Glatiramer acetate - USA

On Oct 12, 2018 Federal Circuit  affirmed decisions of Delaware court and the Patent Trial and Appeal Board that patents on Teva's blockbuster multiple sclerosis drug Copaxone are invalid.

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; 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. The earliest priority date of the Copaxone patents is August 20, 2009. 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. 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. 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. All asserted independent claims require at least one day between doses.

The district court held a seven-day bench trial during which it considered the invalidity of the asserted claims of the Copaxone patents by defendants (Sandoz, Momenta, Dr Reddy’s, Mylan, Synthon, Amneal & Pfizer). The district court found that a 40mg GA dose was explicitly disclosed in references that predate the Copaxone patents, specifically Cohen, Pinchasi, and FORTE. The court rejected Teva’s arguments that Cohen and FORTE taught away from a 40mg dose, and that a person of ordinary skill in the art (“POSITA”) would have thought that 20mg was the optimal dose. The district court also found that, as of the priority date, POSITAs knew that daily injections of 20mg were difficult to tolerate based on the 1996 FDA SBOA, Flechter, and Khan 2008. Relying in part on trial testimony, the district court found that POSITAs were familiar with the adverse reactions, pain, and treatment adherence problems associated with daily injections, and would have been motivated to pursue less frequent dosing with a reasonable probability of success. In light of these factual findings, the district court concluded that a 40mg GA 3x/week dosage would be obvious to try, noting that there were only two tested dosage amounts in the prior art—20mg and 40mg—and that researchers were pursuing less frequent dosing regimens while recognizing there are a limited number of days in a week on which to test frequency. The court recognized that obvious-to-try logic is not always appropriate, but found that “[h]ere, there was market pressure to solve a known problem—the fact that many MS patients could not tolerate daily injections—and there were a finite number of predictable solutions that a person of ordinary skill in the art would have good reason to pursue.”

Teva appealed. On appeal, Teva disputed that the 40mg GA 3x/week dosing regimen disclosed in the Copaxone patents would have been obvious to a person of skill in the art. Teva also appealed the invalidation of claim limitations in the ’250 and ’413 patents relating to improved tolerability and reduced frequency of adverse effects, and the invalidation of the ’776 patent’s claims relating to reduced severity of injection site reactions. Teva contended that the district court erred in finding the claimed 40mg GA 3x/week dosing regimen obvious. Specifically, Teva argued that the district court impermissibly relied on hindsight and an improper “obvious to try” analysis, and analyzed the obviousness of individual claim elements, rather than the invention as a whole. Federal circuit, however, disagreed & said that here the prior art focused on two critical variables, dose size and injection frequency, and provided clear direction as to choices likely to be successful in reducing adverse side effects and increasing patient adherence. As of the priority date, only two GA dose sizes had been shown to be effective, safe, and well-tolerated: 20mg and 40mg. Concerning frequency, the 1996 FDA SBOA, Flechter, and Khan 2008 all encouraged POSITAs to pursue a less frequent than daily dosing regimen; these references indicated that less frequent injections of GA were just as effective as daily injections, and less frequent injections improved patient adherence and reduced adverse reactions. Given this motivation, a POSITA had only a limited number of permutations of dose and frequency to explore that were not already disclosed in the prior art. The district court also gave appropriate weight to the testimony of Dr. Green regarding patient compliance with thrice-weekly administrations and the Rebif® regimen, noting that “even though Rebif® is a different MS drug with a different mechanism of action, those in the art would still be motivated to try dosing GA three times a week based on the higher rates of patient adherence to the Rebif® therapy. Teva made numerous challenges to factual findings by the district court, none of which court found persuasive. Federal circuit finally held that the 40mg GA 3x/week regimen is obvious in light of the prior art, and found no clear error in district court’s analysis.

Next, Teva argued that the prior art did not lead POSITAs to expect improved tolerability and reduced frequency of injection reactions from the claimed regimen compared to 20mg GA daily. Claims 14, 16, and 17 of the ’250 patent and claim 7 of the ’413 patent require that the 40mg GA 3x/week regimen reduce the frequency of injection reactions relative to the daily 20mg GA regimen. Claim 15 of the ’250 patent, on which claims 16 and 17 depend, requires that the claimed regimen improve tolerability as compared to the daily 20mg regimen. Federal circuit disagreed, and found no clear error in the district court’s findings regarding Khan 2008, Caon, and Flechter, all of which demonstrate that improved tolerability and less frequent injection reactions were expected from the claimed less frequent regimen, as compared to 20mg daily. Thus finally federal circuit concluded that the district court did not err in invalidating all asserted claims of the Copaxone patents as obvious.

PTAB proceedings:

Alternatively in PTAB, Mylan filed petitions for inter partes review (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. Subsequently, Amneal later filed the petitions & joined IPR. The Board concluded that, in light of the evidence presented, a POSITA would have had a reason to modify Pinchasi’s dosing regimen of 40mg GA every other day to 40mg GA 3x/week, thus rendering the claimed 40mg 3x/week limitation obvious. Federal circuit here also found no error in the Board’s finding of obviousness & affirmed the decision.