Endo Pharmaceuticals Solutions v. Custopharm Inc. , 894 F.3d 1374 ( 2018 )

United States Court of Appeals
for the Federal Circuit
______________________
ENDO PHARMACEUTICALS SOLUTIONS, INC.,
BAYER INTELLECTUAL PROPERTY GMBH,
BAYER PHARMA AG,
Plaintiffs-Appellees
v.
CUSTOPHARM INC.,
Defendant-Appellant
______________________
2017-1719
______________________
Appeal from the United States District Court for the
District of Delaware in No. 1:14-cv-01422-SLR-SRF,
Judge Sue L. Robinson.
______________________
Decided: July 13, 2018
______________________
NEVIN M. GEWERTZ, Bartlit Beck Herman Palenchar
& Scott LLP, Chicago, IL, argued for plaintiffs-appellees.
Also represented by ADAM MORTARA, JOHN SCOTT
MCBRIDE, TAYLOR A.R. MEEHAN, FAYE PAUL.
DOUGLASS C. HOCHSTETLER, Kelley Drye & Warren,
LLP, Chicago, IL, argued for defendant-appellant. Also
represented by CONSTANTINE KOUTSOUBAS, SARITA
MUTHA, MARK J. SCOTT; CLIFFORD KATZ, New York, NY.
______________________
2 ENDO PHARMACEUTICALS SOLUTIONS v. CUSTOPHARM INC.
Before MOORE, LINN, and CHEN, Circuit Judges.
CHEN, Circuit Judge.
Endo Pharmaceuticals Solutions, Inc. (Endo) holds
the approved New Drug Application for Aveed®, a testos-
terone undecanoate (TU) intramuscular injection. Bayer
Intellectual Property GmbH and Bayer Pharma AG
(Bayer) own the two patents listed in the Orange Book for
Aveed®, U.S. Patent Nos. 7,718,640 (the ’640 patent) and
8,338,395 (the ’395 patent). Custopharm Inc.’s (Custo-
pharm) predecessor-in-interest, Paddock Laboratories,
LLC, submitted an Abbreviated New Drug Application
(ANDA) to the U.S. Food and Drug Administration (FDA)
for approval to produce and market a generic version of
Aveed®. In connection with the ANDA filing, Custopharm
made a Paragraph IV certification and gave notice of the
certification to Endo and Bayer on October 8, 2014. On
November 20, 2014, Endo and Bayer brought an action
alleging infringement of the ’640 and ’395 patents. Dur-
ing the proceedings, Custopharm stipulated to infringe-
ment, and Endo and Bayer limited their asserted claims
to claim 2 of the ’640 patent and claim 18 of the ’395
patent. After a four-day bench trial on invalidity, the
district court concluded that Custopharm had not proven
that the claims were invalid under 35 U.S.C. § 103.
Custopharm appealed. For the reasons below, we find no
reversible errors in the district court’s conclusion and
accordingly, we affirm.
BACKGROUND
Aveed® is a long-acting injectable testosterone re-
placement therapy for men suffering from physiologically
low levels of testosterone, also known as hypogonadism.
Before the 2003 priority date for the invention claimed in
the ’640 and ’395 patents, then-existing testosterone
replacement therapies had three significant shortcomings.
First, the existing injectable therapies required patients
ENDO PHARMACEUTICALS SOLUTIONS v. CUSTOPHARM INC. 3
to visit their doctors every two or three weeks to receive
intramuscular injections, and the available topical thera-
pies required daily application. Second, the available
therapies required the prescribing doctor to adjust the
dosage or intervals of administration for each patient,
which required doctors to frequently monitor their pa-
tients’ testosterone levels. Third, the pre-2003 therapies
did not provide stable testosterone levels, leading to
periods of low testosterone between treatments. Patients
would experience elevated testosterone levels immediate-
ly after an injection, but testosterone levels would fall to
below the normal physiological range before the next
injection.
Aveed®’s patented formulation addressed some of
these shortcomings: (1) after the initial two injections,
Aveed® is only administered five times a year; (2) it is a
treatment that works for nearly all men suffering from
hypogonadism, thus obviating the need for doctors to
personalize testosterone replacement therapy; and (3)
patients on Aveed® avoided the fluctuations in testos-
terone levels associated with other injectable products on
the market before 2003. Claim 2 of the ’640 patent and
claim 18 of the ’395 patent cover Aveed®’s formulation and
injection regimen. Both patents, entitled “Methods and
Pharmaceutical Compositions for Reliable Achievement of
Acceptable Serum Testosterone Levels,” issued from the
same parent application and share a common specifica-
tion.
Claim 2 of the ’640 patent covers a 750 mg dosage of
TU in the composition described in claim 1:
A composition formulated for intramuscular injec-
tion in a form for single injection according to
claim 1, which contains 750 mg testosterone un-
decanoate.
’640 patent, col. 13, ll. 29–31 (emphasis added). Claim 1
reads:
4 ENDO PHARMACEUTICALS SOLUTIONS v. CUSTOPHARM INC.
A composition formulated for intramuscular injec-
tion in a form for single injection which contains
250 mg/ml testosterone undecanoate in a vehi-
cle containing a mixture of castor oil and benzyl
benzoate wherein the vehicle contains castor oil
in a concentration of 40 to 42 vol %.
Id. at col. 13, ll. 24–28 (emphases added).
Claim 18 of the ’395 patent covers a 750 mg dosage of
TU in the composition and method described by claim 14:
The method of claim 14, in which each dose con-
tains 750 mg of TU.
’395 patent, col. 16, ll. 1–2 (emphasis added). Claim 14
reads:
A method of treating a disease or symptom associ-
ated with deficient endogenous levels of testos-
terone in a man, comprising administering by
intramuscular injection a composition comprising
testosterone undecanoate (TU) and a vehicle
consisting essentially of castor oil and a co-
solvent, the castor oil being present in the vehicle
at a concentration of 42 percent or less by vol-
ume, the method further comprising:
(i) an initial phase comprising 2 ini-
tial intramuscular injections of a dose
of TU at an interval of 4 weeks be-
tween injections, each dose including
500 mg to 1000 mg of TU, followed by,
(ii) a maintenance phase comprising
subsequent intramuscular injections
of a dose of TU at an interval of 10
weeks between injections, each dose in-
cluding 500 mg to 1000 mg of TU.
Id. at col. 15, ll. 17–31 (emphases added). The key ele-
ments of both claims in dispute are: (1) 750 mg TU, (2)
ENDO PHARMACEUTICALS SOLUTIONS v. CUSTOPHARM INC. 5
vehicle consisting of castor oil and a co-solvent (benzyl-
benzoate in the ’640 patent) where the castor oil is 42% or
less by volume, and (3) an injection schedule comprising
two initial injections at an interval of four weeks followed
by injections at ten week intervals (’395 patent only).
Bayer and Endo sued Custopharm for infringement of
the ’640 and ’395 patents on November 20, 2014. The
case proceeded to a bench trial on the sole issues of
whether claim 2 of the ’640 patent and claim 18 of the
’395 patent would have been obvious to a skilled artisan
in view of the prior art, which consisted primarily of three
scientific articles: Behre, 1 Nieschlag, 2 and von Eckard-
stein 3 (Articles). These Articles describe small clinical
1 H.M. Behre et al., Intramuscular injection of tes-
tosterone undecanoate for the treatment of male hy-
pogonadism: phase I studies, 140 Eur. J. Endocrinol. 414
(1999). Behre compared the half-life of a single dose of
1000 mg TU in castor oil with a single dose of 1000 mg TU
in tea seed oil.
2 E. Nieschlag et al., Repeated intramuscular injec-
tions of testosterone undecanoate for substitution therapy
in hypogonadal men, 51 Clin. Endocrinol. 757 (1999).
Nieschlag studied the suitability of using four intramus-
cular injections of 1000 mg TU in castor oil at six week
intervals.
3 S. von Eckardstein & E. Nieschlag, Treatment of
Male Hypogonadism with Testosterone Undecanoate
Injected at Extended Intervals of 12 Weeks: A Phase II
Study, 23(3) J. Androl. 419 (2002). von Eckardstein
studied the efficacy and safety of prolonged TU treatment
at extended injection intervals—starting at injections
every six weeks followed by a gradual increase in the
interval to every twelve weeks after the tenth injection—
over a 3.2 year period.
6 ENDO PHARMACEUTICALS SOLUTIONS v. CUSTOPHARM INC.
studies involving 1000 mg TU injections. The Articles
report using a composition of 250 mg/ml TU in castor oil.
The parties agree that the Articles do not disclose or
describe the use of a co-solvent. While the actual formu-
lation of the vehicle used in the studies was 40% castor oil
and 60% benzyl benzoate, this was not reported and thus
unknown to a skilled artisan until 2007, years after the
2003 priority date for the patents-in-suit. In 2007, Saad4
disclosed that the vehicle formulation used in the Articles
was 40% castor oil and 60% benzyl benzoate, also sold as
Nebido®, a 1000 mg TU injection later marketed in
Europe by Bayer.
In addition to the Articles, Custopharm introduced
Pushpalatha 5 and Riffkin 6 as prior art. Pushpalatha is
an article that describes the effects of a commercially
marketed product—Proluton Depot (Proluton). Proluton
is an injectable composition of hydroxyprogesterone in a
mixture of 40% castor oil and 60% benzyl benzoate. It is
administered once a week to pregnant women to prevent
miscarriage. Riffkin is an article that describes the use of
castor oil for the parenteral administration of steroids. It
discloses a castor oil and benzyl benzoate vehicle to im-
prove the solvent abilities of castor oil.
After a four-day trial, the district court found that
Custopharm had not met its burden of proving that the
4 F. Saad, et al., More than eight years’ hands-on
experience with the novel long-acting parenteral testos-
terone undecanoate, 9(3) Asian J. Androl 291 (2007).
5 T. Pushpalatha, et al., Effect of prenatal exposure
to hydroxyprogesterone on steroidgenic enzymes in male
rats, 90 Naturwissenschaften 40 (2003).
6 C. Riffkin, et al., Castor Oil as A Vehicle for Par-
enteral Administration of Steroid Hormones, 53(8) J.
Pharm. Sci. 891 (1964).
ENDO PHARMACEUTICALS SOLUTIONS v. CUSTOPHARM INC. 7
disputed claims would have been obvious. Specifically,
the district court found that the prior art did not disclose
the 750 mg TU injection dosage, and that Custopharm
had not shown, by clear and convincing evidence, that a
skilled artisan would have been motivated to lower the
dosage of TU from 1000 mg to 750 mg due to concerns
patients were being overdosed. Further, the district court
found that the Articles do not inherently disclose benzyl
benzoate as a co-solvent or the particular ratio of solvent
to co-solvent claimed by the patents-in-suit simply be-
cause this formulation was what had been used in the
studies forming the basis of the Articles. Citing Par
Pharmaceutical, Inc. v. TWI Pharmaceutical, Inc., 773
F.3d 1186, 1194–95 (Fed. Cir. 2014), and Continental Can
Co. USA v. Monsanto Co., 948 F.2d 1264, 1268–69 (Fed.
Cir. 1991), the district court noted that inherency may
only supply a missing claim limitation if the limitation at
issue is the “natural result” of the combination of prior art
elements or a “necessarily present” limitation. Custo-
pharm, the district court reasoned, failed to establish that
alternative vehicles could not have been used in the
Articles. Finally, the district court found that the prior
art did not disclose the specific injection schedule claimed
in the ’395 patent and was unpersuaded by Custopharm’s
argument that it would have been obvious to a skilled
artisan to arrive at this specific schedule.
Custopharm appealed. We have jurisdiction pursuant
to 28 U.S.C. § 1295(a)(1).
DISCUSSION
“Obviousness is a question of law based on underlying
findings of fact.” In re Kubin, 561 F.3d 1351, 1355 (Fed.
Cir. 2009). We review the district court’s conclusions of
law de novo. Eli Lilly & Co. v. Teva Parenteral Meds.,
Inc., 845 F.3d 1357, 1372 (Fed. Cir. 2017). And we review
the district court’s factual findings for clear error. Par
Pharm., 773 F.3d at 1194. The inherent teaching of a
8 ENDO PHARMACEUTICALS SOLUTIONS v. CUSTOPHARM INC.
prior art reference is a question of fact. Id. (citing In re
Napier, 55 F.3d 610, 613 (Fed. Cir. 1995)).
The ’640 and ’395 patents disclose three primary ele-
ments in the composition and administration of Aveed®:
(1) 750 mg TU in (2) a 40% castor oil and 60% benzyl
benzoate vehicle (the benzyl benzoate element only ap-
plies to the ’640 patent; the ’395 patent only requires a co-
solvent) (3) administered at an initial interval of two
injections four weeks apart and maintenance injections at
ten week intervals thereafter (’395 patent only). Custo-
pharm contends that the Articles inherently describe the
vehicle formulation (40% castor oil and 60% benzyl ben-
zoate). And a skilled artisan would have recognized that
patients were being overdosed with 1000 mg TU injec-
tions at a concentration of 250 mg/ml (for a total of 4 ml
injected fluid). Relying on that premise, Custopharm
argues that it would have been obvious to a skilled arti-
san to reduce the amount of injected fluid to 3 ml while
maintaining the same TU concentration for a total of
750 mg TU per injection. This dose adjustment would in
turn make the injection interval adjustment, including
the use of a two-phase dosing regimen, obvious. We
disagree, as we see no clear error in the district court’s
underlying factual findings. Below, we discuss each of the
elements in further detail.
A. Testosterone Dose
Neither party contests that the prior art does not dis-
close a 750 mg dosage of TU. Custopharm argues that the
district court clearly erred in finding no motivation for a
skilled artisan to lower the dose of TU from 1000 mg to
750 mg because, in view of the American Association of
Clinical Endocrinologists (AACE) Guidelines, patients in
prior art clinical studies were being overdosed. The
AACE Guidelines set the range of normal testosterone
levels at 200 to 800 nanograms/deciliter (ng/dl) or 9.7 to
27.7 nanomoles/liter (nmol/l). Under these guidelines,
ENDO PHARMACEUTICALS SOLUTIONS v. CUSTOPHARM INC. 9
four of the fourteen patients in the Behre study would be
regarded as having testosterone levels exceeding the
normal range, based on a measurement three days after
an injection of 1000 mg of TU. Accordingly, Custopharm
contends that a skilled artisan would have recognized
that these patients were being overdosed and would have
been motivated to reduce the dose from 1000 mg to
750 mg by injecting patients with 3 ml instead of 4 ml of
solution at a TU concentration of 250 mg/ml. The district
court reasonably rejected this argument.
First, Custopharm’s overdose argument is predicated
on the assumption that a skilled artisan would have
applied the AACE Guidelines to the exclusion of other
guidelines that existed at the time, including the FDA
Guidelines. Under the FDA Guidelines, the range of
normal testosterone is 300 to 1000 ng/dl or 10 to
35 nmol/l. The record evidence sufficiently demonstrates
that the most prevalently applied guidelines in clinical
practice were the FDA Guidelines, not the AACE Guide-
lines. The studies underlying the Articles all employed
the FDA Guidelines. The patents-in-suit also cited the
FDA Guidelines. ’640 patent, col. 8, ll. 59–61; ’395 patent,
col. 9, ll. 24–26. Aveed®’s label similarly references the
300 to 1000 ng/dl normal range. Moreover, a passage in a
textbook that Custopharm’s own expert Dr. Peter Schlegel
edited confirms that “[t]he most common [guideline] in
clinical practice is a Food & Drug Administration range of
300 to 1,000 nanograms per deciliter.” Loren Jones &
Craig Niederberger, Medical Therapy for Male Infertility,
FERTILITY PRESERVATION IN MALE CANCER PATIENTS (John
P. Mulhall, Linda D. Applegarth, Robert D. Oates, Peter
N. Schlegel eds., 2013).
Under the FDA Guidelines, only one participant in
the Behre study had testosterone levels that exceeded the
normal range when measured three days after the injec-
tion of 1000 mg of TU. Four weeks after injection, howev-
er, this individual’s testosterone level dropped below the
10 ENDO PHARMACEUTICALS SOLUTIONS v. CUSTOPHARM INC.
normal range. Further, Behre specifically reported that a
single 1000 mg injection of TU “does not result in su-
pranormal serum testosterone levels, but in much pro-
longed action.” J.A. 1129. 7 Thus, the district court
reasonably rejected Custopharm’s argument that a skilled
artisan would consider 1000 mg of TU to be an overdose
and would have been motivated to lower the dosage to the
patented 750 mg.
Second, Custopharm argues that the obviousness of
an invention does not require using the “best” motiva-
tion 8; only a “suitable” motivation is required. Par
Pharm., 773 F.3d at 1197–98. But this is a misunder-
standing of Custopharm’s burden. While the FDA Guide-
lines do not teach away from using the AACE Guidelines,
the district court found that Custopharm had not shown,
by clear and convincing evidence, that a skilled artisan
would have recognized that patients injected with
1000 mg TU were being overdosed. To meet its burden,
Custopharm needed to do more than merely show that the
prior art does not preclude lowering the dose of TU.
Custopharm needed to affirmatively demonstrate that a
skilled artisan would have been motivated to lower the
dose of TU despite no clear evidence of overdosing under
the FDA Guidelines. See Pfizer, Inc. v. Apotex, Inc., 480
7 Moreover, Custopharm’s argument that four of
the fourteen patients in Behre’s study were being over-
dosed under the AACE Guidelines is based on undisclosed
data underlying the Behre study, which the district court
correctly refused to consider because it is not prior art.
8 Presumably, determining whether patients were
being overdosed under the FDA Guidelines would consti-
tute using the “best” motivation, though Custopharm does
contest whether the FDA Guidelines were the “best” to
apply.
ENDO PHARMACEUTICALS SOLUTIONS v. CUSTOPHARM INC. 11
F.3d 1348, 1361 (Fed. Cir. 2007) (“[T]he burden falls on
the challenger of the patent to show by clear and convinc-
ing evidence that a skilled artisan would have been
motivated to combine the teachings of the prior art refer-
ences to achieve the claimed invention . . . .”).
Third, Custopharm’s overdose theory improperly as-
sumes that the only solution to overdosed patients is to
reduce dosage rather than extending the injection inter-
vals. Endo and Bayer argue that this data would likely
teach a skilled artisan formulating a long-acting testos-
terone injection not to decrease the dose—because four
weeks after the initial injection of 1000 mg TU, five out of
the fourteen patients had testosterone levels below the
normal range—but to alter the injection schedule. Ac-
cordingly, the district court did not err in rejecting Custo-
pharm’s overdose theory.
B. Vehicle Formulation
Regarding the vehicle formulation, Custopharm
makes two arguments on appeal. First, Custopharm
argues that the district court erred in finding that the
vehicle formulation—40% castor oil and 60% benzyl
benzoate—was not inherently described by the Articles.
Second, Custopharm argues that the district court erred
in finding no motivation to combine the vehicle formula-
tion of Proluton with the lowered dose and modified
injection schedule. We discuss each in turn.
Inherency
To establish that a prior art reference inherently—
rather than expressly—discloses a claim limitation, “the
limitation at issue necessarily must be present, or [is] the
natural result of the combination of elements explicitly
disclosed by the prior art.” Par Pharm., 773 F.3d at 1196.
Here, Custopharm argues that the vehicle formulation
was “necessarily present” in the Articles because it was
later revealed to be the actual formulation the authors of
12 ENDO PHARMACEUTICALS SOLUTIONS v. CUSTOPHARM INC.
the Articles used in their reported clinical studies. We
disagree.
An inherent characteristic of a formulation can be
part of the prior art in an obviousness analysis even if the
inherent characteristic was unrecognized or unappreciat-
ed by a skilled artisan. See In re Kao, 639 F.3d 1057,
1070 (Fed. Cir. 2011). But, inherency “may not be estab-
lished by probabilities or possibilities.” Par Pharm., 773
F.3d at 1195 (quoting In re Oelrich, 666 F.2d 578, 581
(CCPA 1981)). “The mere fact that a certain thing may
result from a given set of circumstances is not sufficient.”
Id. (citing In re Rijckaert, 9 F.3d 1531, 1533–34 (Fed. Cir.
1993); Oelrich, 666 F.2d at 581 (“[M]ere recitation of a
newly discovered function or property, inherently pos-
sessed by things in the prior art, does not distinguish a
claim drawn to those things from the prior art.”); In re
Shetty, 566 F.2d 81, 86 (CCPA 1977) (“[T]he inherency of
an advantage and its obviousness are entirely different
questions. . . . Obviousness cannot be predicated on what
is unknown.” (quoting In re Spormann, 363 F.2d 444, 448
(CCPA 1966))).
Custopharm argues that the vehicle formulation was
inherently disclosed because the Articles provide a de-
tailed recitation of the TU injection composition’s phar-
macokinetic performance, from which a skilled artisan
could derive that the vehicle consisted of 40% castor oil
and 60% benzyl benzoate. The district court reasonably
found that this was not enough “to establish that the
Articles barred the possibility of an alternative vehicle
being used in the prior art compositions” to meet the
rigorous standard of inherency. J.A. 38.
First, Custopharm has not demonstrated that a
skilled artisan could extrapolate the vehicle formulation
used in the Articles from pharmacokinetic performance
data. Custopharm’s own opening brief does not argue
that the pharmacokinetic performance reported in the
ENDO PHARMACEUTICALS SOLUTIONS v. CUSTOPHARM INC. 13
Articles can only be attributed to the claimed vehicle
formulation. See Appellant’s Opening Br. at 28 (“Differ-
ences in the formulation could produce pharmacokinetic
differences.”) (emphasis added). Moreover, Custopharm’s
brief incorrectly shifts the burden of proof to Endo and
Bayer. Custopharm argues that Dr. Derendorf, Endo and
Bayer’s pharmacokinetic expert, failed to provide any
evidence to support his view that “it was possible to have
the same pharmacokinetic profile with two different
formulations.” See id. at 29. But, it is Custopharm’s
burden to present clear and convincing evidence that the
Articles necessarily disclosed the vehicle formulation to
one of skill in the art. See Motorola Mobility, LLC v. Int’l
Trade Comm’n, 737 F.3d 1345, 1350 (Fed. Cir. 2013). And
Custopharm’s expert’s testimony and briefing fall short of
meeting this burden.
Second, the prior art was replete with potential co-
solvents such that a skilled artisan, reviewing the Arti-
cles, would not have necessarily recognized that the
Articles’ authors used benzyl benzoate as a co-solvent for
their reported clinical studies. Endo and Bayer’s expert
testified that, based on the Articles’ disclosures, a skilled
artisan would not have recognized that a co-solvent was
necessary. And even if a skilled artisan concluded that a
co-solvent was necessary, there were any number of
available co-solvents, including, for example, benzyl
alcohol, ethanol, cottonseed oil, sesame oil, peanut oil,
corn oil, fractionated coconut oil, ethyl lactate, ethyl
oleate, and isopropyl myristate. Moreover, Custopharm’s
expert conceded that even knowing the identity of the co-
solvent would not necessarily lead a skilled artisan to the
particular ratio claimed in the ’650 and ’395 patents.
J.A. 404 at 92:19–23 (“Q: Now, looking at von Eckard-
stein, two separate questions. A person of ordinary skill
reading von Eckardstein, would he know that it’s neces-
sarily using a 40 percent castor oil, 60 percent benzyl
benzoate solution? A: No.”). Riffkin, for example, disclos-
14 ENDO PHARMACEUTICALS SOLUTIONS v. CUSTOPHARM INC.
es multiple vehicle formulations that range from 50%
castor oil to 98% castor oil.
Third, the cases Custopharm cited to support its in-
herency argument are inapposite. In In re Omeprazole
Patent Litigation, the claims at issue were directed to a
process for making a pharmaceutical composition, which
included an in situ separating layer or subcoating. 483
F.3d 1364 (Fed. Cir. 2007). We found claim 1 to be inher-
ently anticipated in light of a Chong Kun Dan Corpora-
tion (CKD) patent application that disclosed an
omeprazole tablet. Id. at 1373–74. While the CKD appli-
cation expressly disavowed the presence of a separating
layer, the record showed that the in situ separating layer
was, in fact, a natural result of using the ingredients
outlined in the CKD application. Id. at 1373. Thus,
though the inventors “may not have recognized that a
characteristic of CKD’s Method A ingredients, disclosed in
the CKD Patent Application, resulted in an in situ for-
mation of a separating layer,” we held that the in situ
formation was inherent because “the record shows for-
mation of the in situ separating layer in the prior art even
though that process was not recognized at the time.” Id.
Unlike Omeprazole, where we found the in situ separating
layer inherent because it would result each and every
time a skilled artisan followed the prior art process,
Custopharm has not demonstrated, discussed supra, that
the pharmacokinetic performance profile (Cmax—
concentration maximum; tmax—time of reaching Cmax;
T1/2β—terminal elimination half-life; and AUC—area
under the concentration versus time curve) reported in
the Articles could only be achieved using the claimed
vehicle formulation of 40% castor oil and 60% benzyl
benzoate.
Custopharm also analogizes the current situation to
In re Crish, 393 F.3d 1253 (Fed. Cir. 2004). In Crish, the
invention covered a purified oligonucleotide with a human
involucrin gene (HiNV) promoter. Id. at 1254–55. The
ENDO PHARMACEUTICALS SOLUTIONS v. CUSTOPHARM INC. 15
specific nucleotide sequence was recited in the claim and
called “SEQ ID No. 1.” Id. A prior publication disclosed
the structure of the HiNV gene, including the approxi-
mate size of the promoter region, but did not disclose the
sequence of the promoter region. Id. at 1255. We held
that the claimed invention—the specific nucleotide se-
quence—was inherently anticipated. Id. at 1258.
Custopharm argues that, as in Crish, where we found
that “one cannot establish novelty by claiming a known
material by its properties,” Endo and Bayer are trying to
claim a vehicle formulation that was disclosed earlier in a
publication on the basis that the patented claims in
dispute more fully characterize the vehicle formulation
described in the prior publication. Crish, 393 F.3d at
1258. But as with Custopharm’s analogy to Omeprazole,
Custopharm’s argument falls short because it has not
shown through any evidence why the pharmacokinetic
performance profile reported in the Articles could be
obtained only by using the claimed 40% castor oil/60%
benzyl benzoate formulation. In Crish, the record was
clear that the known HiNV promoter region necessarily
contained the sequence that the inventor tried to patent,
whereas in this case, the record is devoid of any proof that
only one vehicle formulation—the claimed vehicle formu-
lation—can be used to achieve the pharmacokinetic
performance reported in the Articles.
Importantly, Crish and Omeprazole were about inher-
ently present properties or characteristics for a “known”
prior art product. But here, the TU injection composition
recounted in the Articles cannot be said to be “known” in
the same way; the Articles failed to disclose that the
composition’s vehicle formulation included another, key
ingredient, benzyl benzoate, let alone the ratio of benzyl
benzoate to castor oil. And there was no evidence in the
record that a skilled artisan could determine the non-
disclosed vehicle formulation based on the reported
pharmacokinetic performance profile, or that the non-
16 ENDO PHARMACEUTICALS SOLUTIONS v. CUSTOPHARM INC.
disclosed vehicle formulation was necessarily a feature of
the TU injection studied in the Articles. Under the cir-
cumstances of this case, the incomplete description of the
TU injection composition elements denied skilled artisans
from having access to that composition, thereby preclud-
ing use of the inherency doctrine to fill in disclosure about
the product missing from the Articles.
Thus, the district court did not err in finding that
Custopharm did not present clear and convincing evi-
dence showing the 40% castor oil to 60% benzyl benzoate
as claimed was necessarily present in the Articles. 9
Motivation to Combine
Regarding the vehicle formulation missing from the
Articles, Custopharm alternatively argues that the dis-
trict court clearly erred in finding no motivation to com-
bine the vehicle formulation of Proluton with the claimed
lowered dose and modified injection schedule. Proluton
was a commercially available, injectable steroid drug
(hydroxy-progesterone) that used a vehicle consisting of
approximately 40% castor oil and 60% benzyl benzoate. It
9 Custopharm also made a public policy argument
in its opening brief applying the policy rationale underly-
ing the public use bar under pre-AIA § 102(b) to the
inherency analysis. Appellant’s Opening Br. at 21–23.
Custopharm, however, did not respond to Endo’s conten-
tion that Custopharm waived this argument by failing to
raise it before the district court. We agree with Endo. In
its reply brief, Custopharm argued that Helsinn
Healthcare S.A. v. Teva Pharmaceuticals USA, Inc., is a
pertinent intervening case, but did not explain how it is
an intervening change in law to the inherency doctrine,
especially given that it is an on-sale bar case. 855 F.3d
1356 (Fed. Cir. 2017).
ENDO PHARMACEUTICALS SOLUTIONS v. CUSTOPHARM INC. 17
was administered on a weekly basis at a concentration of
250 mg/ml to prevent miscarriages. Custopharm argues
that, even though Proluton was administered weekly, a
skilled artisan would have been motivated to use the
vehicle formulation from Proluton to formulate a long-
acting testosterone injection because hydroxyl-
progesterone and TU are both hormones injected at a high
concentration of 250 mg/ml. Moreover, even before the
vehicle in Proluton was disclosed, the combination of
castor oil and benzyl benzoate was taught in Riffkin. 10
Custopharm’s Proluton-based argument lacks merit.
The district court correctly noted that it is Custo-
pharm’s “burden to prove by clear and convincing evi-
dence that a person of ordinary skill in the art would have
been motivated to combine the Articles (and other cited
prior art) with the vehicle used in Proluton.” J.A. 36. The
district court found that Custopharm failed to meet its
burden because, while Proluton and Riffkin do suggest
the use of a co-solvent, they do not suggest that the co-
solvent necessarily be benzyl benzoate as opposed to the
other co-solvents known in the art (see discussion supra
regarding the large number of possible co-solvents).
Further, while Proluton was commercially available
before 2003, it is not a testosterone product for men;
rather, it is administered to pregnant women to prevent
miscarriage. And importantly, it is not an injectable
steroid with prolonged activity. The district court was not
persuaded that a skilled artisan would have turned to the
vehicle in Proluton when formulating a long-acting,
injectable testosterone therapy.
10 Riffkin teaches that the solubility of steroid hor-
mones in oils can be improved through the addition of
benzyl benzoate and specifically referred to Proluton as
using a castor oil and benzyl benzoate mixture.
18 ENDO PHARMACEUTICALS SOLUTIONS v. CUSTOPHARM INC.
Given that Proluton is a weekly injection and is not
directed to prolonged activity, we agree. We conclude that
the district court did not err in rejecting Custopharm’s
argument that the patented formulation for Aveed® was
obvious over Proluton in view of the prior art.
C. Injection Schedule
Custopharm also argues on appeal that once a skilled
artisan recognized that patients injected with 1000 mg
TU were being overdosed, the specific injection schedule
claimed in claim 18 of the ’395 patent would be the result
of routine treatment of individual patients and thus
obvious. Custopharm first argues that there is no basis
for limiting the injection schedule to administration of “a
population dose” because claim 18 would be infringed by
the administration to a single patient. And viewing the
injection schedule from the perspective of individual
patients, it would have been obvious for a skilled artisan,
such as a clinician, to adjust the injection interval for at
least one patient to that disclosed in claim 18—two initial
injections four weeks apart followed by maintenance
injections every ten weeks.
Custopharm points out that both Nieschlag and von
Eckardstein disclosed TU injections resulting in drug
accumulation, i.e. increasingly high testosterone levels
over time. Such drug accumulation makes it possible to
extend the dosing interval. This, Custopharm reasons,
suggests to a skilled artisan a two-phase dosing regimen.
Nieschlag teaches four doses at six week intervals and
that the intervals may be extended to up to ten weeks or
more due to drug accumulation. von Eckardstein disclos-
es that the interval between doses could be increased up
to twelve weeks. Custopharm argues that together, these
Articles suggest a first phase of dosing with a shorter
interval between injections (Nieschlag) and a steady state
phase consisting of a longer interval for maintenance (von
Eckardstein). Further, because a skilled artisan would
ENDO PHARMACEUTICALS SOLUTIONS v. CUSTOPHARM INC. 19
have recognized that each dose would need to be reduced
from 1000 mg to 750 mg to reduce the risk of overdosing,
it follows that he would shorten the six-week interval in
Nieschlag and the twelve-week interval in von Eckard-
stein to prevent TU levels from going below the normal
range. The district court did not err in finding this argu-
ment unpersuasive.
First, this argument is predicated on Custopharm’s
overdose theory, which we have already rejected supra.
Second, read together, the Articles do not clearly con-
template a two-phase dosing regimen with initial loading
doses followed by maintenance doses. The Articles them-
selves do not explicitly teach the use of loading doses.
While it is possible to interpret von Eckardstein as using
loading doses, the district court reasonably characterized
von Eckardstein as a follow-up study to Nieschlag, seek-
ing to investigate prolonged injection intervals. J.A. 25
(“von Eckardstein described a clinical trial investigating
the efficacy and safety of prolonged TU treatment at
extended injection intervals over a 3.2 year period. Seven
patients (who had participated in the study described in
Nieschlag) received four injections at six week intervals,
followed by a gradual increase in the interval between the
fifth and tenth injections. After the tenth injection, the
interval was increased to twelve weeks.”). Thus, the
Articles reasonably teach a skilled artisan to increase the
intervals between doses, not to initially shorten them to
four weeks and then to lengthen them to ten weeks.
Third, Custopharm’s explanation for why a skilled ar-
tisan would have a reasonable expectation of success that
changing the injection regimen would result in a long-
acting testosterone therapy is lacking. Endo presented
evidence that oil based, depot (slow release) injections,
such as TU injections can behave in unpredictable ways
and that such dose and regimen changes would require
more than routine experimentation. Namely, this is
20 ENDO PHARMACEUTICALS SOLUTIONS v. CUSTOPHARM INC.
because it was unclear from the Articles if there is a
linear relationship between the dose amount and the
amount of TU in the patient’s body. Custopharm does not
directly dispute this pharmacokinetic argument; rather, it
contends on appeal that the district court did not give the
proper weight to its argument that the invention should
be viewed from the perspective of the individual patient.
The invention, however, is meant to achieve a commer-
cially viable testosterone therapy. ’640 patent, col. 2, ll.
49–54 (“There is a need of providing reliable standard
regimens acceptable for a broad population of men in need
thereof, preferably regimens without the need of occa-
sional control of serum testosterone levels, and regimens
wherein steady state conditions are achieved within a
shorter time period.”); ’395 patent, col. 2, ll. 57–60. And
Custopharm made no claim construction arguments below
in support of its individual patient rather than population
dose argument. Endo Pharm. Sols. Inc. v. Paddock Labs.,
LLC, 1:14-cv-01422-SLR-SRF, Dkt. 32 (D. Del. July 20,
2015) (stipulating that neither party identified terms that
require construction). Part of the obviousness inquiry
involves examining what a skilled artisan would be
motivated to do given “the effects of demands known to
the design community or present in the marketplace.”
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007).
The district court thus did not err in considering the
obviousness inquiry from the perspective of a skilled
artisan “confronted with the same problems as the inven-
tor,” which in this case is developing a commercially
viable long-acting testosterone therapy. See In re Rouffet,
149 F.3d 1350, 1357 (Fed. Cir. 1998). Doing so, the dis-
trict court properly found that Custopharm failed to meet
its burden of showing that a skilled artisan would com-
bine the lowered dose with the injection schedule in the
manner claimed.
ENDO PHARMACEUTICALS SOLUTIONS v. CUSTOPHARM INC. 21
CONCLUSION
The district court did not commit reversible error in
finding that claim 2 of the ’640 patent and claim 18 of the
’395 patent were not proven to be obvious over the prior
art. We have considered Custopharm’s other arguments
and find them unpersuasive. Therefore, we affirm the
district court’s decision.
AFFIRMED