an inherent pharmacokinetic property of
oxymorphone that was present in controlled-release oxy-
morphone “add[ed] nothing of patentable consequence.”
639 F.3d 1057, 1070 (Fed. Cir. 2011). In In re Kubin, we
found an inherent property obvious, explaining that “[e]ven
if no prior art of record explicitly discusses the [limitation],
the . . . application itself instructs that [the limitation] is
not an additional requirement imposed by the claims on
the [claimed protein], but rather a property necessarily
present in [the claimed protein].”
561 F.3d 1351, 1357
(Fed. Cir. 2009). Our predecessor court similarly concluded
that it “is not the law” that “a structure suggested by the
prior art, and, hence, potentially in the possession of the
public, is patentable . . . because it also possesses an
[i]nherent, but hitherto unknown, function which [the pa-
tentees] claim to have discovered.” In re Wiseman,
596
F.2d 1019, 1023 (C.C.P.A. 1979).
12 PERSION PHARMACEUTICALS LLC v. ALVOGEN MALTA
OPERATIONS LTD.
Inherency, however, is a “high standard,” that is “care-
fully circumscribed in the context of obviousness.”
PAR,
773 F.3d at 1195. Inherency “may not be established by
probabilities or possibilities,” and “[t]he mere fact that a
certain thing may result from a given set of circumstances
is not sufficient.”
Oelrich, 666 F.2d at 581 (emphasis
added) (quoting Hansgirg v. Kemmer,
102 F.2d 212, 214
(C.C.P.A. 1939); see also In re Rijckaert,
9 F.3d 1531, 1533–
34 (Fed. Cir. 1993). Rather, inherency renders a claimed
limitation obvious only if the limitation is “necessarily pre-
sent,” or is “the natural result of the combination of ele-
ments explicitly disclosed by the prior art.”
PAR, 773 F.3d
at 1195–96; see also Alcon Research, Ltd. v. Apotex Inc.,
687
F.3d 1362, 1369 (Fed. Cir. 2012) (relying on inherency
where the claims recited “a property that is necessarily pre-
sent” in the prior art). “If . . . the disclosure is sufficient to
show that the natural result flowing from the operation as
taught would result in the performance of the questioned
function, it seems to be well settled that the disclosure
should be regarded as sufficient” to render the function in-
herent.
Oelrich, 666 F.2d at 581 (quoting Hansgirg v. Kem-
mer,
102 F.2d 212, 214 (C.C.P.A. 1939)).
On appeal, Persion contends that the district court
erred in applying the inherency doctrine in its obviousness
analysis because Devane does not teach administering its
hydrocodone-only formulation to patients with mild or
moderate hepatic impairment. Thus, Persion asserts, “‘the
natural result flowing from the operation as taught’ in
Devane cannot be the claimed [pharmacokinetic] values for
[hepatically impaired] patients.” Appellant’s Br. 37 (quot-
ing
Oelrich, 666 F.2d at 581); Reply Br. 19.
To the extent Persion contends that inherency can only
satisfy a claim limitation when all other limitations are
taught in a single reference, that position is contrary to our
prior recognition that “inherency may supply a missing
claim limitation in an obviousness analysis” where the lim-
itation at issue is “the natural result of the combination of
PERSION PHARMACEUTICALS LLC v. ALVOGEN MALTA 13
OPERATIONS LTD.
prior art elements.”
PAR, 773 F.3d at 1194-95 (emphasis
added, internal quotations omitted). Here, the district
court specifically found that Devane, together with Jain,
the state of the prior art at the time of invention, and the
Vicodin and Lortab labels, taught the combination of ele-
ments that inherently result in the claimed pharmacoki-
netic parameters. The district court found that a person of
ordinary skill in the art would have been motivated, with
reasonable expectation of success, to administer an unad-
justed dose of the Devane formulation to hepatically im-
paired patients. There was also no dispute that the Devane
formulation, which was identical to the Zohydro ER formu-
lation described in the patents in suit, necessarily exhib-
ited the claimed parameters under these conditions.
Pernix, 323 F. Supp. 3d at 607, 610. In this context, the
district court did not err by finding that the pharmacoki-
netic limitations of the asserted claims were inherent and
added no patentable weight to the pharmacokinetic claims.
B. Evidence of Obviousness
Persion also argues that the district court clearly erred
in its obviousness findings by relying on pharmacokinetic
data from formulations and patient groups not covered by
the asserted claims. Persion asserts that pharmacokinetic
data for drug products with more than one active ingredi-
ent, for immediate-release hydrocodone products, or for hy-
drocodone-only products administered to unimpaired
patients is irrelevant to the obviousness inquiry in this
case because that data would not allow a person of ordinary
skill in the art to predict the correct dose of its claimed hy-
drocodone-only extended-release formulation for hepati-
cally impaired patients. Appellant’s Br. 24–28, 30–36. On
this basis, Persion argues that Jain would not have pro-
vided a person of ordinary skill in the art “with any reason-
able expectation that a hydrocodone-only dosage form
could be dosed the same way in patients with and without
[hepatic impairment].” Appellant’s Br. 35; Reply Br. 7–14.
Also on this basis, Persion contends that Devane’s
14 PERSION PHARMACEUTICALS LLC v. ALVOGEN MALTA
OPERATIONS LTD.
pharmacokinetic data is “irrelevant to Jain’s formulation”
because “none of the data in Devane is for [hepatically im-
paired] patients.” Appellant’s Br. 31; Reply Br. 16. We do
not find these arguments persuasive because we find no
clear error in the district court’s analysis.
The district court provided several reasons for its con-
clusion that a person of ordinary skill in the art would have
considered other types of drug products in developing a hy-
drocodone-only extended-release formulation.
Pernix, 323
F. Supp. 3d at 608–09. In particular, the district court
found that in light of acetaminophen’s hepatotoxicity, a
person of skill in the art would have expected that an acet-
aminophen-free hydrocodone formulation, such as the one
disclosed in Devane, would have been even safer for pa-
tients with hepatic impairment than the combination for-
mulations disclosed in Jain and other references.
Id. at
608. While Persion asserts that Jain “extols the ‘signifi-
cantly greater benefits’ of acetaminophen-containing com-
bination products,” and thus undermines the district
court’s finding of a motivation to remove acetaminophen
from Jain’s formulation, Appellant’s Br. 30, Jain only dis-
cusses these benefits in comparison to a placebo used in its
clinical study, not to hydrocodone alone, J.A. 3652, ¶ 89
(emphasis added). Thus, nothing in the text of Jain leads
us to conclude that the district court clearly erred in com-
bining the teachings of Jain with the Devane formulation.
Persion also asserts that the district court improperly
relied on the FDA’s acceptance of safety data for Vi-
coprofen, an immediate-release combination hydrocodone
and ibuprofen drug, as part of the New Drug Application
(“NDA”) for Zohydro ER. Appellant’s Br. 24–25. The dis-
trict court found that the FDA’s willingness to accept such
data supports the view that a combination product contain-
ing hydrocodone would have been relevant to a person of
ordinary skill evaluating the appropriate administration of
the Devane formulation.
Pernix, 323 F. Supp. 3d at 608–
09. Persion argues this finding was clearly erroneous
PERSION PHARMACEUTICALS LLC v. ALVOGEN MALTA 15
OPERATIONS LTD.
because the FDA did not find the Vicoprofen data sufficient
to establish the proper dosing of Zohydro ER for hepatically
impaired patients and had previously refused to rely on
such “combination products” data in evaluating another
hydrocodone-only product. Appellant’s Br. 25. However,
as the district court explained, “[t]he standard to find a mo-
tivation to combine is far below what is sufficient to prove
safety and efficacy to the FDA,” and therefore, “[t]he fact
that the FDA found the comparison [between Vicoprofen
and Zohydro ER] insufficient to satisfy its safety and effi-
cacy standards does not speak to the issue of obviousness.”
Pernix, 323 F. Supp. 3d at 611. We find no clear error in
the district court’s conclusion that the FDA’s approval re-
quirements do not undermine the force of the evidence as
to obviousness.
Id. In light of the record as a whole, we
find no clear error in the district court’s findings on the rel-
evance of combination product data to a person of ordinary
skill considering the administration of a hydrocodone-only
product.
Persion also challenges the district court’s reliance on
Jain’s description of the pharmacokinetic parameters of hy-
drocodone in healthy subjects and in subjects with mild or
moderate hepatic impairment as “similar.” Persion argues
that Jain does not define “similar” and the district court
erred by “presuming” that “similar” meant “less than 34 to
42%” because a presumption is not evidence. Appellant’s
Br. 32–34. Jain, however, expressly distinguishes “similar”
pharmacokinetic results from those that are “34 to 42%
higher.” J.A. 3649; see also
Pernix, 323 F. Supp. 3d at 613.
Thus, the district court did not merely presume to know
what Jain meant by “similar,” contrary to Persion’s argu-
ment. We find no clear error in the district court’s inter-
pretation of Jain or in its conclusion that because Jain
discloses “similar” pharmacokinetic values for both hepat-
ically impaired and unimpaired patients, a person of ordi-
nary skill in the art would understand that no dose
16 PERSION PHARMACEUTICALS LLC v. ALVOGEN MALTA
OPERATIONS LTD.
adjustment would be necessary in administering hydroco-
done to hepatically impaired patients.
Persion next challenges the district court’s reliance on
Devane’s study of healthy patients in finding that the pres-
ence of acetaminophen had no appreciable effect on the
pharmacokinetic profile for hydrocodone. See
Pernix, 323
F. Supp. 3d at 610. The district court credited the testi-
mony of Alvogen’s expert that the relevant pharmacoki-
netic parameter values disclosed in Devane’s study for a
hydrocodone-only product and a hydrocodone-acetamino-
phen product are “virtually identical values.”
Id. Relying
on Devane’s study, the district court found that a person of
ordinary skill in the art would have appreciated that hy-
drocodone and acetaminophen are metabolized differently,
and accordingly, would not have been deterred from relying
on combination products containing acetaminophen for
guidance about the dosing of the Devane formulation.
Id.
Persion asserts that pharmacokinetic data for hepatically
unimpaired patients is irrelevant to motivation or expecta-
tion of success for administration of a drug to patients with
hepatic impairment. Appellant’s Br. 31. We disagree. Per-
sion provides no support for its assertion, and we find no
clear error in the district court’s crediting of expert testi-
mony that relied on the Devane data in discussing how a
person of ordinary skill in the art would have understood
the effect of acetaminophen on the metabolism of hydroco-
done in a combination product. See
Pernix, 323 F. Supp. 3d
at 609 (citing J.A. 552, Trial Tr. 257:1–8); see also J.A.
551:21-25.
Persion also contends that the district court erred by
taking judicial notice of the FDA’s recommendation to
“limit the strength of acetaminophen in prescription drug
products.” Specifically, Persion asserts that Alvogen had
expressly dropped an obviousness combination that in-
cluded the FDA’s statement and thus Persion was deprived
of an adequate opportunity to respond to the statement
during trial. Appellant’s Br. 29 (citing Pernix, 323 F. Supp.
PERSION PHARMACEUTICALS LLC v. ALVOGEN MALTA 17
OPERATIONS LTD.
3d at 609). However, the district court relied on the FDA’s
statements not as part of a prior art combination, but only
in rebutting Pernix’s assertion that there was no motiva-
tion to combine the teachings of Devane with the hydroco-
done-acetaminophen formulations described in Jain and
the Vicodin and Lortab labels. In rejecting Persion’s argu-
ment, the district court relied on three additional bases for
finding a motivation to combine that were independently
supported by other evidence presented at trial.
Pernix, 323
F. Supp. 3d at 609–10. Thus, regardless of whether the
district court’s consideration of the FDA’s statement was
proper, we find no clear error in the court’s finding that
there was a motivation to combine in light of the evidence
as a whole.
In sum, after reviewing the entire evidentiary record,
we are not left with any conviction that the district court
has made a mistake. See
Zenith, 395 U.S. at 123. We
therefore reject Persion’s challenge to the district court’s
factual findings, which are not clearly erroneous.
C. Objective Indicia
Persion argues that the district court erred by finding
the asserted claims obvious before considering the asserted
objective indicia of nonobviousness, which Persion con-
tends clouded the district court’s analysis of the objective
indicia. Appellant’s Br. 38–43. Relying on In re Cycloben-
zaprine Hydrochloride Extended-Release Capsule Patent
Litigation, Persion argues that the district court’s finding
of obviousness was premature.
676 F.3d 1063, 1075 (Fed.
Cir. 2012). We disagree. Unlike the trial court in Cyclo-
benzaprine, the district court here considered Persion’s ev-
idence of objective indicia together with the other evidence
presented at trial on the issue of obviousness. See, e.g.,
Pernix, 323 F. Supp. 3d at 615–16 (considering whether
Persion’s objective indicia arguments were “supported by
other evidence adduced at trial”);
id. at 616–17 (consider-
ing the inventors’ testimony directed to the unexpected
18 PERSION PHARMACEUTICALS LLC v. ALVOGEN MALTA
OPERATIONS LTD.
results factor in the context of “all the evidence at trial”).
While the district court’s discussion of objective indicia fol-
lows its discussion of the asserted prior art, the substance
of the court’s analysis makes clear that it properly consid-
ered the totality of the obviousness evidence in reaching its
conclusion and did not treat the objective indicia as a mere
“afterthought” relegated to “rebut[ting]” a prima facie case.
Leo Pharm. Prods., Ltd. v. Rea,
726 F.3d 1346, 1357–58
(Fed. Cir. 2013);
Cyclobenzaprine, 676 F.3d at 1075.
The remainder of Persion’s arguments amount to chal-
lenges against the district court’s weighing of the objective
indicia. For example, Persion argues that in addressing
the failure of others, the district court did not give any
weight to evidence of Cephalon, Inc.’s failure to develop its
Vantrela drug in a manner that would not require a dose
adjustment for hepatically impaired patients. Appellant’s
Br. 39–40. The district court, however, expressly consid-
ered this evidence and determined that it did not warrant
a finding of nonobviousness. The district court found that
Cephalon, Inc.’s failure was not persuasive in light of evi-
dence demonstrating that others had succeeded in making
a hydrocodone drug that did not require a dose adjustment.
Pernix, 323 F. Supp. 3d at 617. In addition, the district
court heard trial testimony that the FDA would not have
required a dose adjustment for administering Vantrela to
patients with hepatic impairment. See J.A. 596–97 (Trial
Tr. 301:21–302:4). Persion additionally argues that the
district court improperly dismissed the testimony of the in-
ventors regarding unexpected results. Appellant’s Br. 40–
42. However, the district court considered this testimony,
and we see no clear error in the court’s discounting of the
evidence in light of the inventors’ failure to account for the
teachings in Jain.
Pernix, 323 F. Supp. 3d at 616–17.
Overall, we find no clear error with the district court’s as-
sessment of the objective indicia evidence.
PERSION PHARMACEUTICALS LLC v. ALVOGEN MALTA 19
OPERATIONS LTD.
D. Internal Inconsistency
Lastly, Persion argues that the district court’s obvious-
ness decision must be reversed because its obviousness
findings are at odds with its findings concerning the writ-
ten description issue. Persion states that, for example, in
finding a lack of written description support for the as-
serted claims, the district court “found [that] ‘nothing in
the state of the art as of July 2012 . . . would have provided
guidance as to which [ER hydrocodone-only] formulations
would [achieve the claimed PK profile] and which would
not[.]’” Appellant’s Br. 22 (quoting
Pernix, 323 F. Supp. 3d
at 627) (emphasis omitted). Persion asserts this statement
contradicts the district court’s finding that a person of or-
dinary skill in the art “would ‘look to Jain and to the Vi-
codin and Lortab labels for [] guidance as to the
appropriate dosing levels of Devane’s formulation for pa-
tients with mild or moderate [hepatic impairment].’”
Id.
(quoting Pernix, 323 F. Supp. 3d at 612) (emphasis omit-
ted). We reject this argument as we see no inconsistency
in the district court’s findings.
Persion’s entire argument with respect to this issue is
based on incomplete quotations from the district court’s
opinion. For example, a complete reading of the district
court’s statement above belies Persion’s assertion that the
district court’s findings are inconsistent. The district court
stated that “there was nothing in the state of the art as of
July 2012 that would have provided guidance as to which
of the broadly claimed formulations would work and which
would not, with the exception of the single embodiment de-
scribed in Example 8.”
Pernix, 323 F. Supp. 3d at 627 (em-
phasis added). The embodiment described in Example 8 of
the common written description of the ’760 and ’499 pa-
tents is the Devane formulation, which formed the basis for
the district court’s obviousness findings.
Id. at 575, 619.
In contrast to the “essentially limitless number of formula-
tion species” covered by the claims of the ’760 and ’499 pa-
tents, the district court found that the prior art provided
20 PERSION PHARMACEUTICALS LLC v. ALVOGEN MALTA
OPERATIONS LTD.
adequate guidance with respect to the sole formulation de-
scribed in Example 8: the Devane formulation.
Id. at 618–
19, 622–23. Thus, there is no inconsistency between the
statement Persion quotes and the district court’s conclu-
sion that a person of ordinary skill in the art would have
been motivated to combine Devane with Jain and the Vi-
codin and Lortab labels to arrive at the claimed invention.
For the same reason, we reject Persion’s argument that
the district court’s findings with respect to reasonable ex-
pectation of success are inconsistent with its findings con-
cerning the lack of written description. Persion asserts
that the district court “found that there was no ‘way of pre-
dicting which formulations would work and which would
not[,]’ stating that ‘testing results would be fundamental to
determining which formulations would satisfy the asserted
claims[.]’” Appellant’s Br. 20 (quoting Pernix,
323 F. Supp.
3d at 624, 628). According to Persion, this necessity for ex-
perimentation contradicts the district court’s finding that
a person of ordinary skill would have had a reasonable ex-
pectation of success in combining Devane with Jain and the
Vicodin and Lortab labels.
Id. at 20–21. Once again, how-
ever, Persion omits critical context from its quote that
demonstrates the district court was addressing formula-
tions other than the one described in Example 8. See
Pernix,
323 F. Supp. 3d at 623 (declining to credit expert
testimony that “the specification would provide guidance to
a person of skill in the art regarding how to make a formu-
lation that would satisfy the limitations of the asserted
claims, except for the Devane formulation set forth in Ex-
ample 8 or compositions closely similar to that one”) (em-
phasis added). In context, there is no inconsistency
between the district court’s findings underlying its obvious-
ness and lack of written description determinations, and
we will not reverse the district court on this basis.
PERSION PHARMACEUTICALS LLC v. ALVOGEN MALTA 21
OPERATIONS LTD.
CONCLUSION
We have considered Persion’s remaining arguments
and find them unpersuasive. We conclude that the district
court correctly applied inherency to find that the claimed
pharmacokinetic limitations of the asserted claims added
no patentable weight over the combination of Devane and
other prior art references. We further conclude that the
district court’s factual findings concerning obviousness are
not clearly erroneous. We therefore affirm the district
court’s decision that the asserted claims of the ’760 and ’499
patents are invalid as obvious under 35 U.S.C. § 103. We
do not reach the district court’s decision concerning the
lack of written description support.
AFFIRMED
COSTS
Each party will bear its own costs.
