Teva Pharm. USA, Inc. v. Sandoz Inc. (In Re Copaxone Consol. Cases)

United States Court of Appeals
for the Federal Circuit
______________________
IN RE: COPAXONE CONSOLIDATED CASES
---------------------------------------------------------------------------------
TEVA PHARMACEUTICALS USA, INC., TEVA
PHARMACEUTICAL INDUSTRIES, LTD., TEVA
NEUROSCIENCE, INC., YEDA RESEARCH AND
DEVELOPMENT CO., LTD.,
Plaintiffs-Appellants
v.
SANDOZ INC., MOMENTA PHARMACEUTICALS
INC., DR REDDY'S LABORATORIES LTD, DR
REDDY'S LABORATORIES INC., MYLAN
PHARMACEUTICALS INC., MYLAN INC.,
SYNTHON PHARMACEUTICALS, INC., SYNTHON
B.V., SYNTHON S.R.O. BLANSKO, AMNEAL
PHARMACEUTICALS LLC, AMNEAL
PHARMACEUTICALS COMPANY GMBH, PFIZER
INC.,
Defendants-Appellees
______________________
2017-1575
______________________
Appeal 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.
2 TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC.
______________________
Decided: October 12, 2018
______________________
JOHN 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.
DEANNE MAYNARD, Morrison & Foerster LLP, Wash-
ington, 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,
Chicago, IL.
SHANNON BLOODWORTH, Perkins Coie, LLP, Washing-
ton, 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.
FRANK 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.
EDWARD 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
TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC. 3
COCKRUM, SHARON DAVIS, JENNIFER NOCK, BRETT ALAN
POSTAL.
ANTHONY JAMES FITZPATRICK, Duane Morris LLP,
Boston, MA, for defendants-appellees Amneal Pharma-
ceuticals LLC, Amneal Pharmaceuticals Company GmbH,
Pfizer Inc. Also represented by VINCENT CAPUANO,
CHRISTOPHER S. KROON; PATRICK GALLAGHER, Boca Raton,
FL.
______________________
Before REYNA, BRYSON, and STOLL, Circuit Judges.
REYNA, Circuit Judge.
Plaintiffs-Appellants 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 assert-
ed 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. 1
1 In a companion case decided today, Yeda Research
& Development Co., v. Mylan Pharmaceuticals Inc., Nos.
17-1594, 17-1595, 17-1596 (Fed. Cir. Oct. 12, 2018), Yeda
Research and Development Co. appealed from the Patent
Trial and Appeal Board’s final written decisions finding
all claims of U.S. Patent Nos. 8,232,250, 8,399,413, and
8,969,302 unpatentable as obvious in three related inter
partes review proceedings.
4 TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC.
BACKGROUND
I. Patents at Issue
Yeda Research & Development Co., Ltd. is the assign-
ee 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, re-
spectively), 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.
The 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.
The 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 palpi-
tations.
Prior to COPAXONE® 40mg/mL, in 1996 the Food and
Drug Administration (“FDA”) approved COPAXONE®
20mg/mL, a regimen consisting of the daily injection of
TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC. 5
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.
For analyzing the obviousness of the Copaxone pa-
tents in this case, a key limitation of the asserted claims
is the administration of a 40mg GA dose in three subcu-
taneous 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 multi-
ple 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.
Apart from claim 1 of the ’302 patent, 2 all asserted in-
dependent 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.
2 Claim 1 of the ’302 patent does not specify any
particular interval between doses. ’302 patent col. 16 ll.
37–41. 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 injec-
tion.” Id. col. 17 ll. 4–12.
6 TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC.
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..
The ’776 patent contains additional limitations, name-
ly, 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 suffer-
ing from a relapsing form of multiple sclerosis,
while inducing reduced severity of injection site
reactions in the human patient relative to admin-
istration of 20 mg of glatiramer acetate s.c. daily,
the method consisting of one subcutaneous injec-
tion of 1 ml of a pharmaceutical composition com-
prising 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 injec-
tion site reactions relative to administration of
20 mg of glatiramer acetate s.c. daily.
’776 patent col. 16 ll. 35–50 (emphasis added).
TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC. 7
II. Prior Art References
The first clinical trial for using GA to treat multiple
sclerosis took place in 1987 by Dr. Bornstein et al. (“Born-
stein”), 3 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.
The 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 contrib-
uting 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 recommenda-
tions 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.
In 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 intermit-
3 Murray B. Bornstein et al., A Pilot Trial of COP 1
in Exacerbating-Remitting Multiple Sclerosis, 317 New
Eng. J. Med. 408, 408–14 (1987).
8 TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC.
tent 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.
A 2002 study by Flechter et al. 4 (“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 deteriora-
tion.” J.A. 20440. Flechter also noted that patient drop-
out 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).”).
Cohen, 5 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
4 Shlomo Flechter et al., Copolymer 1 (Glatiramer
Acetate) in Relapsing Forms of Multiple Sclerosis: Open
Multicenter Study of Alternate-Day Administration, 25
Clinical Neuropharmacology 11, 11–15 (2002).
5 J.A. Cohen et al., Randomized, Double-Blind,
Dose-Comparison Study of Glatiramer Acetate in Relaps-
ing-Remitting MS, 68 Neurology 939, 939–44 (2007).
TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC. 9
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.
Teva’s 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.
The FORTE study, 6 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”).
6 Giancarlo Comi, Jeffrey A. Cohen, Massimo Filip-
pi for the FORTE Study Group, Results from a Phase III,
One-Year, Randomized, Double-Blind, Parallel-Group,
Dose-Comparison Study with Glatiramer Acetate in Re-
lapsing-Remitting Multiple Sclerosis, 14 Multiple Sclero-
sis S299, S299–S301 (2008).
10 TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC.
A 2008 study by Omar Khan and others 7 (“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 inter-
est in alternate dosing regimens of GA” because daily
injections “can be challenging for long-term patient com-
pliance.” 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, 8 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. 20386.
7 Omar Khan et al., Randomized, Prospective,
Rater-Blinded, Four-Year, Pilot Study to Compare the
Effect of Daily Versus Every-Other-Day Glatiramer Acetate
20 Mg Subcutaneous Injections in Relapsing-Remitting
Multiple Sclerosis, 14 Multiple Sclerosis S296, S296
(2008).
8 Christina Caon et al., Randomized, Prospective,
Rater-Blinded, Four Year Pilot Study to Compare the
Effect of Daily Versus Every Other Day Glatiramer Acetate
20 mg Subcutaneous Injections in RRMS, 72 Neurology
(Suppl. 3) A317 (2009).
TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC. 11
III. State of the Art References
There are two additional references relevant to this
appeal, a 2009 study by Omar Khan 9 (“Khan 2009”) and
Teva’s own Glatiramer Acetate Low-frequency Admin-
istration (“GALA”) Phase III trial of 40mg GA adminis-
tered three times per week. J.A. 23904–05, J.A. 8246–
8417. Khan 2009 and GALA were both published after
August 20, 2009, the priority date of the asserted patents,
and thus do not qualify as statutory prior art.
The district court admitted the Khan 2009 reference
for the limited purpose of showing the state of the art at
the time of the invention. In re Copaxone Consolidated
Cases, No. 14-1171-GMS, 2017 WL 401943, at *14 (D. Del.
Jan. 30, 2017). Khan 2009 was published three weeks
after August 20, 2009, the priority date of the Copaxone
patents, but the study began two years earlier. J.A.
23904–05. 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. 23904. Following
the results of Khan 2008, which showed 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. 23904.
Concerning GALA, the district court recognized that
the GALA trial protocol does not qualify as prior art. In
re Copaxone, 2017 WL 401943, at *20. Instead, the dis-
9 O. Khan et al., Glatiramer Acetate 20mg Subcuta-
neous Twice-Weekly Versus Daily Injections: Results of a
Pilot, Prospective, Randomised, and Rater-Blinded Clini-
cal and MRI 2-Year Study in Relapsing-Remitting Multi-
ple Sclerosis, 15 Multiple Sclerosis S249, S249–50 (2009).
12 TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC.
trict court admitted GALA as an admission by Teva to
inform on the motivations of those having ordinary skill
in the art at the time of the invention. In its submission
to FDA, Teva explained that, after the FORTE study
demonstrated that the 40mg dose was equally effective as
the 20mg dose, “the natural next step [was] to reduce the
dosing regimen of GA and find the optimal regimen that
[would] improve the convenience of treatment and reduce
the burden and adverse events associated with daily
subcutaneous injections.” J.A. 8266. Citing the small-
scale studies with 20mg GA in the prior art, such as Khan
2008, GALA noted that results “demonstrated effects in
relapse rate reduction which were comparable to daily
injections of GA 20mg, suggesting a lower injection fre-
quency can be considered.” J.A. 8266, 8352. The GALA
protocol selected a dosing regimen of 40mg GA 3x/week,
in part because “the subjects will receive approximately
the same weekly dose, given by 3 subcutaneous injections
instead of with a daily injection frequency of 7 injections.”
J.A. 8266.
IV. Proceeding Below
This appeal arises out of five consolidated district
court cases. The Defendants-Appellees in this case are
generic drug manufacturers who (prior to the expiration
of the Copaxone patents) submitted Abbreviated New
Drug Applications (“ANDAs”) to FDA for approval to
engage in the manufacture and sale of generic versions of
COPAXONE® 40mg administered 3 times per week. In re
Copaxone, 2017 WL 401943, at *1–10. Appellants Teva
Pharmaceuticals USA, Inc., Teva Pharmaceutical Indus-
tries, Ltd., Teva Neuroscience, Inc., and Yeda Research
and Development Co., Ltd. (collectively, “Teva”) sued
Appellees in the United States District Court for the
District of Delaware, alleging that their respective ANDA
filings infringed claims 1, 5, 13–17 of the ’250 patent,
claims 1, 7, 15, and 20 of the ’413 patent, claims 1, 10, and
TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC. 13
11 of the ’302 patent, and claims 1, 2, 5, 6, 9, 12, 16, and
17 of the ’776 patent. Id.
Following a Markman hearing, the district court en-
tered a claim construction order. In re Copaxone 40 Mg,
No. 14-1171-GMS, 2016 WL 873062, at *1–2 (Mar. 7,
2016) (“Claim Construction Order”). Relevant to this
appeal, the district court construed the ’250 and ’413
patents’ “sufficiency” 10 terms and the ’776 patent’s “re-
duced frequency of relapses” 11 and “effectiveness” 12 terms
as non-limiting statements of intended effect. Id. at *1 &
nn.1–2.
The district court held a seven-day bench trial during
which it considered the invalidity of the asserted claims of
the Copaxone patents. The district court found that a
40mg GA dose was explicitly disclosed in references that
predate the Copaxone patents, specifically Cohen,
Pinchasi, and FORTE. In re Copaxone, 2017 WL 401943,
at *14. The court rejected Teva’s arguments that Cohen
and FORTE taught away from a 40mg dose, and that a
person of ordinary skill in the art (“POSITA”) would have
thought that 20mg was the optimal dose. Id. at *14–15.
The district court also found that, as of the priority date,
POSITAs knew that daily injections were difficult to
tolerate based on the 1996 FDA SBOA, Flechter, and
10 E.g., ’250 patent col. 16 ll. 44–45 (“the regimen be-
ing sufficient to alleviate the symptom of the patient”);
’413 patent col. 16 ll. 35–36 (“the regimen being sufficient
to reduce the frequency of relapses in the patient”).
11 E.g., ’776 patent col. 17 ll. 20–22 (“which reduces
brain atrophy and for reducing the frequency of relapses
by 30% or more as compared to placebo in a human popu-
lation”).
12 E.g., ’776 patent col. 17 ll. 39–40 (“which is as ef-
fective as administration of 20 mg of glatiramer acetate
s.c. daily”).
14 TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC.
Khan 2008. Id. at *15–16. Relying in part on trial testi-
mony, the district court found that POSITAs were famil-
iar with the adverse reactions, pain, and treatment
adherence problems associated with daily injections, and
would have been motivated to pursue less frequent dosing
with a reasonable probability of success. Id. at *16. The
district court found that Pinchasi is the closest prior art
because it discloses a dosing regimen that differs from the
claimed regimen by only one dose every two weeks. Id. at
*17.
In light of these factual findings, the district court
concluded that a 40mg GA 3x/week dosage would be
obvious to try, noting that there were only two tested
dosage amounts in the prior art—20mg and 40mg—and
that researchers were pursuing less frequent dosing
regimens while recognizing there are a limited number of
days in a week on which to test frequency. See id. at *19.
The court recognized that obvious-to-try logic is not
always appropriate, but found that “[h]ere, there was
market pressure to solve a known problem—the fact that
many MS patients could not tolerate daily injections—and
there were a finite number of predictable solutions that a
person of ordinary skill in the art would have good reason
to pursue.” Id. The district court cited to Khan 2009,
Teva’s GALA study, and trial testimony as evidence of the
motivations of POSITAs at the time of the invention, and
noted evidence and testimony supporting the proposition
that a dosing schedule based on three predetermined days
each week is preferable for patients over an every other
day schedule. Id. at *20. The district court highlighted
testimony from Dr. Green that a regimen of injections on
three pre-determined days of each week is more conven-
ient for patients and has better patient adherence than an
every other day regimen, in which the days on which
patients inject differ depending on the week. Id. The
district court also noted a study showing that Rebif®, an
injectable MS treatment dosed three times a week, has
TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC. 15
increased patient adherence compared to the daily 20mg
GA regimen. Id.
In light of additional testimony that a POSITA would
expect the number of ISRs to decrease as the number of
injections per week decreased, as well as disclosures in
Flechter, Khan 2008, and Caon, the district court held
obvious the dependent claims of the ’250 and ’413 patents
requiring that the 40mg GA 3x/week regimen reduce the
frequency of ISRs and IPIRs as compared to a 20mg/day
regimen. Id. at *17–18. The district court also found
obvious claim 15 of the ’250 patent, which requires the
claimed method improve tolerability as compared to a
20mg/day regimen. Id. at *17. The court further deter-
mined the claims of the ’776 patent to be obvious in light
of Caon and expert evidence presented at trial. Id. at
*22–23. Finally, the court considered objective indicia of
nonobviousness, and concluded that none of them war-
ranted a finding of nonobviousness of the Copaxone
patents. Id. at *25.
Following its analysis, the district court held all as-
serted claims of the Copaxone patents invalid as obvious
under § 103. Teva appeals the district court’s claim
construction and obviousness decisions. We have jurisdic-
tion pursuant to 28 U.S.C. § 1295(a)(1).
DISCUSSION
I. Claim Construction
Claim construction seeks to ascribe the “ordinary and
customary meaning” to claim terms as a person of ordi-
nary skill in the art would have understood them at the
time of invention. Phillips v. AWH Corp., 415 F.3d 1303,
1312–14 (Fed. Cir. 2005) (en banc) (citing Vitronics Corp.
v. Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed. Cir. 1996)).
Where the district court’s claim construction relies only on
intrinsic evidence, as is the case here, the construction is
a legal determination reviewed de novo. Poly-Am., L.P. v.
16 TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC.
API Indus., Inc., 839 F.3d 1131, 1135–36 (Fed. Cir. 2016)
(citing Teva Pharm. USA, Inc. v. Sandoz, Inc., 135 S. Ct.
831, 841 (2015)).
Teva contends that the district court erroneously con-
strued certain claim terms as non-limiting and disregard-
ed them for nonobviousness purposes. Teva points to the
“sufficiency” terms of the ’250 and ’413 patents as being
limiting. Claim 1 of the ’250 patent recites “A method of
alleviating a symptom of relapsing-remitting multiple
sclerosis . . . comprising administering to the human
patient a therapeutically effective regimen . . . , the regi-
men being sufficient to alleviate the symptom of the pa-
tient.” ’250 patent col. 16 ll. 35–45 (emphasis added).
Similarly, claims 1 and 20 of the ’413 patent both recite
“[a] method . . . comprising administering to the human
patient a therapeutically effective dosage regimen . . . ,
the regimen being sufficient to reduce the frequency of
relapses in the patient.” ’413 patent col. 16 ll. 26–36,
col. 18 ll. 14–27 (emphasis added). Teva also contests the
district court’s construction of the “reduced frequency of
relapse” terms and “effectiveness” terms in the ’776
patent as non-limiting. For example, claim 5 of the
’776 patent describes “a method for reducing the frequen-
cy of relapses”; claims 6, 16, and 17 contain similar limi-
tations. ’776 patent col. 16 ll. 61–65, col. 17 ll. 20–22, 65–
66, col. 18 ll. 23–25. Claim 12 describes “[a] method for
improving the tolerability of glatiramer acetate treatment
of a human patient suffering from a relapsing form of
multiple sclerosis which is as effective as administration
of 20 mg of glatiramer acetate s.c. daily,” and claims 16
and 17 contain similar limitations. Id. col. 17 ll. 36–40
(emphasis added), col. 17 l. 65–col. 18 l. 5, col. 18 ll. 23–
25.
The district court construed these terms to be non-
limiting statements of intended effect, holding that those
terms are “strikingly similar to those in the patents in
Bristol-Myers Squibb Co. v. Ben Venue Laboratories, Inc.,
TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC. 17
246 F.3d 1368 (Fed. Cir. 2001).” Claim Construction
Order, 2016 WL 873062, at *2 n.2. In Bristol-Myers, the
court held that certain terms were non-limiting because
they “merely express[ed] a purpose” and “only state[d] an
intended result of the claimed method.” 246 F.3d at
1374–75. The court stated that express dosage amounts
are material claim limitations, but statements of intended
results from their administration, such as “an antineo-
plastically effective amount,” “does not change those
amounts or otherwise limit the claim.” Id. at 1375. Claim
language without any bearing on the claimed methods
should be deemed non-limiting when it does not result in
“a manipulative difference in the steps of the claim.” Id.
at 1376.
We see no meaningful difference between the claims
in Bristol-Myers and those at issue here. The phrase “the
regimen being sufficient to reduce the frequency of re-
lapses in the patient” does not change the express dosing
amount or method already disclosed in the claims, or
otherwise result in a manipulative difference in the steps
of the claims. The claims are clear that the dosing has to
be “therapeutically effective regimen”; the addition of “the
regimen being sufficient to” be therapeutically effective is
superfluous, does not change the claimed method or
require any additional required structure or condition for
the claims, and is therefore non-limiting.
Teva argues that the “‘sufficiency’ terms were added
during prosecution to overcome rejections.” Appellants’
Opening Br. 74. Teva overstates the intrinsic record.
Claim 1 of the ’250 patent was amended to overcome a
§ 112 rejection based on the examiner’s read of the claims
prior to amendment as permitting only a single seven-day
period of administration, rather than an ongoing treat-
ment regimen. See J.A. 26417–18, 26464–65 (same, for
the ’413 patent). The claim was amended to replace the
ambiguous “therapeutically effective dose” with “thera-
peutically effective regimen of,” as follows:
18 TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC.
1. (Currently Amended) A method of alleviat-
ing a symptom of relapsing-remitting multiple
sclerosis in a human patient suffering from re-
lapsing-remitting multiple sclerosis or a patient
who has experienced a first clinical episode and is
determined to be at high risk of developing clini-
cally definite multiple sclerosis comprising admin-
istering to the human patient a therapeutically
effective regimen of three subcutaneous injections
of a therapeutically effective 40mg dose of glati-
ramer acetate over a period of seven days with at
least one day between every subcutaneous injec-
tion, the regimen being sufficient so as to thereby
alleviate the symptom of the patient.
J.A. 26430.
“As amended the claims cannot be reasonably con-
strued to read on only a single seven day period of admin-
istration, at least because the claims as amended require
a ‘regimen.’” J.A. 26436; see also J.A. 26483 (same, for the
’413 patent). Given this evidence, the addition of “a
therapeutically effective regimen” would have alone been
sufficient to overcome the rejection, and thus we are
unpersuaded by Teva’s contention that addition of the
“regimen being sufficient . . .” term was necessary or
relevant to the examiner’s approval. Accordingly, we find
no error in the district court’s construction.
II. Obviousness under 35 U.S.C. § 103
Under 35 U.S.C. § 103(a), a patent may not be ob-
tained “if the differences between the subject matter
sought to be patented and the prior art are such that the
subject matter as a whole would have been obvious at the
time the invention was made to a person having ordinary
TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC. 19
skill in the art.” 35 U.S.C. § 103(a) (2006). 13 Obviousness
is a question of law with underlying factual findings
relating to the scope and content of the prior art; the
differences between the claims and the prior art; the level
of ordinary skill in the pertinent art; and any secondary
considerations of non-obviousness. ZUP, LLC v. Nash
Mfg., Inc., 896 F.3d 1365, 1371 (Fed. Cir. 2018) (citing
Graham v. John Deere Co. of Kan. City, 383 U.S. 1, 17–18
(1966)). 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).
After a bench trial, we review a district court’s conclu-
sions of law de novo and its findings of fact for clear error.
Senju Pharm. Co. v. Lupin Ltd., 780 F.3d 1337, 1341 (Fed.
Cir. 2015). A factual finding is clearly erroneous if the
Court is left with “the definite and firm conviction that a
mistake has been committed.” United States v. U.S.
Gypsum Co., 333 U.S. 364, 395 (1948).
On appeal, Teva disputes that the 40mg GA 3x/week
dosing regimen disclosed in the Copaxone patents would
have been obvious to a person of skill in the art. Teva
also appeals the invalidation of claim limitations in the
’250 and ’413 patents relating to improved tolerability and
reduced frequency of adverse effects, and the invalidation
of the ’776 patent’s claims relating to reduced severity of
13 Congress amended § 103 when it passed the
Leahy-Smith America Invents Act (AIA). Pub. L.
No. 112–29, § 3(c), 125 Stat. 284, 287 (2011). Because the
applications that led to the patents at issue have never
contained a claim having an effective filing date on or
after March 16, 2013 (the effective date of the statutory
changes enacted in 2011), or a reference under 35 U.S.C.
§§ 120, 121, or 365(c) to any patent or application that
ever contained such a claim, the pre-AIA § 103 applies.
Id. § 3(n)(1), 125 Stat. at 293.
20 TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC.
injection site reactions. Teva does not appeal on the
objective indicia of nonobviousness. We address each
argument in turn.
A. 40mg GA 3x/week Dosing Regimen
Teva contends that the district court erred in finding
the claimed 40mg GA 3x/week dosing regimen obvious.
Specifically, Teva argues that the district court impermis-
sibly relied on hindsight and an improper “obvious to try”
analysis, and analyzed the obviousness of individual
claim elements, rather than the invention as a whole.
Teva further maintains that the district court’s decision is
at odds with this court’s decision in In re Cyclobenzaprine
Hydrochloride Extended-Release Capsule Patent Litiga-
tion, 676 F.3d 1063 (Fed. Cir. 2012).
We first address Teva’s contention that the district
court engaged in an impermissible “obvious to try” analy-
sis. In KSR, the Supreme Court endorsed the use of an
“obvious to try” analysis in certain cases:
When there is a design need or market pressure to
solve a problem and there are a finite number of
identified, predictable solutions, a person of ordi-
nary skill has good reason to pursue the known
options within his or her technical grasp. If this
leads to the anticipated success, it is likely the
product not of innovation but of ordinary skill and
common sense. In that instance the fact that a
combination was obvious to try might show that it
was obvious under § 103.
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007).
We have previously identified two categories of im-
permissible “obvious to try” analyses that run afoul of
KSR and § 103: when what was “obvious to try” was (a) to
vary all parameters or try every available option until one
succeeds, where the prior art gave no indication of critical
parameters and no direction as to which of many possibil-
TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC. 21
ities is likely to be successful; or (b) to explore a new
technology or general approach in a seemingly promising
field of experimentation, where the prior art gave only
general guidance as to the particular form or method of
achieving the claimed invention. See In re Kubin, 561
F.3d 1351, 1359 (Fed. Cir. 2009) (quoting In re O’Farrell,
853 F.2d 894, 903 (Fed. Cir. 1988)).
This case falls into neither of the two impermissible
categories. Here, the prior art focused on two critical
variables, dose size and injection frequency, and provided
clear direction as to choices likely to be successful in
reducing adverse side effects and increasing patient
adherence. As of the priority date, only two GA dose sizes
had been shown to be effective, safe, and well-tolerated:
20mg and 40mg. Concerning frequency, the 1996 FDA
SBOA, Flechter, and Khan 2008 all encouraged POSITAs
to pursue a less frequent than daily dosing regimen; these
references indicated that less frequent injections of GA
were just as effective as daily injections, and less frequent
injections improved patient adherence and reduced ad-
verse reactions. The district court also properly relied on
Khan 2009 not as statutory prior art, but for the fact that
POSITAs were interested in pursuing less frequent dosing
regimens. In re Copaxone, 2017 WL 401943, at *14.
Given this motivation, a POSITA had only a limited
number of permutations of dose and frequency to explore
that were not already disclosed in the prior art. Because
a thrice-weekly 40mg injection would result in a total
weekly dose very close to that in the already-approved
daily 20mg injection—120mg/week versus 140mg/week—
the district court found a POSITA would have had a
reasonable expectation of success in pursuing the thrice-
weekly dose frequency in terms of effectiveness, patient
adherence, and FDA approval. Id. at *19 (quoting Aller-
gan, Inc. v. Sandoz Inc., 726 F.3d 1286, 1291 (Fed. Cir.
2013) (“The potential for FDA approval also may properly
be considered, as it was here, in determining whether one
22 TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC.
of ordinary skill would be motivated to develop a drug
product and whether there was skepticism regarding the
efficacy of such a product.”)). The district court gave
appropriate weight to the testimony of Dr. Green regard-
ing patient compliance with thrice-weekly administra-
tions and the Rebif® regimen, noting that “[e]ven though
Rebif® is a different MS drug with a different mechanism
of action, . . . those in the art would still be motivated to
try dosing GA three times a week based on the higher
rates of patient adherence to the Rebif® therapy.” Id. at
*20.
Teva faults the district court for “narrowing the uni-
verse” of possible GA regimens and using hindsight and
the GALA protocol to reach its obviousness conclusion.
Appellants’ Opening Br. 42 (arguing the district court
limited a POSITA to “two dosing options (40mg and
20mg), two regimens (1x/week and 3x/week), and one form
(injections)”). We disagree; the district court had ample
evidence besides hindsight and the disclosures in GALA
on which to find a thrice-weekly dosing regimen of 40mg
GA obvious to try. See In re Copaxone, 2017 WL 401943,
at *17–22. Although the universe of potential GA doses is
theoretically unlimited, the universe of dosages in the
prior art that had clinical support for being effective and
safe consisted of only two doses: 20mg and 40mg. Even if
there were multiple injection frequencies not yet tested in
the prior art—1x, 2x, 3x a week etc.—these still represent
a limited number of discrete permutations.
This is not a situation where the prior art gave no di-
rection in how to reach a successful result; the prior art
clearly indicated that less frequent doses should be ex-
plored (i.e., moving away from the daily, “7x/week” dose
towards less frequent doses) and that higher doses, while
maintaining the same weekly dose (i.e., moving from
20mg daily to 40mg every other day), could increase
efficacy while not affecting adverse reactions. Further-
more, the district court made factual findings specifically
TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC. 23
in support of thrice-weekly injections. E.g., id. at *19
(total weekly dose of 40mg GA 3x/week is very close to the
total weekly dose for the approved daily 20mg GA regi-
men); id. at *20 (“[A] skilled artisan would be motivated
to try regimens close in total milligrams per week to the
regimens already approved by the FDA and known to be
effective.”); id. (finding motivation to pursue a 3x/week
regimen based on patient adherence rates in the Rebif®
therapy). And contrary to Teva’s argument that the court
assumed without support that GA must be injected, the
district court did not err in not considering other forms of
GA. Evidence considered by the district court reveals that
an oral version of Copaxone was proven to be ineffective
by 2005. Id. at *23; J.A. 4016. We recognize that the
prior art did not conclusively teach that a regimen of
40mg GA 3x/week would be effective. However,
“[c]onclusive proof of efficacy is not necessary to show
obviousness. All that is required is a reasonable expecta-
tion of success.” Hoffmann-La Roche Inc. v. Apotex Inc.,
748 F.3d 1326, 1329, 1331 (Fed. Cir. 2014); see also In re
O’Farrell, 853 F.2d at 903 (“Obviousness does not require
absolute predictability of success.”).
Nor do we find merit in Teva’s argument that the dis-
trict court separately analyzed the 40mg dose limitation
and the 3x/week limitation, without considering them
together “except to conclude that the mash-up would be
obvious to try.” Appellants’ Opening Br. 55. We note that
the district court spent considerable time discussing why
the combination of a 40mg dose administered 3x/week
would be obvious to try. See In re Copaxone, 2017 WL
401943, at *19. And while “[t]he determination of obvi-
ousness is made with respect to the subject matter as a
whole, not separate pieces of the claim,” Sanofi-
Synthelabo v. Apotex, Inc., 550 F.3d 1075, 1086 (Fed. Cir.
2008), this court has previously employed the same fre-
quency-and-dosage-amount approach to obviousness used
by the district court here. In Hoffmann-La Roche, 748
24 TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC.
F.3d at 1329, the court considered whether it would have
been obvious at the time of invention to select a once a
month oral dosing regimen of 150mg of ibandronate to
treat osteoporosis. The court first discussed how the prior
art taught that infrequent dosing, such as monthly dos-
ing, was preferred. Id. at 1329–31. The court then sepa-
rately discussed why a POSITA would have selected a
150mg dose, before considering the limitations together
and concluding that “[a]t the very least, the 150mg dose
was obvious to try.” Id. at 1331–33. Teva makes no
convincing argument why a similar approach is inappro-
priate here.
Teva makes numerous challenges to factual findings
by the district court, none of which we find persuasive.
For instance, Teva argues that Cohen and FORTE teach
away from using 40mg GA. The district court, however,
found that the decision to include 40mg in the later
FORTE study indicates that Cohen did not teach away
from trying 40mg. In re Copaxone, 2017 WL 401943, at
*15. The district court further noted although the FORTE
study ostensibly “failed” at meeting its stated goal of
establishing that 40mg/day was 30% more effective than
20mg/day, FORTE still found that 40mg was equally
effective with “no unexpected adverse effect,” and thus did
not teach away. Id. We see no clear error in these find-
ings. See Galderma Labs., L.P. v. Tolmar, Inc., 737 F.3d
731, 738 (Fed. Cir. 2013) (“A reference does not teach
away, however, if it merely expresses a general preference
for an alternative invention but does not criticize, discred-
it, or otherwise discourage investigation into the inven-
tion claimed.”). Nor are we swayed by Teva’s arguments
that the district court misread Khan 2008 and Caon in
suggesting that patients in the 20mg/day group switched
to 20mg every other day to reduce discomfort associated
with daily injections. The district court cited extensive
testimony clearly showing that POSITAs “were familiar
with the adverse reactions, pain, and treatment adher-
TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC. 25
ence problems associated with daily injections.” 14 In re
Copaxone, 2017 WL 401943, at *16. Given the evidence
presented, the district court’s finding that patients want-
ed to switch to the every other day regimen to reduce
discomfort associated with daily injections is a reasonable
conclusion and not clearly erroneous.
Teva further contends that the district court erred in
relying on Flechter for its finding that a POSITA would
have been motivated to pursue a less than daily dosing
regimen. We do not reach this argument given that the
district court correctly found similar motivations in other
references, such as the SBOA and Khan 2008. Teva also
takes issue with the district court’s use of the Pinchasi
reference. Although the court noted that “Pinchasi is the
closest prior art,” id. at *17, this observation is not im-
proper; courts are required to determine “the scope and
content of prior art” and the “differences between prior art
and claims.” PAR Pharm., 773 F.3d at 1193 (emphasis
added). Contrary to Teva’s assertion that the district
court gave no reason why a person of ordinary skill would
have started with Pinchasi, the district court in fact
14 See, e.g., J.A. 4676–77 (Kolodny deposition, de-
scribing needle fatigue associated with Copaxone
20mg/day); J.A. 4869 (Dr. Green, describing Khan 2008:
“It reveals clear and obvious patient preference for an
every-other-day dosing regimen when compared to a daily
dosing regimen given the option.”); J.A. 4857 (Dr. Green:
“As we discussed, most of the adverse events associated
with the use of glatiramer acetate, and in fact the most
troubling set of adverse events had to do with injection
site reactions or immediate post-injection reactions. Both
of those are tied to injections. So if you reduce the fre-
quency of injections, well, it’s clearly obvious that you
would reduce the frequency of those injection site reac-
tions or immediate post-injection reactions.”).
26 TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC.
addressed Pinchasi fourth in its discussion on the thrice
weekly dosing limitation, after the SBOA, Flechter, and
Khan 2008/Caon references. See In re Copaxone, 2017 WL
401943, at *15–17. Teva raises additional arguments
regarding factual findings made by the district court,
none of which we find persuasive.
Finally, this court’s decision in In re Cyclobenzaprine,
676 F.3d at 1063, does not warrant a different outcome.
Teva argues that prior to the invention, higher doses of
GA were not necessarily known to be more effective, GA’s
pharmacokinetic and pharmacodynamic (“pk/pd”) profile
was and remains unknown, GA’s mechanism of action is
still unknown, and the cause of patient’s reactions to
injections of GA is unknown. Teva contends that the
unpredictable nature of GA categorically precludes the
obvious-to-try analysis employed by the district court.
Appellants’ Opening Br. 50.
In Cyclobenzaprine, we held that bioequivalence alone
could not establish obviousness because “skilled artisans
could not predict whether any particular PK profile,
including a bioequivalent one, would produce a therapeu-
tically effective formulation.” 676 F.3d at 1070. The court
applied traditional motivation and reasonable-
expectation-of-success analysis, reasoning that “[w]hile it
may have been obvious to experiment with the use of the
same PK profile [from an immediate-release formulation]
when contemplating an extended-release formulation,
there [wa]s nothing to indicate that a skilled artisan
would have had a reasonable expectation that such an
experiment would succeed in being therapeutically effec-
tive.” Id. In Cyclobenzaprine, there were no prior art
clinical studies to suggest what would be a therapeutical-
ly effective formulation.
We do not read Cyclobenzaprine as establishing a rig-
id rule categorically precluding obviousness findings
without pk/pd data. Further, Cyclobenzaprine is distin-
TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC. 27
guishable in that, there, the obviousness proof relied
entirely on the bioequivalence of certain pharmacokinetic
profiles. Bioequivalence is not argued here; instead,
obviousness is proven through human clinical studies
establishing the safety, efficacy, and tolerability of GA at
doses and dose frequencies similar to the claimed regi-
men. In this case, the evidence shows that pk/pd data
was largely irrelevant to the invention. Numerous clini-
cal studies in the prior art describe GA and its effects on
the human body. Although the precise mechanism of GA
is not known, it is known to be immunomodulating—i.e.,
it changes the immune system—and is not necessarily
measurable in the bloodstream and its levels are not
indicative of efficacy. See In re Copaxone, 2017 WL
401943, at *21–22; J.A. 3998–99, 4886–87. Testimony
was given at trial that pharmacokinetic studies for drugs
like GA are less appropriate than for small molecule
drugs, such as those at issue in Cyclobenzaprine. J.A.
4886–87. GA was also known to be “forgiving,” in that
occasional missed doses would not reduce efficacy, and
that fact gave POSITAs further confidence in eliminating
one dose every two weeks. J.A. 4848–49; 4884–85; 4732.
Higher doses were clinically shown to be at least as
effective as lower doses; Cohen shows, at the very least,
that 40mg is as effective and well-tolerated as 20mg, but
with a more rapid onset of action. Finally, Teva itself, in
its 1996 application to FDA, indicated that pharmacoki-
netic studies “would be of limited value.” J.A. 20689.
In light of the foregoing, we hold that the 40mg GA
3x/week regimen is obvious in light of the prior art, and
find no clear error in the conclusion that a POSITA would
be motivated to combine the 40mg GA dose, which had
proven efficacy, with a 3x/week frequency, which was
desirable because the prior art indicated that less fre-
quent administration increased patient adherence while
maintaining efficacy.
28 TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC.
B. Improved Tolerability and Reduced
Frequency Limitations
Claims 14, 16, and 17 of the ’250 patent and claim 7 of
the ’413 patent require that the 40mg GA 3x/week regi-
men reduce the frequency of ISRs and IPIRs relative to
the daily 20mg GA regimen. Claim 15 of the ’250 patent,
on which claims 16 and 17 depend, requires that the
claimed regimen improve tolerability as compared to the
daily 20mg regimen.
Teva argues that the prior art did not lead POSITAs
to expect improved tolerability and reduced frequency of
injection reactions from the claimed regimen compared to
20mg GA daily. We disagree, and find no clear error in
the district court’s findings regarding Khan 2008, Caon,
and Flechter, all of which demonstrate that improved
tolerability and less frequent injection reactions were
expected from the claimed less frequent regimen, as
compared to 20mg daily. See In re Copaxone, 2017 WL
401943, at *17–18. Caon, for example, disclosed that the
frequency of a severe injection-site reaction, lipoatrophy,
was “significantly less” for the every-other-day patient
group than for the daily group. J.A. 20386. Pinchasi
recognized that a 40mg GA dose resulted in increased
efficacy “not accompanied by a corresponding increase of
adverse reactions.” J.A. 20944. The court also relied
upon testimony from Dr. Green that reducing the fre-
quency of injections was expected to reduce the number of
injection-related reactions.
Teva finds fault with the district court’s reference to
“common sense” in its reliance on Dr. Green’s testimony.
During trial, Appellees’ expert Dr. Green testified that a
POSITA would expect reducing the frequency of injections
to be associated with enhanced overall tolerability of the
regimen. J.A. 4911. In its post-trial briefing, Teva ar-
gued that Dr. Green’s testimony was conclusory and
unsupported by the prior art. The district court rejected
TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC. 29
this characterization, noting that “it is simply common
sense that if a patient experiences adverse reactions from
an injection, reducing the number of injections they
receive would reduce the number of times they have a
reaction.” In re Copaxone, 2017 WL 401943, at *17. The
district court went on to identify additional evidence in
the record to support Dr. Green’s statement, including
evidence in the Khan 2008/Caon and Flechter studies,
and testimony from Dr. Wolinksy, Teva’s own expert, who
testified that he had prescribed COPAXONE® 20mg for
use every other day, off-label use, for his patients who
were “doing extremely well on the drug but [were] having
trouble with injection site problems.” Id. We see no error
in what is essentially a credibility determination, where
the district court credited Dr. Green’s expert testimony,
supported by other evidence in the record, that a reduc-
tion in the number of injections would result in less
frequent reactions. See J.A. 4857.
Teva also argues that the district court erred by rely-
ing on Teva’s GALA protocol. The district court did not
use GALA as invalidating prior art, but instead as evi-
dence of a POSITA’s motivations and expectations when
reading the prior art at the time of the invention. In re
Copaxone, 2017 WL 401943, at *20. With respect to the
sufficiency limitations, the district court used GALA only
for that limited purpose, noting Teva’s statement to FDA
that “one may certainly expect a reduction in the frequen-
cy of such reactions with this new dose regimen, further
enhancing subject adherence to treatment.” Id. at *18
(emphasis added) (quoting J.A. 8267). The district court’s
reliance on GALA merely as confirmation of how a
POSITA would understand FORTE, which is prior art, is
not erroneous.
C. Reduced Severity Claims of the ’776 Patent
The asserted claims of the ’776 patent contain addi-
tional limitations requiring that the 40mg GA 3x/week
30 TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC.
regimen “reduce[s] severity of injection site reactions”
compared to a 20mg daily regimen. See, e.g., ’776 patent
col. 17 ll. 37–54; col. 17 l. 65–col. 18 l. 22. The parties
stipulated that “severity” means “the intensity of a pa-
tient’s ISRs and/or IPIRs.” J.A. 1994. “Severity” appears
in the specification of the ’776 patent only once in connec-
tion with injection site reactions, in the definition of
“tolerability,” which means “associated with the frequency
and severity of post injection reactions and injection site
reactions.” ’776 patent col. 7, ll. 37–42 (emphasis added).
“Tolerability influences the period that a patient can
follow GA treatment.” Id.
After reviewing the prior art, the district court con-
cluded that the ’776 patent’s claims directed to reducing
the severity of injection site reactions would have been
obvious. In re Copaxone, 2017 WL 401943, at *22. The
district court broadly relied on two different types of
evidence in reaching this conclusion: evidence and testi-
mony relating to lipoatrophy and evidence relating to
tolerability.
Concerning the evidence relating to lipoatrophy, the
district court pointed to trial testimony establishing that
lipoatrophy, the loss of subcutaneous fat at the injection
site, is a severe ISR, and Caon’s disclosure that
“[i]njection related lipoatrophy was significantly less” on
the 20mg every other day regimen than on the daily 20mg
regimen. Id. The court also relied on Teva’s expert Dr.
Fox, who testified that “if there is a decrease in the fre-
quency of lipoatrophy, there would, by definition, then
also be a decrease in the severity of the adverse events.”
Id. We agree with the district court that this evidence
“provides a reasonable expectation to those skilled in the
art that reducing the number of injections per week may
also reduce the severity of injection site reactions.” Id.
In addition to the evidence regarding lipoatrophy, the
district court also pointed to a press release issued by
TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC. 31
Teva summarizing FORTE, which admitted that the
40mg dose “maintained the favorable safety and tolerabil-
ity profile of COPAXONE® 20mg,” and testimony from the
named inventor, Dr. Klinger, that “if a 40 mg three-times-
a-week regimen improves patient tolerability, then it
inherently has to reduce the frequency and severity of
injection site reactions.” Id. at *23. Citing Dr. Klinger’s
testimony, the district court correctly concluded that “it
follows that the FORTE study showed that administering
40mg of GA daily to patients did not increase the frequen-
cy or severity of injection site reactions.” Id.
Teva contends that the district court erroneously con-
flated frequency with severity, and that evidence of re-
duced frequency of ISRs cannot prove reduced severity of
ISRs. While we agree that the two concepts are distinct,
we conclude that the district court did not err. Frequency
and severity of ISRs are not interchangeable, but Dr.
Fox’s testimony established that, in certain instances,
they are related:
Q. Doctor, is severity the same thing as fre-
quency?
A. No, they’re related, but they are separate
topics.
Q. How do they relate to one another?
A. There, as I mentioned before . . . , there
are some events like lipoatrophy that
would be considered to be more severe. So
if there is a decrease in the frequency of
lipoatrophy, there would, by definition,
then also be a decrease in the severity of
the adverse events.
Q. So do you consider these two concepts to
be mutually exclusive?
A. No, they are not. They are related.
32 TEVA PHARMACEUTICALS USA, INC v. SANDOZ INC.
J.A. 5523.
Caon showed that reducing the frequency of injections
from daily to every other day resulted in “significantly
less lipoatrophy,” a severe ISR. This statement in Caon
can be read as indicating either that lipoatrophy occurred
less frequently with less frequent injections—which,
according to Dr. Fox’s testimony, “by definition” means
reduced severity—or the expression of the lipoatrophy
itself was less severe. It was not unreasonable for the
district court to conclude from this evidence that a
POSITA would think it obvious that the 40mg GA
3x/week regimen, with its less frequent injections, would
result in reduced severity of at least one ISR, lipoatrophy,
particularly given Dr. Fox’s testimony endorsing the
same. See Hoffman–La Roche, 748 F.3d at 1331 (holding
that prior art references need only demonstrate “a rea-
sonable expectation of success,” not “conclusive proof of
efficacy”).
Teva also disputes the district court’s reliance on the
FORTE press release. However, given that the findings
made by the district court in reaching its obviousness
conclusion, based on the other evidence relied on by the
court, were not clearly erroneous, we do not reach this
argument.
CONCLUSION
In light of the foregoing, we conclude that the district
court did not err in invalidating all asserted claims of the
Copaxone patents as obvious.
AFFIRMED
COSTS
No costs.