from the United States District Court for the District of
Delaware in Nos. 1:14-cv-01171-GMS, 1:14-cv-01172-GMS,
1:14-cv-01278-GMS, 1:14-cv-01419-GMS, 1:15-cv-00124-GMS,
1:15-cv-00306-GMS, Judge Gregory M. Sleet.
C. O'Quinn, Kirkland & Ellis LLP, Washington, DC,
argued for plaintiffs-appellants. Also represented by Leslie
M. Schmidt, New York, NY; Elizabeth Holland, Goodwin Procter
LLP, New York, NY; William G. James, II, William M. Jay,
Washington, DC; Daryl L. Wiesen, Boston, MA.
Maynard, Morrison & Foerster LLP, Washington, DC, argued
for defendants-appellees. Defendants-appellees Sandoz Inc.,
Momenta Pharmaceuticals Inc. also represented by Seth W.
Lloyd; William A. Rakoczy, Matthew V. Anderson, Thomas
Ehrich, Erin Forbes, Christopher Patrick Galligan, Deanne M.
Mazzochi, Rachel Waldron, Rakoczy Molino Mazzochi Siwik LLP,
Shannon Bloodworth, Perkins Coie, LLP, Washington, DC, argued
for defendants-appellees. Defendants-appellees Mylan
Pharmaceuticals Inc., Mylan Inc. also represented by Robert
Swanson, Brandon Michael White; David Lee Anstaett, Madison,
WI; Dan L. Bagatell, Hanover, NH; Christina Jordan
McCullough, Seattle, WA.
D. Rodriguez, Budd Larner, P.C., Short Hills, NJ, for
defendants-appellees Dr. Reddy's Laboratories Ltd, Dr.
Reddy's Laboratories Inc. Also represented by Ellen
Tchorni Lowenthal, Louis Harry Weinstein.
Anthony Figg, Rothwell, Figg, Ernst & Manbeck, PC,
Washington, DC, for defendants-appellees Synthon
Pharmaceuticals, Inc., Synthon B.V., Synthon S.r.o. Blansko.
Also represented by Seth Edward Cockrum, Sharon Davis,
Jennifer Nock, Brett Alan Postal.
Anthony James Fitzpatrick, Duane Morris LLP, Boston, MA, for
defendants-appellees Amneal Pharmaceuticals LLC, Amneal
Pharmaceuticals Company GmbH, Pfizer Inc. Also represented by
Vincent Capuano, Christopher S. Kroon; Patrick Gallagher,
Boca Raton, FL.
Reyna, Bryson, and Stoll, Circuit Judges.
Teva Pharmaceuticals USA, Inc., Teva Pharmaceutical
Industries, Ltd., Teva Neuro-science, Inc., and Yeda Research
and Development Co., Ltd., appeal the decision of the United
States District Court for the District of Delaware
invalidating all asserted claims of patents directed to
COPAXONE® 40mg/mL, a product marketed for
treatment of patients with relapsing forms of multiple
sclerosis. Because the district court correctly held the
asserted claims invalid as obvious under 35 U.S.C. §
103, we affirm.
Patents at Issue
Research & Development Co., Ltd. is the assignee of U.S.
Patent Nos. 8, 232, 250, 8, 399, 413, 8, 969, 302, and 9,
155, 776 (the '250, '413, '302, and '776
patent, respectively), all entitled "Low Frequency
Glatiramer Acetate Therapy." The patents, collectively
referred to as the "Copaxone patents," share a
common specification and claim priority to the same two
provisional applications. J.A. 57-69. The earliest priority
date of the Copaxone patents is August 20, 2009. J.A. 23.
Copaxone patents describe and claim COPAXONE®
40mg/mL, a treatment for relapsing-remitting multiple
sclerosis ("RRMS"). RRMS is a form of multiple
sclerosis, an autoimmune disorder that causes the body's
immune system to attack the central nervous system. RRMS is
characterized by unpredictable relapses followed by periods
of remission with no new signs of disease activity.
active ingredient in COPAXONE® 40mg/mL is
glatiramer acetate ("GA"), a synthetic mixture of
polypep-tides. GA is also known as "copolymer 1" or
"Cop. 1." COPAXONE® 40mg/mL is
supplied as a single-dose prefilled syringe. Broadly, the
treatment consists of the injection of 40mg of GA three times
a week, abbreviated "40mg GA 3x/week." Relevant to
this appeal, side effects of GA injections include
injection-site reactions ("ISRs") and immediate
post-injection reactions ("IPIRs"). ISRs are
physical symptoms at the injection site, such as swelling or
itchiness. IPIRs are reactions immediately following an
injection, such as flushes, sweating, or palpitations.
to COPAXONE® 40mg/mL, in 1996 the Food and
Drug Administration ("FDA") approved
COPAXONE®20mg/mL, a regimen consisting of the
daily injection of 20mg GA. Daily GA injections were known to
subject patients to discomfort, including side effects in the
form of ISRs and IPIRs. J.A. 20692.
analyzing the obviousness of the Copaxone patents in this
case, a key limitation of the asserted claims is the
administration of a 40mg GA dose in three subcutaneous
injections over seven days. Claim 1 of the '250 patent is
1. A method of alleviating a symptom of re-lapsing-remitting
multiple sclerosis in a human patient suffering from
relapsing-remitting multiple sclerosis or a patient who has
experienced a first clinical episode and is determined to be
at high risk of developing clinically definite multiple
sclerosis comprising administering to the human patient a
therapeutically effective regimen of three subcutaneous
injections of a 40 mg dose of glatiramer acetate over a
period of seven days with at least one day between every
subcutaneous injection, the regimen being sufficient to
alleviate the symptom of the patient.
'250 patent col. 16 ll. 35-45.
from claim 1 of the '302 patent,  all asserted independent
claims require at least one day between doses. '250
patent col. 16 ll. 35-45, col. 17 l. 25-col. 18 l. 6;
'413 patent col. 16 ll. 26-36, col. 18 ll. 14-28;
'302 patent col. 17 ll. 4-12; '776 patent col. 16 ll.
35-50, col. 16 l. 61- col. 17 l. 19, col. 17 ll. 37-54, col.
17 l. 65-col. 18 l. 22. Certain dependent claims of the
'250, '413, and '776 patents further require
improved tolerability and/or reduced frequency of injection
reactions in the claimed regimen as compared to a 20mg GA
daily regimen. See, e.g., '250 patent col. 17
ll. 21-24, col. 18 ll. 7-15; '413 patent col. 16 ll.
51-54; '776 patent col. 16 ll. 51-54, col 17 l. 65-col.
18 l. 25..
'776 patent contains additional limitations, namely, the
requirement that the 40mg GA 3x/week regimen "reduce
severity of injection site reactions" compared to a 20mg
daily regimen, as seen in claim 1:
1. A method of treating a human patient suffering from a
relapsing form of multiple sclerosis, while inducing reduced
severity of injection site reactions in the human patient
relative to administration of 20 mg of glatiramer acetate
s.c. daily, the method consisting of one subcutaneous
injection of 1 ml of a pharmaceutical composition comprising
40 mg of glatiramer acetate on only each of three days during
each week of treatment with at least one day without a
subcutaneous injection of the pharmaceutical composition
between each day on which there is a subcutaneous injection,
wherein the pharmaceutical composition is in a prefilled
syringe, and wherein the pharmaceutical composition further
comprises mannitol and has a pH in the range 5.5 to 7.0,
so as to thereby treat the human patient with reduced
severity of injection site reactions relative to
administration of 20 mg of glatiramer acetate s.c.
'776 patent col. 16 ll. 35-50 (emphasis added).
Prior Art References
first clinical trial for using GA to treat multiple sclerosis
took place in 1987 by Dr. Bornstein et al.
("Born-stein"),  which was followed by a Teva Phase III
clinical trial in 1995. Both Bornstein and the Phase III
trial tested 20mg GA daily. J.A. 20378-84, 20464-20782. Since
GA was developed in an expedited manner under orphan drug
status in the United States at a time when no other disease
modifying multiple sclerosis treatments were available, the
20mg/day dose was selected without performing conventional
optimal-dose-finding studies. J.A. 24967.
Bornstein study showed that GA administered subcutaneously
for two years at a daily dose of 20mg "produced
clinically important and statistically significant beneficial
effects." J.A. 20383. Participants in both Bornstein and
the Phase III trial reported ISRs and IPIRs as side effects.
J.A. 20383, 20480. The Phase III trial noted "adverse
experience" as the main reason contributing to patient
dropout, and "[t]he most common adverse event associated
with dropout was injection site reaction." J.A. 20480. A
Phase III trial reviewer made recommendations for future
researchers to explore dose-response and dose-ranging
studies, asking "Is 20 mg the optimum dose? Are daily
injections necessary?" J.A. 20502.
1996, following both Bornstein and the Phase III clinical
trial, FDA approved Teva's New Drug Application
("NDA") for COPAXONE® 20mg, 20mg GA
injected daily. In its 1996 Summary Basis of Approval
("SBOA"), FDA recommended that Teva "evaluate
the necessity of daily [GA] injections as opposed to more
infrequent intermittent administration of the drug"
because the daily dosing regimen "seems like it would
subject the patient to an excessive amount of discomfort if
it is not necessary to maintain efficacy." J.A. 20692.
study by Flechter et al. ("Flechter") evaluated the
treatment of RRMS with 20mg of GA administered every other
day. J.A. 20436-40. Flechter concluded that
"alternate-day treatment with Copolymer 1 is safe, well
tolerated, and probably as effective as daily Copolymer 1 in
reducing relapse rate and slowing neurologic
deterioration." J.A. 20440. Flechter also noted that
patient dropout rates decreased when GA was administered
every other day as opposed to daily. J.A. 20440 ("It
should be stressed that the dropout rate was lower in the
alternate-day group than in the daily-injection regime (39.7%
versus 60.3%, p < 0.01).").
published in 2007, was a "double-blind, dose-comparison
study of glatiramer acetate in relapsing-remitting MS."
J.A. 20388-95. Cohen compared daily subcutaneous injections
of 20mg and 40mg GA dosages, and concluded that the 40mg dose
may be "more effective" than the 20mg dose "in
reducing MRI activity and clinical relapses." J.A.
20389. Cohen also noted that the onset of action of the 40mg
dose is more rapid compared to 20mg. J.A. 20394. ISRs were
the most frequent adverse event for both doses, occurring at
roughly equal rates. J.A. 20392-93. IPIRs occurred more
frequently in the 40mg group than the 20mg group.
Id. Cohen thus concluded that the overall safety and
side effect profile of the 40mg dose was "similar"
to the 20mg dose, but "was associated with a greater
incidence of certain adverse effects." J.A. 20394.
own prior art patent application, International Patent
Application No. WO 2007/081975, Method of Treating
Multiple Sclerosis ("Pinchasi"), was published
shortly after the Cohen study. J.A. 20925-56. Pinchasi
discloses a 40mg GA, every other day dosing regimen for the
treatment of RRMS. Pinchasi cites to the data from Cohen to
conclude that "[t]he increased efficacy observed with 40
mg/day GA in reducing MRI-measured disease activity and
relapse rate indicates that it is well tolerated and can
improve the treatment of RRMS patients. The improvement in
efficacy, however, is not accompanied by a corresponding
increase of adverse reactions which would be expected upon a
doubling of the administered dose." J.A. 20944.
FORTE study,  published in 2008, evaluated the safety,
tolerability, and efficacy of 40mg GA compared to 20mg GA.
J.A. 20411, 20414-22. FORTE concluded that both the 40mg and
20mg doses "were equally effective in reducing clinical
relapses and MRI activity," and that the 40mg dose has a
"safety profile similar to that observed in previous
studies of 20mg GA." J.A. 20411. FORTE also confirmed
Cohen's finding that the 40mg dose provided an earlier
onset of action. J.A. 20422 (noting a "[t]rend for an
earlier effect of high [40mg] dose on MRI activity").
study by Omar Khan and others ("Khan 2008") compared
the effect of daily versus every other day administration of
20mg GA subcutaneous injections for the treatment of RRMS.
J.A. 20883. The study abstract noted that although the
recommended dose for treating RRMS is daily 20mg GA
injections, "the optimal dose remains unknown" and
that there is "considerable interest in alternate dosing
regimens of GA" because daily injections "can be
challenging for long-term patient compliance." J.A.
20883. Thirty patients were randomly assigned to receive 20mg
GA dosed daily or every other day. After two years, there
were "no differences" between the two groups in
relapse rate or disease progression. J.A. 20883.
Additionally, after the first two years elapsed, patients in
each group were given the option to continue or switch
groups, and were monitored for an additional two years. Every
patient in the daily group opted to switch to every other day
administration. After four years, there was no difference
between the crossover group and the group that was always
dosed every other day. The Caon reference,  published in
2009, reports the same data from the Khan 2008 study, but
further noted that "[i]njection related lipoatrophy was
significantly less" in the every other day group. J.A.
State of the Art References
are two additional references relevant to this appeal, a 2009
study by Omar Khan ("Khan 2009") and Teva's own
Glatiramer Acetate Low-frequency Administration
("GALA") Phase III trial of 40mg GA administered
three times per week. J.A. 23904-05, J.A. 8246- 8417. Khan
2009 and GALA were both published after August 20, 2009, the