Teva Pharmaceuticals USA Inc. et al v. Sandoz Inc. et al.

Filing 294

MEMORANDUM. Signed by Judge Gregory M. Sleet on 1/30/2017. (mdb)

IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF DELAWARE

IN RE COPAXONE CONSOLIDATED
CASES

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Civil Action No. 14-1171-GMS
(CONSOLIDATED)

MEMORANDUM
I.

INTRODUCTION
In this consolidated Hatch-Waxman patent infringement action, Plaintiffs Teva

Pharmaceuticals USA Inc. ("Teva"), Teva Pharmaceutical Industries Ltd. ("Teva Ltd."), Teva
Neuroscience Inc., and Yeda Research and Development Co. Ltd. ("Yeda") (collectively "T.eva")
allege patent infringement by Defendants Sandoz Inc., Momenta Pharmaceuticals Inc., Dr. Reddy' s
Laboratories Inc. ("DRL"), Dr. Reddy's Laboratories Ltd. ("DRL Ltd."), Mylan Pharmaceuticals
Inc., Synthon Pharmaceuticals Inc. ("Synthon"), Synthon B.V., Synthon s.r.o. Blansko ("Synthon
s.r.o"), Amneal Pharmaceuticals LLC ("Amneal"), Amneal Pharmaceuticals Company GinbH
("Amneal GmbH"), and Pfizer Inc.

Plaintiffs allege that, by filing Abbreviated New Drug

Applications ("AND As") seeking approval to market generic versions of COPAXONE® 40mg,
Defendants infringed

U.S. Patent Nos. 8,399,413 ("the '413 patent"), 8,232,250 ("the '250

patent"), 8,969,302 (''the '302 patent"), and 9,155,776 ("the '776 patent"). The court held a sevenday bench trial in this matter beginning on September 26, 2016. Presently before the court are the
parties' post-trial proposed findings of fact and conclusions of law concerning the validity of the
patents-in-suit and whether Defendants' generic pharmaceutical compositions infringe the patentsin-suit. (D.I. 272); (D.I. 273).

Pursuant to Federal Rule of Civil Procedure 52(a), and after having considered the entire
record in this case and the applicable law, the court concludes that all asserted claims of the patentsin-suit are invalid as obvious. The findings of fact and conclusions of law relevant to the court's
decision are set forth in further detail below.

II.

FINDINGS OF FACT 1
A.

1.

The Parties

Plaintiff Teva is a Delaware Corporation with its principal place ofbusiness at 1090

Horsham Road, North Wales, PA 19454.
2.

Plaintiff Teva Ltd. is an Israeli company with its principal place of business at 5 Basel

Street, P.O. Box 3190, Petah Tikva, 49131, Israel.
3.

Plaintiff Teva Neuroscience is a Delaware corporation with its principal place of business

at 901E.104th Street, Suite 900, Kansas City, Missouri 64131.
4.

Plaintiff Y eda is an Israeli company with its principal place of business at P .0. Box 95,

Rehovot, 76100, Israel.
5.

Defendant Amneal is a limited liability company organized and existing under the laws of

Delaware with a principal place of business at 400 Crossing Blvd., Third Floor, Bridgewater, NJ
08807-2863.

1

Prior to trial, the parties submitted an exhibit of uncontested facts in conjunction with their Pretrial Order.
(D.I. 254, Ex. A.) The court takes most of its findings of fact from the parties' uncontested facts. The court has also
reordered and renumbered some paragraphs, corrected some formatting errors, and made minor edits for the purpose
of concision and clarity that it does not believe alters the meaning of the paragraphs from the Pretrial Order. Otherwise,
any differences between this section and the parties' statement of uncontested facts are unintentional.
The court's findings of fact with respect to matters that were the subject of dispute between the parties are
included in Part III of this opinion ("Discussion and Conclusions of Law"), preceded by the phrase "the court finds" or
"the court concludes."

2

6.

Defendant Amneal GmbH is a limited liability company organized and existing under the

laws of Switzerland with a principal place of business at Turnstrasse 30, 6312 Steinhausen,
Switzerland.
7.

Defendant DRL Ltd. is a corporation organized and existing under the laws of India with

its principal place of business at 8-2-337, Road No. 3, Banjara Hills, Hyderabad, Telangana 500
034, India.
8.

Defendant DRL is a corporation organized and exiting under the laws of New Jersey with

its principal place of business at 107 College Road East, Princeton, NJ 08540, and is a whollyowned subsidiary ofDRL Ltd.
9.

Defendant Mylan is a corporation organized and existing under the laws of West Virginia

with its principal place of business at 781 Chestnut Ridge Rd., Morgantown, WV 26505. Mylan
is a wholly-owned subsidiary of Mylan Inc., which is a corporation organized and existing under
the laws of Pennsylvania with its principal place of business at 1000 Mylan Blvd., Canonsburg,
PA15317.
10.

Defendant Sandoz is a corporation organized and existing under the laws of Colorado with

its principal place of business at 100 College Road West, Princeton, NJ 08540.
11.

Defendant Momenta is a corporation organized and existing under the laws of Delaware

with its principal place of business at 675 West Kendall Street, Cambridge, MA 02142.
12.

Defendant Synthon is a corporation organized and existing under the laws of North

Carolina with its principal place of business at 1007 Slater Road, Suite 150, Durham, NC 27703.
13.

Defendant Synthon B.V. is a corporation organized and existing under the laws of the

Netherlands with its principal place. of business at Microweg 22, P.O. Box 7071, 6503 CM
Nijmegen, The Netherlands.

3

14.

Synthon s.r.o is a Czech entity having a principal place of business at Bmenska 32/cp.597,

678 17 Blansko, Czech Republic. Synthon and Synthon s.r.o are sister companies with Synthon
B.V. as their ultimate parent company.
15.

Defendant Pfizer is a corporation organized and existing under the laws of Delaware with

its principal place of business at 23 5 East 42nd Street, New York, NY 1001 7.
16.

The court has subject matter jurisdiction as well as personal jurisdiction over all parties.

B.
17.

Background

These consolidated actions arise out of Defendants' respective submissions of ANDAs

under§ 505G) of the Federal Food, Drug and Cosmetic Act to the United States Food and Drug
Administration ("FDA") with certifications pursuant to 21 U.S.C. § 355G)(2)(A)(vii)(IV), seeking
approval to market and sell glatiramer acetate ("GA") for injection, in 40 mg/mL prefilled
synnges.
18.

The three-times-weekly 40 mg/mL dose of GA was approved by the FDA in January

2014.
19.

Teva is the holder of New Drug Application ("NDA") number 20-622, which was

supplemented by Teva in 2013 to receive approval by the FDA of the use of GA 40 mg/mL three
times per week, marketed as COP AXONE® 40 mg/mL, for the treatment of patients with
relapsing forms of multiple sclerosis such as relapse-remitting multiple sclerosis.
20.

Teva, Teva Ltd. and Teva Neuroscience's (collectively, "Teva") COPAXONE® 40

mg/mL product is supplied as single-dose prefilled synringes that contain 40 mg/mL GA for
injection, manufactured by Teva Ltd., and marketed and sold in the United States by Teva
Neuroscience.

4

C.

The Patents-in-Suit
i.

21.

The '250 Patent

The '250 patent, entitled "Low Frequency Glatiramer Acetate Therapy" was issued on

July 31, 2012.
22.

Ety Klinger is the named inventor of that patent.

23.

The '250 patent was submitted by Teva to the FDA to be listed in the FDA publication

"Approved Drug Products with Therapeutic Equivalence Evaluations," commonly referred to as
"the Orange Book" with respect to the COPAXONE® 40 mg/mL product.
ii.

24.

The '413 Patent

The '413 patent, entitled "Low Frequency Glatiramer Acetate Therapy" was issued on

March 19, 2013.
25.

Ety Klinger is the named inventor of that patent.

26.

The '413 patent was submitted by Teva to the FDA to be listed in the Orange Book with

respect to the COP AXONE® 40mg/mL product.
iii.

27.

The '302 Patent

The '302 patent, entitled "Low Frequency Glatiramer Acetate Therapy" was issued on

March 3, 2015.
28.

Ety Klinger is the named inventor of the '302 patent.

29.

The '302 patent was submitted by Teva to the FDA to be listed in the Orange Book with

respect to the COPAX ONE® 40 mg/mL product.
iv.

30.

The '776 Patent

The '776 patent, entitled "Low Frequency Glatiramer Acetate Therapy" was issued on

October 13, 2015.

5

31.

Ety Klinger is the named inventor of the '776 patent.

32.

The'776 patent was submitted by Teva to the FDA to be listed in the Orange Book with

respect to the COPAX.ONE® 40 mg/mL product.

D. The Asserted Claims
i.

'250 patent, Claims 1, 5, 13-17

Claims 1, 5, 13-17 read:
1.
A method of alleviating a symptom of relapsing-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 effedive 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.
5.
The method of claim 1, wherein alleviating a symptom comprises reducing brain atrophy
in the patient.
13.
The method of claim 1, wherein the patient has not received glatiramer acetate therapy
prior to initiation of the regimen.
14.
The method of claim 1, wherein the frequency of an immediate post injection reaction or
the frequency of an injection site reaction is reduced relative to daily subcutaneous administration
of 20 mg glatiramer acetate.
15.
A method of increasing the tolerability of GA treatment in a human patient suffering from
relapsing-remitting multiple sclerosis or a patient who has experienced a first clinical episode and
is determined t9 be at high risk of developing clinically definite multiple sclerosis which
comprises reducing frequency of subcutaneous injections from daily subcutaneous injections of a
pharmaceutical composition comprising a 20 mg dose of glatiramer acetate to a 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 injection, wherein the regimen is therapeutically effective, so as to
thereby increase the tolerability of GA treatment in the patient.
16.
The method of claim 15, wherein increasing the tolerability of glatiramer acetate treatment
in the human patient suffering from a relapsing form of multiple sclerosis comprises reducing the
frequency of an immediate post injection reaction.
17.
The method of claim 15, wherein increasing the tblerability of glatiramer acetate treatment
in the human patient suffering from a relapsing form of multiple sclerosis comprises reducing the
frequency of an injection site reaction.
6

ii.

'413 patent, claims 1, 7, 15, and 20

1.
A method of reducing the frequency of relapses in a human patient suffering from
relapsing-remitting multiple sclerosis or a patient who has experienced a first clinical episode and
has MRI featur_es consistent with multiple sclerosis comprising administering to the human
patient a therapeutically effective dosage regimen of three subcutaneous injections of 1 ml of a
pharmaceutical composition comprising 40 mg of glatiramer acetate over a period of seven days
with at least one day between every subcutaneous injection, the regimen being sufficient to reduce
the frequency of relapses in the patient.
7.
The method of Claim 1, wherein the frequency of an immediate post injection reaction or
the frequency of an injection site reaction is reduced relative to daily subcutaneous administration
of 20 mg glatiramer acetate.
15.
The method of claim 14, wherein, the lesion is a demyelinating white matter lesion visible
on brain MRI and wherein the white matter lesion is at least 3 mm in diameter.
20.
A method of reducing the frequency of relapses in a human patient who has experienced a
first clinical episode and has MRI features consistent with multiple sclerosis comprising
administering to the human patient a therapeutically effective dosage rvgimen of three
subcutaneous injections of 1 ml of a pharmaceutical composition comprising 40 mg of glatiramer
acetate over a period of seven days with at least one day between every subcutaneous injection,
wherein the pharmaceutical composition is in a prefilled syringe for self administration by the
patient, wherein the pharmaceutical composition further comprises mannitol, and wherein the
pharmaceutical composition has a pH in the range of 5.5 to 7.0, the regimen being sufficient to
reduce the frequency of relapses in the patient.
ii.

'302 patent, claims 1, 10, and 11

1.
A method of treatment of a human patient suffering from a relapsing form of multiple
sclerosis comprising administration to the human patient of three subcutaneous injections of a 40
mg/ml dose of glatiramer acetate per week so as to treat the human patient.
10.
A method of treatment of a human patient suffering from a relapsing form of multiple
sclerosis comprising subcutaneous injection by the human patient of a 40 mg/ml dose of
glatiramer acetate three times per week with at least one day between every subcutaneous
injection, wherein the glatiramer acetate is present in 1 ml of a pharmaceutical composition in a
prefilled syringe for self injection by the human patient, and wherein the pharmaceutical
composition further comprises mannitol and has a pH in the range of 5.5 to 7.0.
11.
The method of claim 10, wherein each subcutaneous injection is on day 1, day 3 and day
5; day 1, day 3 and day 6; day 1, day 4 and day 6; day 2, day 4 and day 6; day 2, day 4 and day 7;
2, day 5 and day 7; or day 3, day 5 and day 7 every week.

7

iii.

'776 patent, claims 1, 2, 5, 6, 9, 12, 16, and 17

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 of20 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.O,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. daily.
2.
The method of claim 1, which induces reduced frequency and severity of immediate post
injection reactions and injection site reactions in the human patient relative to administration of
20 mg of glatiramer acetate s.c. daily.
5.
A method for reducing the frequency of relapses by 3 0% or more as compared to placebo
in a human population, for reducing brain atrophy, for reducing the cumulative number of
enhancing lesions on Tl-weighted images, or for reducing the level of disability as measured by
EDSS Score of a human patient suffering fyom 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, which method consists 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 .O,so as to thereby reduce the frequency· of relapses by 30% or more as compared to placebo in
a human population, reduce brain atrophy, reduce the cumulative number of enhancing lesions on
Tl- weighted images, or reduce the level of disability as measured by EDSS Score of the human
patient with reduced severity of injection site reactions relative to administration of20 mg of
glatiramer acetate s.c. daily.
6.
The method of claim 5, which reduces brain atrophy and for reducing the frequency of
relapses by 30% or more as compared to placebo in a human population.
9.
The method of claim 5, which induces reduced frequency and severity of immediate post
injection reactions and injection site reactions in the human patient relative to administration of
20 mg of glatiramer acetate s.c. daily.
12.
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, which method consists 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
8

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 as effectively as by administration of 20 mg of glatiramer acetate s.c. daily, and
with reduced severity of injection site reactions relative to administration of 20 mg of glatiramer
acetate s.c. daily.
16.
A met]}od for improving the tolerability of glatiramer acetate therapy reducing the
frequency of relapses, reducing brain atrophy, reducing the cumulative number of enhancing
lesions on Tl- weighted images, or reducing the level of disability as measured by EDSS Score,
of a human patient suffering from a relapsing form of multiple sclerosis as effectively as
administration of20 mg of glatiramer acetate s.c. daily, which method consists 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 I 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 reduce the frequency of relapses, reduce brain atrophy, reduce the
cumulative number of enhancing lesions on Tl weighted images, or reduce the level of disability
as measured by EDSS Score, of the human patient as effectively as by administration of20 mg of
glatiramer ac~tate s.c. daily, and with reduced severity of injection site reactions relative to
administration of20 mg of glatiramer acetate s.c. daily.
17.
The method of claim 16, which reduces the frequency of relapses as effectively as
administration of 20 mg of glatiramer acetate s.c. daily.
E. Defendants' ANDAs
"i.

33.

Amneal ANDA

Amneal GmbH, through its U.S. agent Amneal LLC, filed an ANDA under 21 U.S.C. §

355(i) seeking FDA approval for GA injection, 40 mg/mL, which was assigned ANDA number
207553 ("Amneal's GA Product"), prior to the expiration of the '250 and '413 patents.
34.

Amneal GmbH also filed with the FDA a certification pursuant to 21 U.S.C. §

355G)(2)(A)(vii)(IV) alleging that the claims of the '250 and '413 patents are invalid,
unenforceable, and/or would not be infringed by Amneal's GA Product.

9

35.

By letter dated January 23, 2015, Amneal LLC sent notice to Teva that Amneal LLC had

filed ANDA No. 207553 seeking approval to market Amneal's GA Product prior to the expiration
of the '250 and '413 patents ("First Notice Letter").
36.

Amneal also filed with the FDA a certification pursuant to 21 U.S.C.

§ 355G)(2)(A)(vii)(IV) alleging that the claims of the '302 patent are invalid, unenforceable,
and/or would not be infringed by Amneal's GA Product.
37.

By letter dated March 18, 2015, Amneal LLC notified Teva that it had filed an amendment

to ANDA No. 207553 with a Paragraph IV certification related thereto seeking approval to market
Amneal's GA Product prior to the expiration of the '302 patent.
38.

Amneal also filed with the FDA a certification pursuant to 21 U.S.C. § 355G)(2)(A)(vii)(IV)

alleging that the claims of the '776 patent are invalid, unenforceable, and/or would not be infringed
by Amneal' s GA Product.
39.

By letter dated October 29, 2015, Amneal LLC notified Teva that it had filed an amendment

to ANDA No. 207553 with a Paragraph IV certification related thereto seeking approval to market
Amneal's GA Product prior to the expiration of the '776 patent.
ii.

40.

Amneal Procedural History

On February 3, 2015, Plaintiffs sued Amneal LLC in this court for patent infringement of

the '250 and '413 patents, related to ANDA No. 207553. See Teva Pharms. USA, Inc., et al. v.
Amneal Pharms. LLC, C.A. No. 15-124-GMS (D. Del.). Pursuant to 21 U.S.C. § 355G)(5)(B)(iii),
Plaintiffs sued Amneal within 45 days ofreceipt of Amneal's First Notice Letter.
41.

On March 9, 2015, this court consolidated the multiple pending actions regarding GA 40

mg/mL products into Civil Action No. 1: 14-cv-01171-GMS.

10

42.

On April 10, 2015, Plaintiffs also sued Amneal LLC in this court for patent infringement of

the '302 patent, related to ANDA No. 206767. See Teva Pharms. USA, Inc., et al. v. Dr. Reddy's
Labs., Ltd., et al., C.A. No. 1:15-0306-GMS (D. Del.). That action was consolidated with the current
action.
43.

On April 30, 2015, Plaintiffs filed a First Amended Complaint in In re Copaxone 40 mg

Consolidated Cases, C.A. No. 1:14-cv-01171-GMS (D. Del.). The First Amended Complaint
named both Amneal LLC and Amneal GmbH as defendants.
44.

On November 10, 2015, Plaintiffs filed a Second Amended Complaint in In re Copaxone

40 mg Consolidated Cases, C.A. No. 1:14-cv-01171-GMS (D. Del.). The Second Amended
Complaint alleged infringement of the '776 patent.
iii.

45.

Amneal Stipulations

Amneal has stipulated that, for purposes of this action, its ANDA product contains "GA" as

recited in the claims of the patents-in-suit. (D.I. 195).
iv.

46.

DRLANDA

DRL filed an ANDA under 21 U.S.C. § 355G) seeking FDA approval for GA injection, 40

mg/mL, which was assigned ANDA number 206767 ("DRL's GA Product"), prior to the expiration
of the '250 patent and the '413 patent.
47.

DRL also filed with the FDA a certification pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV)

alleging that the claims of the '250 and '413 patents are invalid, unenforceable, and/or would not
be infringed by DRL's GA Product.
48.

By letter dated August 1, 2014, DRL sent notice to Teva that DRL had filed ANDA No.

206767 seeking approval to market DRL's GA Product prior to the expiration of the '250 and '413
patents ("First Notice Letter").

11

49.

.Teva received DRL's First Notice Letter on or about August 6, 2014.

50.

DRL also filed with the FDA a certification pursuant to 21 U.S.C. § 355(i)(2)(A)(vii)(IV)

alleging that the claims of the '302 patent are invalid, unenforceable, and/or would not be infringed
by DRL's GA Product.
51.

By letter dated May 19, 2015, DRL sent notice to Teva that DRL had filed ANDA No.

206767 seeking approval to market DRL's GA Product prior to the expiration of the '302 patent.
52.

DRL also filed with the FDA a certification pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV)

alleging thatthe claims of the '776 patent are invalid, unenforceable, and/or would.not be infringed
by DRL's GA Product.
53.

By letter dated January 14, 2016, DRL sent notice to Teva that DRL had filed ANDA No.

206767 seeking approval to market DRL's GA Product prior to the expiratio~ of the '776 patent.
v.

53.

DRL Procedural History

On September 10, 2014, Plaintiffs sued DRL in this court for patent infringement of the

'250 and '413 patents, related to ANDA No. 206767. See Teva Pharms. USA, Inc., et al. v. Dr.
Reddy's Labs., Ltd., et al., C.A. No. 14-1172-GMS (D. Del.). Pursuant to 21 U.S.C. §
355(i)(5)(B)(iii), Plaintiffs sued DRL within 45 days of receipt ofDRL's First Notice Letter.
54.

On March 9, 2015, this Court consolidated the multiple pending actions regarding GA 40

mg/mL products into Civil Action No. 1:14-cv-01171-GMS.
55.

On April 10, 2015, Plaintiffs also sued DRL in this court for patent infringement of the '302

patent, related to ANDA No. 206767. See Teva Pharms. USA, Inc., et al. v. Dr. Reddy's Labs.,
Ltd., et al., C.A. No. 1:15-0306-GMS (D. Del.). That action was consolidated with the current
action.

12

56.

On November 10, 2015, Plaintiffs filed a Second Amended Complaint in In re Copaxone

40 mg Consolidated Cases, C.A. No. 1:14-cv-01171-GMS (D. Del.). The Second Amended
Complaint alleged infringement ofthe'776 patent.
vi.
57.

DRL Stipulations

DRL has stipulated that, for purposes of this action, its ANDA product contains "GA" as

recited in the claims of the patents-in-suit. (D.I. 195).
vii.

58.

Mylan ANDA

Mylan filed an ANDA under 21 U.S.C. § 355G) seeking FDA approval for GA injection,

40 mg/mL, which was assigned ANDA number 206936 ("Mylan's GA Product") prior to the
expiration of the '250 and '413 patents.
59.

Mylan also filed with the FDA a certifica~ion pursuant to 21 U.S.C. § 355G)(2)(A)(vii)(IV)

alleging that the claims of the '250 and '413 patents are invalid, unenforceable, and/or would not
be infringed by Mylan's GA Product.
60.

By letter dated August 28, 2014, Mylan sent notice to Teva that Mylan had filed ANDA No.

206936 seeking approval to market Mylan' s GA Product prior to the expiration of the '250 and
'413 patents ("First Notice Letter").
61.

Mylan also filed with the FDA a certification pursuant to 21 U.S.C. § 355G)(2)(A)(vii)(IV)

alleging that the claims of the '302 patent are invalid, unenforceable, and/or would not be infringed
by Mylan's GA Product.
62.

By letter dated March 9, 2015, Mylan sent notice to Teva that Mylan had filed ANDA No.

206936 seeking approval to market Mylan's GA Product prior to the expiration of the '302 patent.

13

63.

Mylan also filed with the FDA a certification pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV)

alleging that the claims of the '776 patent are invalid, unenforceable, and/or would not be infringed
by Mylan's GA Product.
64.

Mylan also notified Teva that it had filed an amendment to ANDA No. 206936 with a

Paragraph IV certification related thereto seeking approval to market Mylan's GA Product prior to
the expiration of the '776 patent.
viii.
65.

Mylan Procedural History

On October 6, 2014, Plaintiffs sued Mylan in this court for patent infringement of the '250

and '413 patents, related to ANDA No. 206936. See Teva Pharms. USA, Inc., et al. v. Mylan
Pharms Inc., et al., C.A. No. 14-1278-GMS (D. Del.). Pursuant to 21 U.S.C. § 355(j)(5)(B)(iii),
Plaintiffs sued Mylai;i within 45 days of receipt ofMylan's First Notice Letter.
66.

On March 9, 2015, this court consolidated the multiple pending actions regarding GA 40

mg/mL products into Civil Action No. 1:14-cv-01171-GMS.
67.

On April 10, 2015, Plaintiffs sued Mylan in this court for patent infringement of the '302

patent, related to ANDA No. 206936. See Teva Pharms. USA, Inc., et al. v. Dr. Reddy's Labs.,
Ltd., et al., C.A. No. 1:15-0306-GMS (D. Del.). That action was consolidated with the current
·action.
68.

On November 10, 2015, Plaintiffs filed a Second Amended Complaint in In re Copaxone

40 mg Consolidated Cases, C.A. No. 1:14-cv-01171-GMS (D. Del.). The Second Amended
Complaint alleged infringement ofthe'776 patent.
ix.

69.

Mylan Stipulations

Mylan has stipulated that, for purposes of this action, its ANDA product contains "GA" as

recited in the claims of the patents-in-suit. (D.I. 195).

14

x.
70.

Sandoz Inc. ANDA

Sandoz Inc. filed an ANDA under 21 U.S.C. § 355(j) seeking FDA approval for GA

injection, 40 mg/mL, purported to be generic to Teva's COPAXONE® 40 mg/mL product, which
was assigned ANDA number 206921 ("Sandoz Inc.'s GA Product"), prior to the expiration of the
'250 and '413 patents.
71.

Sandoz Inc. also filed with the FDA a certification pursuant to 21 U.S.C. §

355(j)(2)(A)(vii)(IV) alleging that the claims of the '250 and '413 patents are invalid,
unenforceable, and/or would not be infringed by Sandoz Inc.' s GA Product.
72.

By letter dated August 27, 2014, Sandoz Inc. sent notice to Teva that Sandoz Inc. had filed

ANDA No. 206921 seeking approval to market Sandoz Inc.'s GA Product prior to the expiration
ofthe '250 and '413 patents ("First Notice Letter").
73.

Teva received Sandoz Inc.'s First Notice Letter on or about August 28, 2014.

74.

Sandoz Inc. also filed with the FDA a certification pursuant to 21 U.S.C. §

355G)(2)(A)(vii)(IV) alleging that the claims of the '302 patent are invalid, unenforceable, and/or
would not be infringed by Sandoz Inc. 's GA Product.
75.

By letter dated March 6, 2015, Sandoz Inc. sent notice to Teva that Sandoz Inc. had filed

ANDA No. 206921 seeking approval to market Sandoz Inc.'s GA Product prior to the expiration
of the '302 patent.
76.

Sandoz Inc. also filed with the FDA a certification pursuant to 21 U.S.C. §

355G)(2)(A)(vii)(IV) alleging that the claims of the '776 patent are invalid, unenforceable, and/or
would not be infringed by Sandoz Inc.' s GA Product.

15

77.

Sandoz Inc. also notified Teva that it had filed an amendment to ANDA No. 206921 with a

Paragraph IV certification related thereto seeking approval to market Sandoz Inc.'s GA Product
prior to the expiration of the '776 patent.
xi.
78.

Sandoz Procedural History

On September 10, 2014, Plaintiffs sued Sandoz Inc. and Momenta Pharmaceuticals, Inc. in

this court for patent infringement of the '250 and '413 patents, related to ANDA No. 206921. See
Teva Pharm. USA, Inc., et al. v. Sandoz, Inc., et al., C.A. No. 1:14-cv-01171 GMS (D. Del.).
Pursuant to 21 U.S.C. § 355G)(5)(B){iii), Plaintiffs sued Sandoz Inc.. and Momenta
Pharmaceuticals, Inc. within 45 days of receipt of Sandoz Inc.' s First Notice Letter.
79.

On March 9, 2015, this Court consolidated the multiple pending actions regarding GA 40

mg/mL produds into Civil Action No. 1:14-cv-01171-GMS.
80.

On April 10, 2015, Plaintiffs sued Sandoz Inc. and Momenta Pharmaceuticals, Inc. in this

court for patent infringement of the '302 patent, related to ANDA No. 206921. See Teva Pharm.
USA, Inc., et al. v. Dr. Reddy's Labs., Ltd., et al., C.A. No. 1:15-cv-00306-GMS (D. Del.). That
action was consolidated with the current action.
81.

On November 10, 2015, Plaintiffs filed a Second Amended Complaint in In re Copaxone

40 mg Consolidated Cases, C.A. No. 1:14-cv-01171-GMS (D. Del.). The Second Amended
Complaint alleged infringement ofthe'776 patent.

xii.
82.

Synthon Pharmaceuticals, Inc.'s ANDA

Synthon Pharmaceuticals, Inc. filed an ANDA under 21 U.S.C. § 355G) seeking FDA

approval for GA injection, 40 mg/mL, purported to be generic to Teva' s COP AXONE® 40 mg/mL
product, which was assigned ANDA number 206873 ("Synthon Pharmaceuticals' GA Product"),
prior to the expiration of the '250 and '413 patents.

16

83.

Synthon Pharmaceutical Inc. also filed with the FDA a certification pursuant to 21 U.S.C.

§ 355(j)(2)(A)(vii)(IV) alleging that the claims of the '250 and '413 patents are invalid,

unenforceable, and/or would not be infringed by Synthon Pharmaceuticals' GA Product.
84.

By letter dated October 8, 2014, Synthon Pharmaceutical Inc. sent notice to Teva that

Synthon Pharmaceutical Inc. had filed ANDA No. 206873 seeking approval to market Synthon
Pharmaceuticals' GA Product prior to the expiration of the '250 and '413 patents ("First Notice
Letter").
-85.

Teva received Synthon Pharmaceuticals Inc.'s First Notice Letter on or about October 9,

2014.
86.

Synthon Pharmaceutical Inc. also filed with the FDA a certification pursuant to 21 U.S.C.

§ 355G)(2)(A)(vii)(IV) alleging that the claims of the '302 patent are invalid, unenfo~ceable, and/or

would not be infringed by Synthon Pharmaceuticals' GA Product.
87.

By letter dated March 27, 2015, Synthon Pharmaceutical Inc. sent notice to Teva that

Synthon had filed ANDA No. 206873 seeking approval to market Synthon Pharmaceuticals' GA
Product prior to the expiration of the '302 patent.
88.

Synthon Pharmaceutical Inc. filed with the FDA a certification pursuant to 21 U.S.C. §

355G)(2)(A)(vii)(IV) alleging that the claims of the '776 patent are invalid, unenforceable, and/or
would not be infringed by Synthon Pharmaceuticals' GA Product.
89.

Synthon Pharmaceutical Inc. notified Teva that it had filed an amendment to ANDA No.

206873 with a Paragraph IV certification related thereto seeking approval to market Synthon
Pharmaceuticals' GA Product prior to the expiration of the '776 patent.

17

xiii.
90.

Synthon Procedural History

On November 18, 2014, Plaintiffs sued Synthon Pharmaceuticals, Inc., Synthon s.r.o., and

Synthon B.V. in this Court for patent infringement of the '250 and '413 patents, related to ANDA
No. 206873. See Teva Pharms. USA, Inc., et al. v. Synthon Pharms. Inc., et al., C.A. No. 14-1419GMS (D. Del.). Pursuant to 21 U.S.C. § 355G)(5)(B)(iii), Plaintiffs sued Synthon Pharmaceuticals,
Inc., Synthon s.r.o., and Synthon B.V. within 45 days ofreceipt of Synthon Pharmaceuticals, Inc.'s
First Notice Letter.
91.

On March 9, 2015, this court consolidated the multiple pending actions regarding GA 40

mg/mL products into Civil Action No. 1:14-cv-01171-GMS.
92.

On April 10, 2015, Plaintiffs sued Synthon Pharmaceuticals, Inc., Synthon s.r.o., and

Synthon B.V. in this court for patent infringement of the. '302 patent, related to ANDA No. 206873.
See Teva Pharms. USA, Inc., et al. v. Dr. Reddy's Labs., Ltd., et al., C.A. No. 1:15- 0306-GMS (D.
Del.). That action was consolidated with the current action.
93.

On November 10, 2015, Plaintiffs filed a Second Amended Complaint in In re Copaxone

40 mg Consolidated Cases, C.A. No. 1:14-cv-01171.:.GMS (D. Del.). The Second Amended
Complaint alleged infringement of the' 77 6 patent.
xiv.

94.

Synthon Stipulations

Synthon Pharmaceuticals, Inc., Synthon s.r.o., Synthon B.V., and Pfizer, Inc. have

stipulated that, for purposes of this action, SynthonPharmaceuticals, Inc.'s ANDA product contains
"GA" as recited in the claims of the patents-in-suit. (D.I. 195).
III.

DISCUSSION AND CONCLUSIONS OF LAW

The court has jurisdiction over the subject matter of this action pursuant to 28 U.S.C. §§
1331 and 1338(a). Venue is proper under 28 U.S.C. §§ 1391(b), (c), and (d), and 1400 (b). After

18

having considered the entire record in this case, the substantial evidence in the record, the parties'
post-trial submissions, and the applicable law, the court concludes that all asserted claims of the
patents-in-suit are invalid. The court's reasoning follows.
A.

Obviousness 2
i.

The Legal Standard

Under 35 U.S.C. § 103(a), a patent may not be obtained "if the differences between the
claimed invention and the prior art are such that the claimed invention as a whole would have been
obvious before the effective filing date of the claimed invention to a person having ordinary skill
in the art." 35 U.S.C. § 103(a). Obviousness is a question of law that is predicated on several
factual inquires. See Richardson-Vicks v. Upjohn Co., 122 F.3d 1476, 1479 (Fed. Cir. 1997).
Specifically, the trier of fa~t is directed to assess four considerations: (1) the scope and content of
the prior art; (2) the level of ordinary skill in the art; (3) the differences between the claimed subject
matter and the prior art; and (4) secondary considerations of non-obviousness, such as commercial
success, long-felt but unsolved need, failure of others, acquiescence of others in the industry that
the patent is valid, and unexpected results. See Graham v. John Deere Co., 383 U.S. 1, 17-18
(1966).
"A patent shall be presumed valid." 35 U.S.C. § 282(a). A party seeking to challenge the
validity of a patent based on obviousness must demonstrate by "clear and convincing evidence"3
that the invention described in the patent would have been obvious to a person of ordinary skill in
the art at the time the invention was made. See Procter & Gamble Co. v. Teva Pharm. USA, Inc.,

2

The court acknowledges that Defendants asserted affirmative defenses of non-infringement, obviousness, nonenablement, and indefiniteness. Because the court found all asserted claims of the patents-in-suit invalid as obvious,
it declined to address Defendants other affirmative defenses.
3
"Clear and convincing evidence is evidence that places in the fact finder 'an abiding conviction that the truth of [the]
factual contentions are 'highly probable."' Alza Corp v. Andrx Pharms., LLC, 607 F. Supp. 2d 614, 631 (D. Del. 2009)
(quoting Colorado v. New Mexico, 467 U.S. 310, 316 (1984)).

19

. 566 F.3d 989, 993-94 (Fed. Cir. 2009). Importantly, in determining what would have been obvious
to one of ordinary skill in the art, the use of hindsight is not permitted. See KSR Int 'l Co. v. Teleflex,

Inc., 550 U.S. 398, 421 (2007) (cautioning the trier of fact against "the distortion caused by
hindsight bias" and "arguments reliant upon ex post reasoning" in determining obviousness). In

KSR, the Supreme Court rejected the rigid application of the principle that there should be an
explicit teaching, suggestion, or motivation in the prior art, the "TSM test," in order to find
obviousness. See id. at 415. The KSR Court acknowledged, however, the importance of identifying
"a reason that would have prompted a person of ordinary skill in the relevant field to combine the
elements in the way the claimed new invention does." Id. at 418.
"Obviousness does not require absolute predictability of success," but rather, requires "a
. reasonable expectation of success." See Medichem, S.A. v. Rolado, S.L., 437 F.3d 1157, 1165 (Fed.
Cir. 2006) (quoting In re O'Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988)).

To this end,

obviousness "cannot be avoided simply by a showing of some degree of unpredictability in the art
.so long as there was a reasonable probability of success." Pfizer, Inc. v. Apotex, Inc., 480 F.3d
"1348, 1364 (Fed. Cir. 2007). Moreover, while the Federal Circuit has noted that pharmaceuticals
can be an "unpredictable art" to the extent that results may be unexpected, it also recognizes that,
per KSR, evidence of a "finite number of identified, predictable solutions" KSR Int'! Co., 550 U.S.
at 421, "might support an inference of obviousness." Ortho-McNeil Pharmaceutical, Inc. v. Mylan

Laboratories, Inc., 520 F.3d 1358, 1364 (Fed. Cir. 2008).
ii.

The Level of Ordinary Skill in the Art

A person of ordinary skill in the art with respect to all the patents-in-suit would have: (1)
several years' experience in the pharmaceutical industry or in practicing medicine; (2) experience
with drug development in the pharmaceutical industry or in medical practice; (3) a Ph.D. in

20

pharmacology or an M.D. with experience in clinical pharmacology; and (4) experience with MS
and GA. (D.I. 273 at 13-14); (D.I. 272 at 6).
iii.

Obviousness of the '250, '413 and '302 Patents

Defendants challenge the validity of the asserted claims of the '250, '413, '302, and '776
patents. Because the '776 patent includes limiting language not found in the other three patents, .
the obviousness of the '776 patent will be addressed separately. (D.I. 273 at 13); see infra §
III(A)(iv).
Plaintiffs assert claims 1, 5 and 13-17 of the '250 patent, claims 1, 7, 15 and 20 of the '413
patent, and claims 1, 10 and 11 of the '302 patent. (D.I. 273 at 14). The obviousness analysis for
the '250, '413, and '302 patents hinges on the core elements of the asserted claims: (1) a40mg dose
of GA that is (2) administered in three subcutaneous injections over seven days with at least one
day between injections. Id. Although claim 1 of the '302 patent does not include the limitation
that the injections be at least one day apart, claims 4 and 5 provide that the three injections be
administered on three days of each week selected from a group of various combinations of days of
the week, all with at least one day between injections. '302 patent, col. 1611. 47-58. Independent
claim 10 of the '3 02 patent further discloses administering 40mg of GA "three times per week with
at least one day between every subcutaneous injection." '302 patent, col. 17H. 7-8.
Defendants contend that the '250, '413 and '302 patents are obvious because the prior art
provided motivation to create a 40mg, thrice-weekly injection regimen, as well as a reasonable
expectation of success with that regimen. It is well-established that "when there is a design need
or market pressure to solve a problem and there are a finite number of identified, and predictable
solutions, a person of ordinary skill has good reason to pursue the known options." KSR Int'l Co.,
550 U.S. at 421. When the solution does in fact yield the anticipated success, that result cannot be

21

deemed a product of innovation. Id. Defendants argue that there was clear market pressure to
create a less frequent dosage form of GA to improve patient tolerability, and, due to prior art
disclosures of positive results with less frequent dosing, there was a reasonable expectation that
such a dosage form would be successful. Prior to addressing expert testimony on motivations to
combine prior art references, the court will conduct a detailed analysis of the statutory prior art
published before the earliest priority date of the patents-in-suit: August 20, 2009.

1.

Scope and Content of the Prior Art

As early as 1996, an FDA reviewer suggested t~ Teva that they explore less frequent dosing
of GA. JTX7079 at 252. That suggestion was part of_ the FDA's Summary Basis of Approval
(SBOA) for 20mg daily COPAXONE®. The reviewer included a section in the summary entitled,
"[a]re daily injections really necessary?" Id. In that section, the toxicology reviewer expla~ned that
the daily injection dosing regimen seemed "like it would subject the patient to an excessive amount
of discomfort if it is not necessary to maintain efficacy."

Id.

The toxicology reviewer

recommended that Teva "evaluate the necessity of daily s.c. injections as opposed to more
infrequent intermittent administration of the drug." Id.
The Fiechter reference was a 2002 open, multicenter two-year study on patients suffering
from a relapsing form of MS. The study evaluated the "long-term neurologic course of the disease
and the long-term safety of [GA] in patients" receiving 20 mg on an alternate-day basis. JTX7078
at 1. The study performed analyses on "two efficacy parameters: :frequency of exacerbations and
score on the Expanded Disability Status Scale (EDSS)." Id. at 1-2 (internal citations omitted).
Flechter discloses, at the least, that daily injections may be unnecessary. (D.I. 271 at 20). Though
Flechter notes that the results of the preliminary open-label study "should be confirmed by
randomized double-blind examinations," the study's results nonetheless suggest that alternate-day

22

therapy is well tolerated and "compar[es] favorably with the effects of daily injections of [GA] in
patients with relapsing MS." JTX7078 at 1.
The Cohen reference, a "Randomized, Double-Blind, Dose-Comparison Study of
Glatiramer Acetate in Relapsing-remitting MS," was published in 2007. The study compared the
20mg and 40mg GA dosage forms. The nine-month study, which started enrolling participants as
early as 2003, concluded that "onset of action of the 40-mg dose is more rapid compared with 20
mg." The study noted, however, that "[a] larger, longer study will be necessary to confirm the
sustainability of the efficacy advantage of the higher dose." The study also went on to explain that
"[t]he overall safety and side effect profile of the 40-mg dose in this trial [was] similar [to the 20mg dose], although it was associated with a greater incidence of certain adverse effects." JTX7060
at 7.
Plaintiffs' own prior art patent application ("Pinchasi") was published only a few months
after the Cohen study, though it claimed a January 11, 2006, priority date. The Pinchasi reference
discloses a 40mg GA, every other day, dosing regimen to treat MS. Pinchasi cites to the data from
the 2007 Cohen 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 [relapsing-remitting multiple sclerosis patients]." JTX7101 at 19. The
Pinchasi reference also cites to the Cohen study data for the conclusion that there was an
"accelerated rate at which the 40mg/day dose became effective." Id. at 20. The Pinchasi reference
further notes that the improvement in efficacy was not accompanied by an increase in adverse
reactions. Id. at 19.
The FORTE study, published in 2008, reported the results of a phase III, one-year,
randomized, double-blind parallel-group, dose-comparison study with GA in relapsing-remitting

23

MS. JTX7063 at 1. The study sought to expand upon the phase II Cohen study, which found the
40mg daily dosing of GA may be more effective than 20mg daily dosing. Id. The study compared
the safety, tolerability and efficacy of the 20mg/daily dosage regimen to the 40mg/daily regimen.
Id.

The primary endpoint of the study was the rate of confirmed relapses observed during the

study. Id. The conclusions from the FORTE study were that both dosage forms were safe, welltolerated and "equally effective in reducing clinical relapses and MRI activity." Id.

Though

seventy-seven percent of patients in both treatment groups remained relapse-free and both groups
showed a reduction in new T2 lesions over time, the study still reported _a trend for a faster reduction
in the first trimester in the 40mg dose group. Id.
In 2008, Omar Khan, along with others from the Wayne State University School of

Medicine, published the results o.f a randomized, prospective, rater-blinded, four-year pilot study
to compare the effect of daily versus every-other-day dosing of 20mg GA in relapsing-remitting
multiple sclerosis patients. JTX7089 at 4. The background section of the abstract for that study
stated that "[t]he recommended dose of GA in RRMS is 20 mg subcutaneous (SC) daily (QD)
although the optimal dose remain unknown. There is considerable interest in alternate dosing
regimens of GA in RRMS. Daily SC injectable therapy can be challenging for long-term patient
compliance." Id. Thirty patients were randomly assigned to receive 20mg of GA dosed every-day
or every-other-day (QOD). Id. "After 2 years, there were no differences in the relapse rate, disease
progression, T2W lesion volume or Gd enhancing lesions between the two groups." Id. After 2
years, all patients in the everyday group opted to switch to the every-other-day group. Id. When
the researchers followed-up after four years there was no difference between the group that decided
to cross-over from every-day to every-other-day and the group that was always dosed every-other-

24

day. Id. The researchers did note that large, multi-center studies were still necessary to confirm
their findings.
The Caon reference, published in 2009, reports the same data from the Khan 2008 study.
Trial Tr. 1320:14-18. As such, the study objective indicates that the researchers "conducted a pilot
trial to compare the effect of GA 20 mg SC daily to every other day (QOD) in clinical, MRI, and
immunologic outcomes in RRMS." JTX7058 at 2. Caon, like Khan 2008, reported that after two
years there was no difference in relapse rate, MRI outcome, or disease progression between the
QOD and QD groups. Id.

Caon additionally noted that "[i]njection related lipoatrophy was

significantly less in the QOD group." Id.
Omar Khan conducted another study that was published in 2009, although it began two
years. earlier. The study is not statutory prior-art because it was published three-weeks after the
priority date of the patents-in-suit. 35 U.S.C. § 102(a). The court ruled, however, that because the
study began before the priority date, it could be used to show the state of the art at or around the
time of the invention. Tr. 721:6-724:17; see Thomas & Betts Corp. v. Litton Systems, Inc., 720
F.2d 1"572, 1581 (Fed. Cir. 1983) ("Thus, the M & E criteria, though not technically prior art, were,
in effect, properly used as indicators of the level of ordinary skill in the art to which the invention
pertained."). The pilot, prospective, randomized, and rater-blinded two-year study examined GA
20mg SC twice-weekly injections versus daily injections in relapsing-remitting MS patients.
Though the court cannot consider the results of the study, the objective section of the abstract
evidences the state of the art in 2007 when the study began: "[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." DTXl 154 at 1.

25

2.

Selecting the 40mg Dose

As is clear after a recitation of the prior art, a 40mg dosage form of GA was explicitly
disclosed in references that pre-date the patents-in-suit. The Cohen study reported that the overall
safety and side-effect profile of the 40mg dose was similar to the 20mg dose.

JTX7060 at 7.

Plaintiffs' own prior art patent application claimed a 40mg dosage form. JTX7107 at 22. The
FORTE study also disclosed that the 40mg dosage form was safe, well-tolerated and "equally
effective in reducing clinical relapses and MRI activity." JTX7063 at 1.
Plaintiffs highlight that the Cohen study was small, found "no statistically significant ..
difference between the 20mg and the 40mg daily dosages" and showed "that 40 mg was more
painful, not as well tolerated, and resulted in increased adverse events as compared to 20mg." (D.I.
272 at 18). Plaintiffs additionally argue that the Pinchasi reference, claiming a 40mg dosage form
of GA, would not render the patents-in-suit obvious because the FORTE study caused the MS
community to "abandon[] the 40mg dose." (D.I. 272 at 17). FORTE post-dates Pinchasi, and
Plaintiffs contend that the FORTE study failed in that the 40mg/daily dose of GA did not
demonstrate increased efficacy over the 20mg/daily dose. (D.I. 272 at 19). After the FORTE study,
Teva announced in a July 7, 2008 press release that "COPAXONE® 20mg, the leading multiple
sclerosis therapy, remains the optimal treatment dose." JTX7035 at 1. Plaintiffs' expert, Dr.
Ziemssen, concluded that the 40mg dose was "dead" after the FORTE results were release. Trial
Tr. 1340:9-15. After analysis of the FORTE and Cohen studies, however, the court disagrees with
Dr. Ziemssen.
First, the court finds that persons having ordinary skill in the art would not agree with Teva' s
statement that 20mg is the optimal treatment dose. JTX7035 at 1. Though not a study investigating
the efficacy of the 40mg dosage form of GA, Khan 2008 states that ''the optimal treatment dose

26

remains unknown." JTX7089 at 4. Khan 2009, admitted for the limited purpose of showing the
state of the art at the time of invention, also indicates that "[t]he optimal dose of glatiramer acetate
(GA) in RRMS remains unknown." DTX1154 at 1. Khan 2009 demonstrates that, even after
FORTE, persons having ordinary skill in the art would not consider 20mg/day to be the optimal
dose.
Second, the court finds that Cohen and FORTE do not teach away from a 40mg dose.
Despite the fact that the Cohen study reported higher incidences ofcertain adverse effects in patients
given the 40mg GA dose, Dr. Cohen still concluded that overall efficacy results suggested -that
40mg of GA may be more effective than the 20mg dose in reducing clinical relapse. JTX7060 at
2. Further, Teva decided to conduct the FORTE study, a large Phase III clinical trial of 40mg/daily
versus 20mg/daily, after the Cohen results were published. See JTX7063 at 1. The court finds

th~t

. Teva would not have invested in a large Phase III clinical trial were it not intrigued by the prospects
of the 40mg dosage form and the Cohen study results. The court also finds that the results of the
FORTE study-a 40mg dosage form was as effective as 20mg, yet did not cause an increase in
adverse effects-completely undermines Plaintiffs argument. See See Hoffmann-La Roche Inc. v.
Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014) (finding that a later prior art study demonstrating
that intermittent dosing was as effective as continuous treatment undermined any argument that
earlier study taught away from monthly dosing); see also Galderma Labs., L.P. v. Tolmar, Inc., 737
F.3d 731, 738 (Fed. Cir. 2013) ("A reference does not teach away, however, ifit merely expresses
a general preference for an alternative invention but does not criticize, discredit, or otherwise
discourage investigation into the invention claimed.").
Dr. Ziemssen contends that because the FORTE study failed, persons having ordinary skill
in the art would have abandoned efforts to create a 40mg dosage form of GA. Trial Tr. 1246:19-

27

23. Dr. Ziemssen agreed with Defendants, however, when they asked "[w]e can agree that the
FORTE study was powered to try to find a 30-percent improvement in the 40-milligram product
versus the 20-milligram product for the efficacy end point. Right?" Trial Tr. 1401:12-22. While
the FORTE study "failed" in the sense that it did not meet its primary endpoint-establishing that
40mg/day GA reduced annual relapse rates by thirty-percent compared to GA 20mg/day-it did
not fail in the sense that it declared the 40mg dose ineffective. Trial Tr. 1401:23-1402:13. See
Hoffman La-Roche, 748 F.3d at 1331 (stating that, while a study failed to demonstrate that

intermittent dosing reduced vertebral :fractures by a statistically significant amount, it did not teach
that infrequent dosing is ineffective in treating osteoporosis).
The FORTE study reported that the 40 mg and 20 mg GA formulations "were safe and welltolerated, and were equally effective in reducing clinical relapses

an~

MRI activity." JTX7063 at

1. The study also reported a trend for faster reduction of gadolinium-enhancing and new T2 lesions
in the first trimester of treatment with 40mg GA. Id. When Dr. Cami, the principal investigator
for the FORTE study, presented the results of the FORTE study at the preeminent MS seminar, he
stated that the 40mg dose was equally effective to 20mg with "no unexpected adverse effect with
high dose." JTX7064 at 9. The court, therefore, is not persuaded that it would have been
nonobvious to a person having ordinary skill in the art to use a 40mg dosage form, or that success
with that dosage form would have been unexpected. See Hoffmann-La Roche, 748 F.3d at 1332
("Even though the 5mg dose did not demonstrate greater efficacy than the 2.5mg dose, it was still
deemed an equivalently effective dose so that someone scaling it to a single monthly dose of l 50mg
... would have anticipated equivalent success ....").

28

3.

TIW Dosing Regimen

By the priority date, persons having ordinary skill in the art knew that daily injections
were difficult to tolerate. Trial Tr. 894:16-896:17. Specifically, they knew that injection-site
reactions ("ISRs") and immediate post-injection reactions ("IPIRs") were reasons for
nonadherence to the 20mg/daily COP AXONE® treatment regimen. Id.
In 1996, the SBOA posed the question, "[a]re daily injections really necessary." JTX7079
at 252. Plaintiffs suggest that the reviewer asked that question out of concern that too much GA
would accumulate in the system with daily dosing. (D.I. 272 at 20). The paragraph that follows
the heading, "[a]re daily injections really necessary," however, makes clear that the examiner was
concerned with "subject[ing] the patient to an excessive amount of discomfort" with a daily
dosing regimen. JTX7079 at 252. OnlY. after first voicing a concern about the discomfort of daily
injections does the reviewer then state "[f]urthermore, ifthere should be a problem in humans
with saturation of the clearance mechanism ... this problem might be lessened with intermittent
rather than daily administration." Id. Us.e of the word "furthermore" indicates that the reviewer's
concern about patient discomfort with daily injections was distinct from his concern about GA
accumulation in the system over time. The court thus finds that the reviewer's question and his
recommendation "that the Sponsor evaluate the necessity of daily s.c. injections as opposed to
more infrequent intermittent administration of the drug," id., would have motivated those having
ordinary skill in the art to pursue less frequent GA dosing schedules.
The 2002 Flechter study only provided further motivation to pursue less frequent GA
dosing schedules. The main conclusion from the Flechter study was that "alternate-day treatment
with [GA] [was] safe, well tolerated, and probably as effective as daily [GA]." JTX7078 at 5.
Plaintiffs contend that the study's size and methodological flaws preclude a person having

29

ordinary skill in the art from drawing conclusions about the efficacy ofless frequent GA dosing.
(D.I. 272 at 25). Flechter does acknowledge that because the study was uncontrolled, "all
conclusions cannot be used to prove efficacy." JTX7078 at 5. Regardless of Plechter's
methodological flaws, the court is not persuaded by Plaintiffs argument. The court finds that the
preliminary observations made in the Flechter study combined with the statement that preliminary
observations would "have to be examined in larger studies, preferably comparing daily with
alternate-day administration of Copolymer 1 in a blinded manner," JTX7078 at 5, would provide
those in the art with motivation to conduct further studies on less :frequent GA dosing.
Just like Flechter, the Khan 2008 study demonstrated that 20mg administered every other
day may be as effective as 20mg of GA administered every day. The court finds that the study
added furth~r support to Defendants' proposition that there was considerable interest in alternate
dosing regimens of GA for relapsing-remitting MS patients. Aside from explicitly noting such an
interest existed as part of the background section of the study's abstract, the study also reported
that when the patients in the 20 mg every day dose group were given the option to switch to
receiving 20·mg every other day, all of them opted to switch to less :frequent dosing. JTX7089 at
4.
Plaintiffs seek to discredit the Khan reference by pointing out that, like Flechter, Khan
was an open label, small study that reported no data and was not designed to demonstrate the
efficacy of an every-other-day GA regimen. (D.I. 272 at 25).

Plaintiffs further explain that

those in the art would not conclude that patients chose to switch from every day injections to
every-other-day injections because of improved tolerability. Plaintiffs make a good point
considering that the patients in the Khan "had not previously taken GA, and therefore, would not
have experienced both regimens, and could not be comparing their tolerabilities, in making the

30

decision to switch." (D.1. 272 at 25). The court finds, however, that those in the art would, in
fact, conclude that patients decided to switch to reduce the discomfort associated with daily
injections. Trial testimony clearly showed that those in the art were familiar with the adverse
reactions, pain, and treatment adherence problems associated with daily injections. Trial Tr.
89:5-16, 733:18-734:9, 926:3-14. Testimony additionally demonstrated that those in the art
would opine that reducing the number of injections would reduce the pain and adverse reactions
they cause. Trial Tr. 914:5-13 ("If you reduce the frequency of injections, well, it's clearly
obvious that yo;i would reduce the :frequency of those injection site reactions or immediate postinjection reactions.").
Even if Khan were a small study with ill-defined endpoints, as Plaintiffs claim, it
nonetheless demonstrated that "[a]fter 2 years, there were no differences in the relapse rate,
disease progression, change in T2W lesion volume, or Gd enhancing lesions between the two
groups." JTX7089 at 4. As Caon reported, the study also showed that "[i]njection related
lipoatrophy was significantly less in the [every other day] group." JTX7058 at 2. Plaintiffs
maintain that those in the art would not draw conclusions about tolerability based on Khan/Caon
because the reference provides "no information regarding the tolerability of the 40mg dose, no
description of what is meant by significantly less lipoatrophy, and no information about how the
two regimens compared with respect to the other adverse events." (D.I. 272 at 26).

Regardless

of the purported shortcomings of the Khan 2008 study, the court finds that even the preliminary
findings would have motivated a person having ordinary skill in the art to pursue less frequent
dosing and given them a reasonable probability of success. The court also finds it unlikely that
Khan and his associates would invest in another study, Khan 2009, investigating even less
.

'

:frequent GA dosing, had they not been encouraged by the results of Khan 2008. DTXl 154 1-2.

31

The Pinchasi patent application claims a 40mg GA dose, administered every other day.
The court agrees with Defendants that Pinchasi is the closest prior art because Pinchasi differs
from the claimed regimen by only one dose every two weeks. (D.I. 272 at 17). Plaintiffs argue
that a person having ordinary skill in the art would not have used the 40 mg every-other-day
regimen as the starting point for development because the MS community abandoned the 40mg
dose after the FORTE study. Trial Tr. 1340:9-15. For the reasons previously stated, the court
does not find Plaintiffs argument persuasive.
Plaintiffs further argue that Pinchasi would not provide those in the art with the motivation
to pursue less frequent dosing because "it provides no data (or even a clinical trial protocol) on
EOD administration." (D.I. 272 at 18). Again, the court does not find that argument persuasive.
Dr. Klinger, the inventor of the 40mg, thrice-weekly GA dosage form, admitted that the patentsin-suit provided no clinical or pre-clinical data to support a 40mg dose of GA administered three
times a week. Trial Tr. 198:14-20. While the lack of clinical data in the Pinchasi patent might
have caused the MS community to be skeptical of the efficacy of every-other-day administration,
the patents-in-suit disclose no additional data beyond the teaching of Pinchasi or the other prior
art references. It would constitute clear error for the court to discredit the Pinchasi reference for
the same lack of dosing frequency clinical data from which the patents-in-suit suffer. See Merck
& Co. v. Teva Pharm. USA, Inc., 395 F.3d 1364, 1374 (Fed. Cir. 2005) (finding clear error where

the district court held an invention nonobvious because prior art failed to explain how a higher
once-weekly dose would avoid adverse effects, but the patent-in-suit also did not provide any
clinical data showing the tolerability of the higher once-weekly dose).

32

4.

Improved Tolerability and Reduced Frequency Limitations

Claims 7, 14, 16, and 17 of the '250 patent and claim 7 of the '413 patent require that the
40mg, three-times-a-week regimen reduce the frequency of injection site reactions and immediate
post-injection reactions as compared to a 20mg daily regimen. Claim 15 of the '250 patent
requires that the claimed regimen improve tolerability as compared to a 20mg daily regimen. The
court finds these claim limitations obvious as well.
Plaintiffs take issue with the fact that Defendants' expert, Dr. Green, provided no support
for his "conclusory" assertion that those in the art would expect that the number of injection site
reactions decrease as the number of injections per week decreased. (D.I. 272 at 31). The court
disagrees with Plaintiff's characterization of Dr. Green's testimony as conclusory. Instead, it is
simply common sense that if a patient experiences adverse reactions from ap injection, reducing
the number of injections they receive would reduce the number of times they have a reaction. It is
unclear to the court why Dr. Green would need to support that statement with evidence. There is,
however, evidence on the record that does provide the support Plaintiffs seek.
Dr. Wolinksy, a person having ordinary skill in the art, realized the association between
injection site reactions and the number of injections per week. On some occasions, he would
prescribe COPAX ONE® 20mg for use every other day, and off-label use, for his patients who
were "doing extremely well on the drug but[were] having trouble with injection site problems."
Trial Tr. 762:11-763:10. Even more persuasive evidence that the improved tolerability and
reduced frequency limitations are obvious can be found in the Khan/Caon and Fiechter studies.
That Khan/Caon study, researching the effects of administering 20mg of GA every other
day, found that the frequency of one type of injection-related adverse event-lipoatrophy-was
"significantly less" in the every-other-day group as opposed to the group receiving daily

33

injections. JTX7058 at 2. The Flechter study also supports Defendants' assertion that those in
the art would expect a smaller number of injections per week to lead to a reduced frequency in
injection-site reactions. Flechter reported that the patient drop-out rate was lower in the group
that received 20mg every other day, than in the group that received 20mg da,ily-"(39.7% versus
60.3%, p<0.01)." JTX7078 at 5. The prior art, analyzed as a whole, supports Defendants'
contention that the improved tolerability and reduced frequency of injection site reactions claim
limitations are obvious.
Plaintiffs argue that the prior art actually suggests that a 40mg dose of GA would increase
the frequency of adverse events. Accordingly, there could be no reasonable expectation that a
40mg dose, administered thrice-weekly would reduce the frequency of injection-site reactions as
compared to a 20mg daily regimen. (D.I. 272

~t

25). The court disagrees.

The Pinchasi application explicitly states that the 2007 Cohen study demonstrated an
improvement in efficacy associated with the 40mg dose, "not accompanied by a corresponding
increase of adverse reactions which would be expected upon a doubling of the administered
dose." JTX7107 at 19. The FORTE study als6 disclosed that injection site reactions were
reported with similar incidence for both the 20mg and 40 mg doses. JTX7063 at 1; JTX7035 at 1
("The 40mg dose did not demonstrate increased efficacy in reducing the relapse rate; however,
the higher dose maintained the favorable safety and tolerability profile of COPAXONE®
20mg."). Plaintiffs' even stated to the FDA that the FORTE study showed "local reactions at the
injection sites and immediate transient reactions following injection were reported with a similar
incidence for both doses" and "one may certainly expect a reduction in the frequency of such
reactions with this new dose regimen, further enhancing subject adherence to treatment."
JTX7033 at 22. The court therefore disagrees with Plaintiffs that a 40mg, thrice-weekly dosing

34

regimen would not be expected to reduce the frequency of injection-site reactions and improve
tolerability.
5.

Obvious to Try

A 40mg d?sage form was explicitly mentioned in the prior art, and there was a
motivation in the MS community to explore a less frequent dosing regimen to alleviate the wellknown adverse side effects associated with daily injections. As Plaintiffs point out however,
there exists no prior art reference explicitly disclosing a three-times-a-week injection regimen.
This is a case where evidence adduce~ at trial renders a less frequent dosage form obvious to try.
See Hoffinann-La Roche, 748 F.3d at 1331 (holding the "150 mg dose was obvious to try"

because "[t]here was a need to solve the problem of patient compliance by looking to lessfrequent dosing regimens").
The court wishes to make clear that it is not applying what amounts to an impermissible
"obvious-to-try" standard. The Federal Circuit has cautioned time and again that the obvious-totry standard commonly leads to two types of errors:
In some caS"es, what would have been "obvious to try" would have been to vary all
parameters or try each of numerous possible choices until one possibly arrived at a
successful result, where the prior art gave either no indication of which parameters
were critical or no direction as to which of many possible choices is likely to be
successful. In others, what was "obvious to try" was to explore a new technology
or general approach that seemed to be a promising field of experimentations, where
the prior art gave only general guidance as to the particular form of the claimed
invention or how to achieve it.
In re O'Farrell, 853 F.2d at 903. This case does not fall into either of the scenarios outlined

in 0 'Farrell. Here, 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. See KSR Int'l Co., 550 U.S. at 421. Once it became clear that researchers could
35

maintain the efficacy of GA treatments while decreasing the total amount of the drug
patients received or the frequency with which they received it, there were only so many
combinations of dosage and frequency that they could study.
The 40mg dose was obvious to try because it was one of two doses studied
extensively. The prior art demonstrates that a number of studies looked at the safety,
efficacy, and tolerability of a 20mg dose and a 40mg dose. The 40mg dose was shown to
be as safe, effective, and tolerable as the 20mg dose. JTX7063 at 1. It was therefore
obvious for Plaintiffs to experiment with and have a reasonable probability of success with
that dose. See Hoffinann-La Roche, 748 F.3d at 1331 (holding that "a person skilled in the
art looking to scale to a monthly dose ... was faced with a very limited set of possibilities"
because "even though the 5 mg dose did not demonstrate greater efficacy than the 2.5 mg
dose, it was still deemed an equivalently effective dos.e so that someone scaling it to a
single monthly dose ... would have anticipated equivalent success").
There were also a finite number of days on which to administer injections
considering there are only seven days in a week. The prior art disclosed that administering
GA every other day was as effective as administering it every day, while decreasing the
adverse side effects associated with daily injections. JTX7078 at 4-5; JTX7089 at 4. At
the time of the priority date, those having ordinary skill in the art, including Teva, would
have known that researchers were pursuing even less frequent dosing. See DTXl 154 at 12 (investigating bi-weekly injections). This really left Teva with only two options that
were not already disclosed in the prior art and that allowed at least one day between
injections: (1) once-weekly injections; or (2) thrice-weekly injections.

36

The studies already completed .by those in the art provided more support for a
thrice-weekly injection regimen. It is well known that the FDA considers the safety and
efficacy of a proposed drug or clinical trial protocol before granting a pharmaceutical
manufacturer the ability to run those trials on human subjects. 21 C.F.R. § 312.56 (2016).
It is therefore not farfetched to assume a person of ordinary skill in the art would have been

motivated to pursue a regimen close .to the ones already known to be safe and effective.
See Allergan, 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
of ordinary skill would be motivated to develop a drug product and whether there was
skepticism regarding the efficacy of such a product."). Further, the decision to use a 40mg
GA dose with a thrice-weekly injection regimen was obvious to try because, again, it
increased the chances of FDA approval. The total weekly dose the patients would receive
under the new regimen was very close to the total weekly dose for the approved 20mg,
everyday regimen-120mg/week versus 140mg/week. Trial Tr. 940:17-941:13. Such
actions by Teva are actually supported by their disclosures to the FDA in the GALA
protocol.
The court recognizes that the GALA protocol is not prior art. The court agreed
with Defendants at trial, however, that the GALA protocol can properly be considered as
an admission of a party opponent. See Fed. R. Evid. 801 (d)(2). Similar to how the court
treated the Khan 2009 reference, the court will use Teva's admissions in the GALA
protocol to inform its analysis of the motivations of those having ordinary skill in the art at
the time of the invention. The statements that Teva made to the FDA in the GALA protocol

37

confirm the court's analysis and the art's inherent motivations to pursue a 40mg threetimes-a-week GA regimen.
Plaintiffs explained to the FDA that after the FORTE study demonstrated that a
higher dose is just as 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." JTX7022 at 21. The use of the 40mg dose and the characterization of the
FORTE study to the FDA as "show[ing] [a] similar quality? _safety and efficacy profile
compared to that of the GA 20mg dose" undermines Plaintiffs argument that the 40mg dose
was "dead" after FORTE. Id.
Plaintiffs also cited to the Fiechter and Khan 2008 studies to support their proposed
regimen because patients that participated in those studies "found the reduced frequency
regimens preferable and associated with a lower of [sic] injection related adverse events.
Id. Plaintiffs state that because the prior art studies were not large or well controlled, they

decided on a "conservative" regimen where the patients "[would] receive approximately
the same weekly dose, given by 3 subcutaneous injections instead of with a daily injection
frequency of 7 injections" and the "reduction in injection frequency would be offset by the
use of a higher dose already shown to be effective and safe in daily use." Id. This comports
with the court's finding that 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.
As part of the rationale for the three-injections-per-week dose regimen, Plaintiffs
explained to the FDA that such a schedule would be more convenient for patients,

38

enhancing long-term adherence. The court finds that Plaintiff's statement to the FDA
accurately reflects the motivations of those in the art. Defendants' expert, Dr. Green,
testified that those having ordinary skill in the art would have been motivated to pursue a
set dosing regimen where patients inject GA on three pre-determined days each week. Trial
Tr. 90017-901, 933:21-24, 972:9-13. Such a regimen would be more convenient for
patients than every-other-day dosing where the number of times and the days on which you
inject will differ depending on the week. This point is underscored by the fact that Rebif®,
another injectable MS treatment, was dosed three times a week. Id.. Plaintiffs claim that
those in the art would not have been motivated to pursue three injections per week based
on Rebif® because it was a completely different type of MS therapy. (D.I. 272 at 20). The
court disagrees, however, considering a study showed. that patient adherence to the Rebif®
regimen was better than it was for the 20mg daily GA regimen. JTX7069 at 3 (Global
Adherence Study). Even though Rebif® is a different MS drug with a different mechanism
of action, the court finds that 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.
Plaintiffs argue that their admissions to the FDA could not provide support for the
obviousness of the patents-in-suit because Defendants' admitted in emails and PowerPoint
presentations that it was unlikely Plaintiffs' would secure FDA approval with such little
evidence of efficacy. (D.I. 272 at 30). Defendants explain that their internal records only
show that they were "uncertain the FDA would grant approval to run trials comparing TIW
[three injections per week] to placebo (no treatment), instead of 20mg daily GA-not
whether GA TIW would itself show efficacy." (D.I. 273 at 26). Because the GALA
protocol proposed comparing 40mg, three-times-a-week to placebo and not 20mg GA

39

daily, it would not be possible to definitively show that the new regimen was worse,
equivalent, or better than 20mg every day.

Id.

The court agrees with Defendants

characterization of their statements in the PowerPoint presentation, and, accordingly, does
not find Plaintiffs arguments persuasive on this point.
Plaintiffs offer Momenta's Senior Vice President of Development and Chief
Medical Officer's deposition testimony as proof of nonobviousness. At his deposition, Dr.
Roach testified that he was personally not convinced by "an every-other-day dosing
schedule and wouldn't be surprised if other AEs show up with this higher dose." Trial Tr.
1506:2-6. The court, however, gives little weight to that statement. First, it appears that
Dr. Roach was talking about the GALA protocol, but the GALA protocol did not even
disclose an

every-other-~ay

dosing schedule. More important, Dr. Roach admitted that

most ofMomenta's work with GA had nothing to do with his group or his responsibilities.
Trial Tr. 1493:14-18. Dr. Roach also stated in his deposition that he was not familiar with
the pharmacokinectics of.GA in any significant detail. Id. at 19-21. It therefore does not
appear to the court that Dr. Roach could offer a credible opinion on the efficacy of everyother-day dosing or the adverse effects that may occur with a higher dose.
Plaintiffs maintain that a person having ordinary skill in the art would not have been
motivated to try dosing GA three times a week because those in the art believed that daily
injections of GA were necessary to maintain efficacy. (D.I. 272 at 22). Though the
mechanism of action for GA remains unknown, one of the proposed theories necessitates
constant activation of the GA T cells to enable them to cross the blood brain barrier and
overcome the constant pro-inflammatory effects of MS. JTX7120 at 3-4. Plaintiffs expert
argued that the only way to achieve that constant activation of the GA T cells was with

40

daily injections. Trial Tr. 1268:2-8. The court does not give much weight to this argument
because the prior art clearly establishes that many researchers were experimenting with
less frequent dosing of GA. See JTX7089 at 4; JTX7058; JTX7078; DTXl 154. Fiechter,
Khan 2008, Khan 2009, and Plaintiffs' own patent application all disclosed less frequent
dosing schedules. Fiechter and Khan 2008 showed that administering GA every other day
did not affect efficacy.

JTX7089 at 4; JTX7078 at 4-5. Teva's expert, Dr. Ziemssen,

also admitted that there is no paper suggesting that the activated GA T cells that cross the
blood-brain barrier die within 24 hours of activation. Trial Tr. 1435:17-21. The court thus
does not find that GA's mechanism of action teaches away from three-times-a-week
dosing.
Plaintiffs insist that because "GA is not a typical small molecule drug and has no
known [pharmacokinetic/pharmacodynamic] relationship ... the effect of any changes to
its regimen cannot be predicted." Therefore, even though the prior art discloses an everyother-day regimen with a 48-hour gap between doses, that would not have provided those
in the art with a reasonable expectation that a thrice-weekly regimen with a 72-hour gap
would be effective. Plaintiffs cite Jn re Cyclobenzaprine, 676 F.3d 1063 (Fed. Cir. 2012),
for the general proposition that when the pharmacokinetic/pharmacodynamic ("PK/PD")
profile of a drug is unknown, it is hard for skilled artisans to predict how changes to the
drug dosage form will change the effect that the drug renders on the body. See 676 F.3d at
1070.
The PK/PD profile represents the relationship between how a person's body
metabolizes a drug (PK) and how the drug effects the patient's body (PD). Id. at 1067. In
Cyclobenzaprine, the Federal Circuit overturned the district court's obviousness

41

conclusion. Id. at 1070. The district court concluded that the PK/PD relationship was
irrelevant to the obviousness inquiry because a skilled artisan would expect the extended
release formulation to have the same PD effect on the body if it mirrors the immediate
release formulation's PK profile. See id. The Federal Circuit found, to the contrary, that
though "it may have been obvious to experiment with the use of the same PK profile when
contemplating an extended-release formulation, there is nothing to indicate that a skilled
artisan would have had a reasonable expectation that such an experiment would succeed in
being therapeutically effective." Id. Cyclobenzaprine is inapposite to the issues currently
before the court.
In Cyclobenzaprine, the Federal Circuit explained that the district court "could not

find obviousness without finding that the prior art would have taught or suggested a
therapeutically effective formulation to one of ordinary skill in the art." Id. The record
was devoid of such evidence. Id. Here, the prior art suggests a number of therapeutically
effective dosing regimens for GA. See JTX7063 at 1 (demonstrating that a 40mg daily
formulation was safe and effective); JTX7078 at 4-5 (demonstrating that a 20mg everyother-day formulation was safe and effective).
Additionally, the fact that the PK/PD profile was unknown is irrelevant here. GA
is an immunomodulating drug that is not necessarily measurable in the bloodstream, and,
even if it is, measuring the levels in the blood does not indicate anything about the effect
of the drug on the patient. Trial Tr. 86:20-87:16. In fact, because the mechanism of action
for GA was unknown, there was absolutely no reason to believe that a gap of 72 hours
between injections would be detrimental, whereas a gap of 48 hours between injections
would be tolerable and effective. The contention that those in the art would have been

42

dissuaded from pursuing any gaps between dosing over 48 hours is further undermined by
the Khan 2009 study started two years before the priority date, studying a twice-weekly
GA dosing schedule. As a result, the court does not find Cyclobenzaprine instructive.

iv.

Obviousness of the '776 Patent

Teva asserts claims 1, 2, 5, 6, 9, 12, 16 and 17 of the '776 patent. The '776 patent claims
a 40 mg, thrice-weekly GA dosing regimen that reduces severity, not just frequency, of injection
site reactions and/or immediate post-injection reactions relative to the 20mg GA daily regimen.
The specification of the '776 patent defines tolerability as "associated with the frequency and
severity of post injection reactions and injection site reactions." JTX7003 at col.7, 11.38--42. The
court has already addressed why the claims directed to reducing the frequency of injection site
reactions are obvious. See supra § III(A)(3)(iv). The court finds that the claims directe~ to
reducing the severity of injection site reactions are also obvious.
Defendants' expert, Dr. Fox, testified at trial that those in the art consider lipoatrophy"the destruction of subcutaneous fat at the injection site," Trial Tr. 681 at 16-17-to be an
inherently severe injection site reaction. Trial Tr. 1580:12-19. Dr. Fox stated that "ifthere is a
decrease in the frequency of lipoatrophy, there would, by definition, then also be a decrease in the
severity of the adverse events." Id. As previously stated, the Caon prior art reference disclosed
that "[i]njection related lipoatrophy was significantly less" on the 20mg every-other-day regimen
than it was on the 20mg daily regimen. JTX7058 at 1. Though the court recognizes the
shortcomings of this testimony and the fact that it conflates frequency and severity, it nonetheless
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. See Hoffman-La Roche, 748

43

F .3d at 1331 (holding that prior art references need only demonstrate "a reasonable expectation of
success," not "conclusive proof of efficacy").
Teva stated in its press release summarizing the FORTE trial that the 40mg dose
"maintained the favorable safety and tolerability profile ofCOPAXONE® 20mg." JTX7035 at 1.
Dr. Klinger testified 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. Trial Tr.
230:3-6. Applying Dr. Klinger's testimony to Teva's statement in the press release, it follows
that the FORTE study showed that administering 40mg of GA daily to patients did not increase
the frequency or severity of injection site reactions. That understanding, combined with
previously mentioned prior art regarding the effects ofless frequent injections, would lead a
skilled artisan to expect a reduction in the frequency of inje~tions to lead to a reduction in the
severity of injection site reactions.
v.

Secondary Considerations of Nonobviousness
1. Long-felt Need and the Failure of Others

There existed a long-felt need in the art for a GA regimen not requiring everyday
injections. Evidence of a long-felt need is only probative of nonobviousness, however, when both
"a demand existed for the patented invention, and others tried but failed to satisfy that demand."
In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063,

1083 (Fed. Cir. 2012). Here, those having ordinary skill in the art did not try, but fail to find a
solution to the known issues with daily injections.
It is true that the court heard testimony on Teva's failed endeavors to find an alternate
dosage form. Trial Tr. 100:25-110:25. Among those failures were a higher molecular weight
version of COP AXONE® and an oral. formulation that would eliminate the need for injections all

44

together. Trial Tr. 109: 11-25. By the priority date, however, there were solutions in the prior art.
The Flechter and Khan 2008 studies demonstrated that less frequent injections could possibly lead
to increased tolerability. JTX7089 at 4; JTX7078 at 4--5. Teva even filed the Pinchasi
application, directed at solving the very problem they claim to solve with the patents-in-suit.
JTX7107 at 20, 22. It is not clear to the court why solutions to the known problem of patient
tolerability were not commercialized sooner, but the court does not think that this fact weighs in
Plaintiffs favor.
Defendants' expert, Dr. Hay, testified that Teva had several molecule patents that would
prevent another entity from commercializing a less frequently dosed GA product. Trial Tr. 1696
at 9-11. Plaintiffs tried to undermine Dr. Hay's testimony on blocking patents by noting that
Sandoz had filed an ANDA for. GA in 2008 and Momenta had filed a patent application for GA at
that time as well. Trial Tr. 1724: 17-21. It is not clear to the court exactly how those facts
undermine Dr. Hay's testimony. The court thus finds it plausible that the existence ofTeva's GA
patents could have deterred other large pharmaceutical companies from investing in research for a
less frequently dosed form of GA. See Galderma Laboratories, L.P. v. Tolmar, Inc., 737 F.3d ,at
740 (holding that any inference of non-obviousness gleaned from evidence of commercial success
is undermined when blocking patent preclude others from entering the market). The court does
not find that there was a long-felt, but unresolved need, probative of nonobviousness. Instead, the
court finds that the prior art disclosed solutions to the long-felt need, and Teva simply won the
race to the patent office.

45

2. Unexpected Results
A prima facie showing of obviousness can be rebutted by a demonstration of
"unexpected results"-"the claimed invention exhibits some superior property or advantage that a
person of ordinary skill in the relevant art would have found surprising or unexpected." In re

Soni, 54 F.3d 746, 750 (Fed. Cir. 1995). The court finds that the though the claimed invention
exhibits an advantage over the 20mg daily form of COPAXONE, that advantage was not
surprising or unexpected given the prior art studies.
The FORTE study showed that a 40mg dos_e of GA, administered daily, was as safe and
effective as a 20mg dose, and was not associated with more injection site reactions. JTX7063 at
1. Flechter and Khan 2008 showed that less :frequent dosing was as effective as every day
inj~ctions,

and less frequent dosing could reduce the number of injection site reactions patients

experienced as a result of the injections. JTX7089 at 4; JTX7078 at 4-5. Accordingly, the fact
that the 40mg dose, administered three times a week, was effective in reducing the number of
relapses, lesions, and injection site reactions was expected.
According to the Plaintiffs, a person of skill in the art would not have expected the 40mg,
three-times-a-week regimen to be as effective as 20mg daily, while also improving tolerability.
(D.I. 272 at 33). Plaintiffs maintain that an improvement in tolerability associated with a 40mg,

thrice-weekly dosing regimen for GA was not confirmed until the results of the GLACIER study
were published in 2015. Id. The court previously articulated why it was expected that a 40mg,
three-times-a-week dose would improve tolerability. See supra§ III(A)(3)(iv), (A)(4). The court
therefore finds that there were no unexpected results to support a finding of nonobviousness.
, At trial, Dr. Klinger testified that Teva's admissions to the FDA in the GALA protocol
were incorrect. To support a 40mg, three-times-a-week regimen, Teva cited to the FORTE,

46

Flechter, and Khan 2008 studies. JTX7022. Dr. Klinger agreed that the FORTE study provided
motivation to investigate the safety and efficacy of a reduced frequency injection. Trial Tr.
193:25-194:8. She disagreed, however, with the GALA protocol's use ofFlechter and Khan
2008 to support the three-times-a-week injection regimen. Trial Tr. 195:7-15; 198:6-13. The
court does not give much weight to Dr. Klinger's testimony. It appears to the court that Dr.
Klinger's testimony was offered as convenient support fora finding of unexpected results. Dr.
Klinger claims there was no preclinical or clinical data by the priority date to support the efficacy
and tolerability of the 40mg, three-times-a-week regimen. Trial Tr. 199:15-19. If the court were
to find Dr. Klinger's testimony credible, Teva would have administered a drug to hundreds of
chronically ill patients with no reasonable expectation that the drug would be effective, safe or
tolerable.
Dr. Klinger states that it was actually the TV-5010 clinical trial conducted by Teva that
convinced her that a 40mg, three-times-a-week dosage regimen could be effective and more
tolerable. Trial Tr. 226:24-227:7. TV-5010 was a mixture of peptides, very similar to
COP AXONE®, except, on average, it contained peptides with higher molecular weights. Trial
Tr. 106:10-18. Teva's admissions in the GALA protocol m:idermine the veracity of Dr. Klinger's
testimony because the protocol completely fails to mention the TV-5010 studies as a rationale for
the proposed dosage regimen. JTX7022 at 21. The inconsistencies between Dr. Klinger's
testimony and Teva's Gala protocol admissions serve to only further support the court's belief
that both Teva and Dr. Klinger were well aware of the race to patent a more tolerable form of
COPAXONE® 20mg daily. The court sees the '250, '413, '302, and '776 patents as nothing
more than "life-cycle management"-an attempt to continue to monopolize a multi-billion dollar
market for a blockbuster drug. See DTX1339 at 3 (recognizing that Teva was "playing against

47

the clock," so the short term objective for GA life-cycle management was to use current GA in a
"high dose (>20 mg) 2-3 times a week," which wouldn't require preclinical studies, to "fight
generics").
3. Commercial Success

The court gives little probative weight to the fact that COPAX ONE® 40mg was
commercially successful. The commercial success of an invention may be relevant to
nonobviousness if a nexus exists between the commercial success and the claimed invention.
Takai Corp. v. Easton Enterprises, Inc., 632 F.3d 1358,-1369 (Fed. Cir. 2011). If, however,
"commercial success is due to an element in the prior art, no nexus exists." Id.
No evidence was adduced at trial supporting a nexus between COPAXONE® 40mg,
three-times-a-week's success and features not already found in the prior art. No one disputes t~iat
COPAXONE® 40 is a successful drug. The court, however, finds Defendants' arguments
persuasive that COPAXONE® 40's success was due to "aggressive pricing, promotion, and
COPAXONE® brand loyalty." See Trial Tr. 1456:9-16; 1677:17-19 ("COPAXONE® 40 has,.
since the first month oflaunch, also been priced substantially lower than COP AXONE® 20,
roughly four to five hundred dollars lower on average."); DTX1491 at 1 ("Slide 10 in the pricing
assumptions you can see that we are planning a 10% increase on the 20mg in July of2015 to
increase the spread between 20mg and 40mg to help drive 40mg conversions."). The commercial
success ofCOPAXONE® 40mg, three-times-a-week thus does not undermine the court's
obviousness finding.
None of the secondary considerations warrant a finding of nonobviousness of the patentsin-suit.

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III.

CONCLUSION
In sum, the court finds that all asserted claims of the patents-in-suit are invalid as

Dated: January

J..Y, 2017

4

The court wishes to note that in IPR proceedings, the PTAB also found all claims of the '250, '413, and '302 patents
unpatentable. See Mylan Pharms. Inc. v. Yeda Research and Dev. Co., No. IPR2015--00643 (PTAB Aug. 24, 2016);
Mylan Pharms. Inc. v. Yeda Research and Dev. Co., No. IPR2015-00644 (PTAB Aug. 24, 2016); Mylan Pharms.
Inc. v. Yeda Research and Dev. Co., No. IPR2015--00830 (PTAB Sept. I, 2016). The patentees may appeal the
PTAB decisions to the Federal Circuit, potentially presenting an interesting procedural issue. If the Federal Circuit
chooses to hear the appeal from the PTAB and the Plaintiffs in this case decide to appeal to the Federal Circuit, two
essentially identical cases, albeit with different standards of proof, will be before the Federal Circuit.

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