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Yeda Research and Development Co., Ltd. v. Mylan Pharmaceuticals Inc.

United States Court of Appeals, Federal Circuit

October 12, 2018


          Appeals from the United States Patent and Trademark Office, Patent Trial and Appeal Board in Nos. IPR2015-00643, IPR2015-00644, IPR2015-00830, IPR2015-01976, IPR2015-01980, IPR2015-01981.

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

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

          Anthony James Fitzpatrick, Duane Morris LLP, Boston, MA, for appellee Amneal Pharmaceuticals LLC. Also represented by Vincent Capuano, Christopher S. Kroon; Patrick Gallagher, Boca Raton, FL.

          Before Reyna, Bryson, and Stoll, Circuit Judges.

          Reyna, Circuit Judge.

         In this consolidated appeal, Appellant Yeda Research & Development Co., Ltd. challenges the Patent Trial and Appeal Board's final written decisions finding the claims of U.S. Patent Nos. 8, 232, 250, 8, 399, 413, and 8, 969, 302 unpatentable as obvious in three inter partes review proceedings. We affirm the Board's decisions.[1]


         I. Patents at Issue

         Yeda Research and Development Co., Ltd. ("Yeda") is the assignee of U.S. Patents Nos. 8, 232, 250, 8, 399, 413, and 8, 969, 302 (the '250, '413, and '302 patents, respectively), all entitled "Low Frequency Glatiramer Acetate Therapy." The patents, collectively referred to as the "Copaxone patents," share a common specification and claim priority to the same two provisional applications. See J.A. 267, 279, 291. The earliest priority date of the Copaxone patents is August 20, 2009. Id.

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

         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. 6956.

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

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

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

         Certain claims of the '250 and '413 patents further require improved tolerability and/or reduced frequency of injection reactions in the claimed regimen as compared to 20mg daily. '250 patent col. 17 l. 24-col. 18 l. 6; '413 patent col. 16 ll. 51-54.

         Apart from claim 1 of the '302 patent, all independent claims require at least one day between doses. '250 patent col. 16 ll. 35-45, col. 17 l. 25-col. 18 l. 6, col. 18 ll. 19-26; '413 patent col. 16 ll. 26-36, col. 18 ll. 1-13, col. 18 ll. 14-28; '302 patent col. 17 ll. 4-12. Claim 1 of the '302 patent does not specify any particular interval between doses, but dependent claims 4 and 5 limit injections to certain combinations of days of the week, all with at least one day between injections, and independent claim 10 of the '302 patent requires that the injection be administered "three times per week with at least one day between every subcutaneous injection." '302 patent col. 16 ll. 37-41, col. 16 ll. 47-58, col. 17 ll. 4-12.

         II. Prior Art References

         The first clinical trial for using GA to treat multiple sclerosis was in 1987 by Dr. Bornstein et al. ("Bornstein"), [2] which was followed later by a Teva Phase III clinical trial in 1995. Both Bornstein and the Phase III trial tested 20mg GA daily. J.A. 7279- 80, 7282-85, 6895-7235. The 20mg/day dose was selected without performing conventional optimal-dose-finding studies. J.A. 7239.

         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. 7284. Participants in both Bornstein and the Phase III trial reported ISRs and IPIRs as side effects. J.A. 7284, 6934. The Phase III trial noted "adverse experience" as the main reason contributing to patient dropout, and "[t]he most common adverse event associated with dropout was injection site reaction." J.A. 6934. A Phase III trial reviewer made recommendations for future researchers to explore dose-response and dose-ranging studies, asking "Is 20 mg the optimum dose? Are daily injections necessary?" J.A. 6956.

         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"), the FDA recommended that Teva "evaluate the necessity of daily [GA] injections as opposed to more infrequent intermittent administration of the drug" because the daily dosing regimen "seems like it would subject the patient to an excessive amount of discomfort if it is not necessary to maintain efficacy." J.A. 7146.

         A 2002 study by Flechter et al.[3] ("Flechter") evaluated the treatment of RRMS with 20mg of GA administered every other day. J.A. 7236-40. Flechter concluded that "alternate-day treatment with Copolymer 1 is safe, well tolerated, and probably as effective as daily Copolymer 1 in reducing relapse rate and slowing neurologic deterioration." J.A. 7240. Flechter also noted that patient dropout rates decreased when GA was administered every other day as opposed to daily. J.A. 7240 ("It should be stressed that the dropout rate was lower in the alternate-day group than in the daily-injection regime (39.7% versus 60.3%, p < 0.01).").

         A prior art patent application, International Patent Application No. WO 2007/081975, Method of Treating Multiple Sclerosis ("Pinchasi"), was published in 2007. J.A. 6857-88. Pinchasi discloses a 40mg GA, every other day dosing regimen for the treatment of RRMS. Pinchasi cites to the data from Cohen, another GA study, to conclude that "[t]he increased efficacy observed with 40 mg/day GA in reducing MRI-measured disease activity and relapse rate indicates that it is well tolerated and can improve the treatment of RRMS patients. The improvement in efficacy, however, is not accompanied by a corresponding increase of adverse reactions which would be expected upon a doubling of the administered dose." J.A. 6876.

         III. State of the Art Reference

         There is an additional reference relevant to this appeal, a 2009 study by Omar Khan[4] ("Khan 2009"). J.A. 9331-32. Khan 2009 was published three weeks after August 20, 2009, the priority date of the asserted patents, and thus does not qualify as statutory prior art, but the study began two years earlier. J.A. 9331-32. The study abstract noted that "[t]here is considerable interest in studying a more patient friendly dosing regimen of GA that may be as efficacious and better tolerated than daily GA." J.A. 9331. Following the results of an earlier study, Khan 2008, showing that alternate day administration of GA appears to be as effective as daily administration, Khan 2009 compared 20mg GA administered twice a week to 20mg GA administered daily in a pilot, prospective, randomized, and rater-blinded two-year study. J.A. 9331; see infra note 8.

         IV. Proceedings before the Board

         Mylan Pharmaceuticals, Inc. ("Mylan") filed petitions for inter partes review ("IPR") in IPR2015-00643, IPR2015-00644, and IPR2015-00830, challenging all claims of the '250, '413, and '302 patents, respectively, on grounds pursuant to 35 U.S.C. §§ 102 and 103. The Patent Trial and Appeal Board (the "Board") instituted review of all claims of the Copaxone patents on two grounds: obviousness over Pinchasi in view of FDA's 1996 SBOA, and over Pinchasi in view of Flechter.[5] J.A. 644 (instituting IPR on the '250 patent), 1720-21 ('413 patent), 2710- 11 ('302 patent). Subsequently, Amneal Pharmaceuticals LLC filed for each patent substantially identical petitions to those already filed by Mylan, and moved to join Mylan's proceedings. The Board subsequently consolidated Amneal Pharmaceuticals' petitions with those already filed by Mylan. J.A. 894-898, 1970-74, 3489-95. Amneal Pharmaceuticals and Mylan are collectively referred to as "Petitioners."

         The Board's analysis of the independent claims was similar for all three patents. The Board first noted that Pinchasi discloses every limitation of the independent claims of the Copaxone patents, except for the dosing regimen of three doses per seven day period. The Board found that a person of ordinary skill in the art ("POSITA") would have been motivated to use a 40mg dose, crediting the testimony of Petitioners' expert, Dr. Green, who noted that Pinchasi demonstrated increased efficacy of 40mg GA compared to 20mg with no significant difference in side effects, and citing Cohen, [6] a study which concluded that daily administration of 40mg GA was effective, safe, and well tolerated. In reaching this finding, the Board also found that FORTE, [7] a phase III clinical trial comparing 40mg GA and 20mg GA, would not have taught away from using 40mg because it did not criticize, discredit, or discourage the 40mg GA dose.

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The Board next considered whether there was a motivation to modify Pinchasi&#39;s 40mg every other day regimen. The Board noted that the difference between the challenged claims (6 doses over 2 weeks) and Pinchasi (7 doses over 2 weeks) was only one less injection every two weeks. The Board then found motivation to eliminate one injection every other week to increase patient compliance, relying in part on Petitioners&#39; expert Dr. Green, who testified that decreasing the frequency of injections helps with patient adherence to a treatment regimen, and FDA&#39;s 1996 SBOA, which recommended that the necessity of daily injections, as opposed to less frequent administration, be evaluated. The Board further relied on other prior art references, including Flechter, Khan 2008, [8] and Caon, [9] which showed that alternate-day dosing of 20mg was safe, well-tolerated, as effective as daily 20mg, reduced injection reactions, and ...

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