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In re Copaxone Consolidated Cases

United States Court of Appeals, Federal Circuit

October 12, 2018


          Appeal from the United States District Court for the District of Delaware in Nos. 1:14-cv-01171-GMS, 1:14-cv-01172-GMS, 1:14-cv-01278-GMS, 1:14-cv-01419-GMS, 1:15-cv-00124-GMS, 1:15-cv-00306-GMS, Judge Gregory M. Sleet.

          John C. O'Quinn, Kirkland & Ellis LLP, Washington, DC, argued for plaintiffs-appellants. Also represented by Leslie M. Schmidt, New York, NY; Elizabeth Holland, Goodwin Procter LLP, New York, NY; William G. James, II, William M. Jay, Washington, DC; Daryl L. Wiesen, Boston, MA.

          Deanne Maynard, Morrison & Foerster LLP, Washington, DC, argued for defendants-appellees. Defendants-appellees Sandoz Inc., Momenta Pharmaceuticals Inc. also represented by Seth W. Lloyd; William A. Rakoczy, Matthew V. Anderson, Thomas Ehrich, Erin Forbes, Christopher Patrick Galligan, Deanne M. Mazzochi, Rachel Waldron, Rakoczy Molino Mazzochi Siwik LLP, Chicago, IL.

          Shannon Bloodworth, Perkins Coie, LLP, Washington, DC, argued for defendants-appellees. Defendants-appellees Mylan Pharmaceuticals Inc., Mylan Inc. also represented by Robert Swanson, Brandon Michael White; David Lee Anstaett, Madison, WI; Dan L. Bagatell, Hanover, NH; Christina Jordan McCullough, Seattle, WA.

          Frank D. Rodriguez, Budd Larner, P.C., Short Hills, NJ, for defendants-appellees Dr. Reddy's Laboratories Ltd, Dr. Reddy's Laboratories Inc. Also represented by Ellen Tchorni Lowenthal, Louis Harry Weinstein.

          Edward Anthony Figg, Rothwell, Figg, Ernst & Manbeck, PC, Washington, DC, for defendants-appellees Synthon Pharmaceuticals, Inc., Synthon B.V., Synthon S.r.o. Blansko. Also represented by Seth Edward Cockrum, Sharon Davis, Jennifer Nock, Brett Alan Postal.

          Anthony James Fitzpatrick, Duane Morris LLP, Boston, MA, for defendants-appellees Amneal Pharmaceuticals LLC, Amneal Pharmaceuticals Company GmbH, Pfizer Inc. Also represented by Vincent Capuano, Christopher S. Kroon; Patrick Gallagher, Boca Raton, FL.

          Before Reyna, Bryson, and Stoll, Circuit Judges.

          Reyna, Circuit Judge.

         Plaintiffs-Appellants Teva Pharmaceuticals USA, Inc., Teva Pharmaceutical Industries, Ltd., Teva Neuro-science, Inc., and Yeda Research and Development Co., Ltd., appeal the decision of the United States District Court for the District of Delaware invalidating all asserted claims of patents directed to COPAXONE® 40mg/mL, a product marketed for treatment of patients with relapsing forms of multiple sclerosis. Because the district court correctly held the asserted claims invalid as obvious under 35 U.S.C. § 103, we affirm.[1]


         I. Patents at Issue

         Yeda Research & Development Co., Ltd. is the assignee of U.S. Patent Nos. 8, 232, 250, 8, 399, 413, 8, 969, 302, and 9, 155, 776 (the '250, '413, '302, and '776 patent, respectively), all entitled "Low Frequency Glatiramer Acetate Therapy." The patents, collectively referred to as the "Copaxone patents," share a common specification and claim priority to the same two provisional applications. J.A. 57-69. The earliest priority date of the Copaxone patents is August 20, 2009. J.A. 23.

         The Copaxone patents describe and claim COPAXONE® 40mg/mL, a treatment for relapsing-remitting multiple sclerosis ("RRMS"). RRMS is a form of multiple sclerosis, an autoimmune disorder that causes the body's immune system to attack the central nervous system. RRMS is characterized by unpredictable relapses followed by periods of remission with no new signs of disease activity.

         The active ingredient in COPAXONE® 40mg/mL is glatiramer acetate ("GA"), a synthetic mixture of polypep-tides. GA is also known as "copolymer 1" or "Cop. 1." COPAXONE® 40mg/mL is supplied as a single-dose prefilled syringe. Broadly, the treatment consists of the injection of 40mg of GA three times a week, abbreviated "40mg GA 3x/week." Relevant to this appeal, side effects of GA injections include injection-site reactions ("ISRs") and immediate post-injection reactions ("IPIRs"). ISRs are physical symptoms at the injection site, such as swelling or itchiness. IPIRs are reactions immediately following an injection, such as flushes, sweating, or palpitations.

         Prior to COPAXONE® 40mg/mL, in 1996 the Food and Drug Administration ("FDA") approved COPAXONE®20mg/mL, a regimen consisting of the daily injection of 20mg GA. Daily GA injections were known to subject patients to discomfort, including side effects in the form of ISRs and IPIRs. J.A. 20692.

         For analyzing the obviousness of the Copaxone patents in this case, a key limitation of the asserted claims is the administration of a 40mg GA dose in three subcutaneous injections over seven days. Claim 1 of the '250 patent is representative:

1. A method of alleviating a symptom of re-lapsing-remitting multiple sclerosis in a human patient suffering from relapsing-remitting multiple sclerosis or a patient who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis comprising administering to the human patient a therapeutically effective regimen of three subcutaneous injections of a 40 mg dose of glatiramer acetate over a period of seven days with at least one day between every subcutaneous injection, the regimen being sufficient to alleviate the symptom of the patient.

'250 patent col. 16 ll. 35-45.

         Apart from claim 1 of the '302 patent, [2] all asserted independent claims require at least one day between doses. '250 patent col. 16 ll. 35-45, col. 17 l. 25-col. 18 l. 6; '413 patent col. 16 ll. 26-36, col. 18 ll. 14-28; '302 patent col. 17 ll. 4-12; '776 patent col. 16 ll. 35-50, col. 16 l. 61- col. 17 l. 19, col. 17 ll. 37-54, col. 17 l. 65-col. 18 l. 22. Certain dependent claims of the '250, '413, and '776 patents further require improved tolerability and/or reduced frequency of injection reactions in the claimed regimen as compared to a 20mg GA daily regimen. See, e.g., '250 patent col. 17 ll. 21-24, col. 18 ll. 7-15; '413 patent col. 16 ll. 51-54; '776 patent col. 16 ll. 51-54, col 17 l. 65-col. 18 l. 25..

         The '776 patent contains additional limitations, namely, the requirement that the 40mg GA 3x/week regimen "reduce[] severity of injection site reactions" compared to a 20mg daily regimen, as seen in claim 1:

1. A method of treating a human patient suffering from a relapsing form of multiple sclerosis, while inducing reduced severity of injection site reactions in the human patient relative to administration of 20 mg of glatiramer acetate s.c. daily, the method consisting of one subcutaneous injection of 1 ml of a pharmaceutical composition comprising 40 mg of glatiramer acetate on only each of three days during each week of treatment with at least one day without a subcutaneous injection of the pharmaceutical composition between each day on which there is a subcutaneous injection, wherein the pharmaceutical composition is in a prefilled syringe, and wherein the pharmaceutical composition further comprises mannitol and has a pH in the range 5.5 to 7.0, so as to thereby treat the human patient with reduced severity of injection site reactions relative to administration of 20 mg of glatiramer acetate s.c. daily.

'776 patent col. 16 ll. 35-50 (emphasis added).

         II. Prior Art References

         The first clinical trial for using GA to treat multiple sclerosis took place in 1987 by Dr. Bornstein et al. ("Born-stein"), [3] which was followed by a Teva Phase III clinical trial in 1995. Both Bornstein and the Phase III trial tested 20mg GA daily. J.A. 20378-84, 20464-20782. Since GA was developed in an expedited manner under orphan drug status in the United States at a time when no other disease modifying multiple sclerosis treatments were available, the 20mg/day dose was selected without performing conventional optimal-dose-finding studies. J.A. 24967.

         The Bornstein study showed that GA administered subcutaneously for two years at a daily dose of 20mg "produced clinically important and statistically significant beneficial effects." J.A. 20383. Participants in both Bornstein and the Phase III trial reported ISRs and IPIRs as side effects. J.A. 20383, 20480. The Phase III trial noted "adverse experience" as the main reason contributing to patient dropout, and "[t]he most common adverse event associated with dropout was injection site reaction." J.A. 20480. A Phase III trial reviewer made recommendations for future researchers to explore dose-response and dose-ranging studies, asking "Is 20 mg the optimum dose? Are daily injections necessary?" J.A. 20502.

         In 1996, following both Bornstein and the Phase III clinical trial, FDA approved Teva's New Drug Application ("NDA") for COPAXONE® 20mg, 20mg GA injected daily. In its 1996 Summary Basis of Approval ("SBOA"), FDA recommended that Teva "evaluate the necessity of daily [GA] injections as opposed to more infrequent intermittent administration of the drug" because the daily dosing regimen "seems like it would subject the patient to an excessive amount of discomfort if it is not necessary to maintain efficacy." J.A. 20692.

         A 2002 study by Flechter et al.[4] ("Flechter") evaluated the treatment of RRMS with 20mg of GA administered every other day. J.A. 20436-40. Flechter concluded that "alternate-day treatment with Copolymer 1 is safe, well tolerated, and probably as effective as daily Copolymer 1 in reducing relapse rate and slowing neurologic deterioration." J.A. 20440. Flechter also noted that patient dropout rates decreased when GA was administered every other day as opposed to daily. J.A. 20440 ("It should be stressed that the dropout rate was lower in the alternate-day group than in the daily-injection regime (39.7% versus 60.3%, p < 0.01).").

         Cohen, [5] published in 2007, was a "double-blind, dose-comparison study of glatiramer acetate in relapsing-remitting MS." J.A. 20388-95. Cohen compared daily subcutaneous injections of 20mg and 40mg GA dosages, and concluded that the 40mg dose may be "more effective" than the 20mg dose "in reducing MRI activity and clinical relapses." J.A. 20389. Cohen also noted that the onset of action of the 40mg dose is more rapid compared to 20mg. J.A. 20394. ISRs were the most frequent adverse event for both doses, occurring at roughly equal rates. J.A. 20392-93. IPIRs occurred more frequently in the 40mg group than the 20mg group. Id. Cohen thus concluded that the overall safety and side effect profile of the 40mg dose was "similar" to the 20mg dose, but "was associated with a greater incidence of certain adverse effects." J.A. 20394.

         Teva's own prior art patent application, International Patent Application No. WO 2007/081975, Method of Treating Multiple Sclerosis ("Pinchasi"), was published shortly after the Cohen study. J.A. 20925-56. Pinchasi discloses a 40mg GA, every other day dosing regimen for the treatment of RRMS. Pinchasi cites to the data from Cohen to conclude that "[t]he increased efficacy observed with 40 mg/day GA in reducing MRI-measured disease activity and relapse rate indicates that it is well tolerated and can improve the treatment of RRMS patients. The improvement in efficacy, however, is not accompanied by a corresponding increase of adverse reactions which would be expected upon a doubling of the administered dose." J.A. 20944.

         The FORTE study, [6] published in 2008, evaluated the safety, tolerability, and efficacy of 40mg GA compared to 20mg GA. J.A. 20411, 20414-22. FORTE concluded that both the 40mg and 20mg doses "were equally effective in reducing clinical relapses and MRI activity," and that the 40mg dose has a "safety profile similar to that observed in previous studies of 20mg GA." J.A. 20411. FORTE also confirmed Cohen's finding that the 40mg dose provided an earlier onset of action. J.A. 20422 (noting a "[t]rend for an earlier effect of high [40mg] dose on MRI activity").

         A 2008 study by Omar Khan and others[7] ("Khan 2008") compared the effect of daily versus every other day administration of 20mg GA subcutaneous injections for the treatment of RRMS. J.A. 20883. The study abstract noted that although the recommended dose for treating RRMS is daily 20mg GA injections, "the optimal dose remains unknown" and that there is "considerable interest in alternate dosing regimens of GA" because daily injections "can be challenging for long-term patient compliance." J.A. 20883. Thirty patients were randomly assigned to receive 20mg GA dosed daily or every other day. After two years, there were "no differences" between the two groups in relapse rate or disease progression. J.A. 20883. Additionally, after the first two years elapsed, patients in each group were given the option to continue or switch groups, and were monitored for an additional two years. Every patient in the daily group opted to switch to every other day administration. After four years, there was no difference between the crossover group and the group that was always dosed every other day. The Caon reference, [8] published in 2009, reports the same data from the Khan 2008 study, but further noted that "[i]njection related lipoatrophy was significantly less" in the every other day group. J.A. 20386.

         III. State of the Art References

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;There are two additional references relevant to this appeal, a 2009 study by Omar Khan[9] ("Khan 2009") and Teva's own Glatiramer Acetate Low-frequency Administration ("GALA") Phase III trial of 40mg GA administered three times per week. J.A. 23904-05, J.A. 8246- 8417. Khan 2009 and GALA were both published after August 20, 2009, the ...

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