Appeals from the United States Patent and Trademark Office,
Patent Trial and Appeal Board in Nos. IPR2015-00643,
IPR2015-00644, IPR2015-00830, IPR2015-01976, IPR2015-01980,
William M. Jay, Goodwin Procter LLP, Washington, DC, argued
for appellant. Also represented by William G. James, II;
Elizabeth Holland, New York, NY; Daryl L. Wiesen, Boston, MA;
John C. O'Quinn, Kirkland & Ellis LLP, Washington,
DC; Leslie M. Schmidt, New York, NY.
Lee Anstaett, Perkins Coie, LLP, Madison, WI, argued for
appellees. Appellee Mylan Pharmaceuticals Inc. also
represented by Shannon Bloodworth, Robert Swanson, Brandon
Michael White, Washington, DC; Dan L. Bagatell, Hanover, NH;
Christina Jordan McCullough, Seattle, WA.
Anthony James Fitzpatrick, Duane Morris LLP, Boston, MA, for
appellee Amneal Pharmaceuticals LLC. Also represented by
Vincent Capuano, Christopher S. Kroon; Patrick Gallagher,
Boca Raton, FL.
Reyna, Bryson, and Stoll, Circuit Judges.
consolidated appeal, Appellant Yeda Research &
Development Co., Ltd. challenges the Patent Trial and Appeal
Board's final written decisions finding the claims of
U.S. Patent Nos. 8, 232, 250, 8, 399, 413, and 8, 969, 302
unpatentable as obvious in three inter partes review
proceedings. We affirm the Board's
Patents at Issue
Research and Development Co., Ltd. ("Yeda") is the
assignee of U.S. Patents Nos. 8, 232, 250, 8, 399, 413, and
8, 969, 302 (the '250, '413, and '302 patents,
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. See J.A. 267, 279, 291. The earliest
priority date of the Copaxone patents is August 20, 2009.
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
polypeptides. 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. 6956.
analyzing the obviousness of the Copaxone patents, a key
limitation of the claims is the administration of a 40mg GA
dose in three subcutaneous injections over seven days. Claim
1 of the '250 patent is representative:
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.
claims of the '250 and '413 patents further require
improved tolerability and/or reduced frequency of injection
reactions in the claimed regimen as compared to 20mg daily.
'250 patent col. 17 l. 24-col. 18 l. 6; '413 patent
col. 16 ll. 51-54.
from claim 1 of the '302 patent, all independent claims
require at least one day between doses. '250 patent col.
16 ll. 35-45, col. 17 l. 25-col. 18 l. 6, col. 18 ll. 19-26;
'413 patent col. 16 ll. 26-36, col. 18 ll. 1-13, col. 18
ll. 14-28; '302 patent col. 17 ll. 4-12. Claim 1 of the
'302 patent does not specify any particular interval
between doses, but dependent claims 4 and 5 limit injections
to certain combinations of days of the week, all with at
least one day between injections, and independent claim 10 of
the '302 patent requires that the injection be
administered "three times per week with at least one day
between every subcutaneous injection." '302 patent
col. 16 ll. 37-41, col. 16 ll. 47-58, col. 17 ll. 4-12.
Prior Art References
first clinical trial for using GA to treat multiple sclerosis
was in 1987 by Dr. Bornstein et al. ("Bornstein"),
which was followed later by a Teva Phase III clinical trial
in 1995. Both Bornstein and the Phase III trial tested 20mg
GA daily. J.A. 7279- 80, 7282-85, 6895-7235. The 20mg/day
dose was selected without performing conventional
optimal-dose-finding studies. J.A. 7239.
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. 7284. Participants in both Bornstein and
the Phase III trial reported ISRs and IPIRs as side effects.
J.A. 7284, 6934. 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. 6934. 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. 6956.
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"), the 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."
study by Flechter et al. ("Flechter") evaluated the
treatment of RRMS with 20mg of GA administered every other
day. J.A. 7236-40. 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. 7240. Flechter also noted that
patient dropout rates decreased when GA was administered
every other day as opposed to daily. J.A. 7240 ("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).").
art patent application, International Patent Application No.
WO 2007/081975, Method of Treating Multiple
Sclerosis ("Pinchasi"), was published in 2007.
J.A. 6857-88. Pinchasi discloses a 40mg GA, every other day
dosing regimen for the treatment of RRMS. Pinchasi cites to
the data from Cohen, another GA study, 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. 6876.
State of the Art Reference
is an additional reference relevant to this appeal, a 2009
study by Omar Khan ("Khan 2009"). J.A. 9331-32.
Khan 2009 was published three weeks after August 20, 2009,
the priority date of the asserted patents, and thus does not
qualify as statutory prior art, but the study began two years
earlier. J.A. 9331-32. The study abstract noted that
"[t]here is considerable interest in studying a more
patient friendly dosing regimen of GA that may be as
efficacious and better tolerated than daily GA." J.A.
9331. Following the results of an earlier study, Khan 2008,
showing that alternate day administration of GA appears to be
as effective as daily administration, Khan 2009 compared 20mg
GA administered twice a week to 20mg GA administered daily in
a pilot, prospective, randomized, and rater-blinded two-year
study. J.A. 9331; see infra note 8.
Proceedings before the Board
Pharmaceuticals, Inc. ("Mylan") filed petitions for
inter partes review ("IPR") in
IPR2015-00643, IPR2015-00644, and IPR2015-00830, challenging
all claims of the '250, '413, and '302 patents,
respectively, on grounds pursuant to 35 U.S.C. §§
102 and 103. The Patent Trial and Appeal Board (the
"Board") instituted review of all claims of the
Copaxone patents on two grounds: obviousness over Pinchasi in
view of FDA's 1996 SBOA, and over Pinchasi in view of
Flechter. J.A. 644 (instituting IPR on the '250
patent), 1720-21 ('413 patent), 2710- 11 ('302
patent). Subsequently, Amneal Pharmaceuticals LLC filed for
each patent substantially identical petitions to those
already filed by Mylan, and moved to join Mylan's
proceedings. The Board subsequently consolidated Amneal
Pharmaceuticals' petitions with those already filed by
Mylan. J.A. 894-898, 1970-74, 3489-95. Amneal Pharmaceuticals
and Mylan are collectively referred to as
Board's analysis of the independent claims was similar
for all three patents. The Board first noted that Pinchasi
discloses every limitation of the independent claims of the
Copaxone patents, except for the dosing regimen of three
doses per seven day period. The Board found that a person of
ordinary skill in the art ("POSITA") would have
been motivated to use a 40mg dose, crediting the testimony of
Petitioners' expert, Dr. Green, who noted that Pinchasi
demonstrated increased efficacy of 40mg GA compared to 20mg
with no significant difference in side effects, and citing
Cohen,  a study which concluded that daily
administration of 40mg GA was effective, safe, and well
tolerated. In reaching this finding, the Board also found
that FORTE,  a phase III clinical trial comparing 40mg
GA and 20mg GA, would not have taught away from using 40mg
because it did not criticize, discredit, or discourage the
40mg GA dose.
Board next considered whether there was a motivation to
modify Pinchasi's 40mg every other day regimen. The Board
noted that the difference between the challenged claims (6
doses over 2 weeks) and Pinchasi (7 doses over 2 weeks) was
only one less injection every two weeks. The Board then found
motivation to eliminate one injection every other week to
increase patient compliance, relying in part on
Petitioners' expert Dr. Green, who testified that
decreasing the frequency of injections helps with patient
adherence to a treatment regimen, and FDA's 1996 SBOA,
which recommended that the necessity of daily injections, as
opposed to less frequent administration, be evaluated. The
Board further relied on other prior art references, including
Flechter, Khan 2008,  and Caon,  which showed that alternate-day
dosing of 20mg was safe, well-tolerated, as effective as
daily 20mg, reduced injection reactions, and ...