ENDO PHARMACEUTICALS SOLUTIONS, INC., BAYER INTELLECTUAL PROPERTY GMBH, BAYER PHARMA AG, Plaintiffs-Appellees
CUSTOPHARM INC., Defendant-Appellant
from the United States District Court for the District of
Delaware in No. 1:14-cv-01422-SLR-SRF, Judge Sue L. Robinson.
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.
Moore, Linn, and Chen, Circuit Judges.
Pharmaceuticals Solutions, Inc. (Endo) holds the approved New
Drug Application for Aveed®, a testosterone
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 (Custopharm)
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. During the proceedings, Custopharm
stipulated to infringement, 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.
is a long-acting injectable testosterone replacement 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 to visit
their doctors every two or three weeks to receive
intramuscular injections, and the available topical therapies
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 patients'
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 immediately after an injection,
but testosterone levels would fall to below the normal
physiological range before the next injection.
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
testosterone 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 specification.
of the '640 patent covers a 750 mg dosage of TU in the
composition described in claim 1:
A composition formulated for intramuscular injection 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
A composition formulated for intramuscular injection in a
form for single injection which contains 250 mg/ml
testosterone undecanoate in a vehicle 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).
18 of the '395 patent covers a 750 mg dosage of TU in the
composition and method described by claim 14:
method of claim 14, in which each dose contains 750 mg of
TU. '395 patent, col. 16, ll. 1-2 (emphasis added).
Claim 14 reads:
A method of treating a disease or symptom associated with
deficient endogenous levels of testosterone 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 volume,
the method further comprising:
(i) an initial phase comprising 2 initial intramuscular
injections of a dose of TU at an interval of 4 weeks between
injections, each dose including 500 mg to 1000 mg of TU,
(ii) a maintenance phase comprising subsequent
intramuscular injections of a dose of TU at an interval of 10
weeks between injections, each dose including 500 mg to
1000 mg of TU.
Id. at col. 15, ll. 17-31 (emphases added). The key
elements of both claims in dispute are: (1) 750 mg TU, (2)
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
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,  Nieschlag,  and von Eckardstein (Articles). These
Articles describe small clinical 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 formulation 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 ...