Teva Pharms. USA, Inc. v. Sandoz Inc.

The Federal Circuit concluded that the district court did not err in invalidating all asserted claims of the Copaxone patents as obvious.

October 12, 2018

GENERICally Speaking

Case Name: Teva Pharms. USA, Inc. v. Sandoz Inc. (In re Copaxone Consol. Cases), 906 F.3d 1013, Fed. Cir. No. 2017-1575, 2018 U.S. App. LEXIS 28751 (Fed. Cir. Oct. 12, 2018) (Circuit Judges Reyna, Bryson, and Stoll; Opinion by Reyna, J.) (Appeal from D. Del., Sleet, J.) 

Drug Product and Patent(s)-in-Suit: Copaxone® (glatiramer acetate (“GA”)); U.S. Patents Nos. 8,232,250 (“the ’250 patent”), 8,399,413 (“the ’413 patent”), 8,969,302 (“the ’302 patent”), and 9,155,776 (“the ’776 patent”)

Nature of Case and Issue(s) Presented: Plaintiff Teva manufactured and marketed Copaxone, a glatiramer acetate injection for the treatment of relapsing-remitting multiple sclerosis. Defendants Sandoz, Momenta, Dr. Reddy’s Laboratories, Mylan, and Amneal submitted ANDAs to the FDA for approval to engage in the manufacture and sale of generic versions of Copaxone 40 mg administered thrice weekly. Teva sued the generic manufacturers in the District of Delaware. After a seven-day bench trial, the district court determined that the asserted claims of the Asserted Patents were invalid as obvious. Teva appealed, and the Federal Circuit affirmed the district court’s ruling.

Why Defendants Prevailed: The claim limitations at issue on appeal were: (i) administration of a 40 mg dose in three subcutaneous injections over seven days; (ii) improved tolerability and/or reduced frequency of injection reactions in the claimed regimen as compared with 20 mg daily regimen; and (iii) reduced severity of injection site reactions. The district court found that claims containing these limitations were obvious over the following prior art:

  • Bornstein and Teva Phase III Clinical Trial: Tested 20mg GA and showed that GA administered daily for two years produced beneficial effects, but that the main reason contributing to patient dropout was injection-site reactions. Recommended that future researchers explore dose-response and dose-ranging studies, and raised the question of whether 20mg was the optimum dose and whether daily injections were necessary;
  • FDA approval of Copaxone 20 mg: the FDA recommended that Teva evaluate the necessity of daily injections as opposed to more infrequent administration because a daily-dosing regimen may subject patients to unnecessary discomfort;
  • Fletcher: Evaluated 20 mg dose administered every other day and determined that such treatment was safe, well tolerated, and probably as effective as daily administration. Also noted that patient dropout rates decreased with every-other-day administration versus daily administration;
  • Cohen: Conducted comparison of 20mg versus 40mg daily injections and concluded that 40 mg was more effective. Also noted that the onset of action for the 40 mg dose was faster than for the 20 mg dose, but 40 mg was associated with a greater incidence of certain adverse effects;
  • Pinchasi: Disclosed a 40 mg GA, every-other-day dosing regimen;
  • Forte: Evaluated the safety and efficacy of 40 mg GA compared to 20 mg GA and concluded both doses were equally effective and had similar safety profiles. Confirmed that the 40 mg dose had earlier onset of action; and
  • Khan: Compared the effect of daily versus every-other-day administration of 20 mg GA injections. Noted there was considerable interest in alternative dosing regimens given that daily injections were challenging for long-term patient compliance. Found that after two years, there was no difference between the group dosed daily and the group dosed every other day.

The district court also considered references that were not prior art but that showed the “state of the art” at the time of the invention. Those references noted that there was interest in alternative dosing regimens and that the natural next step was to reduce the dosing regimen of GA.

The district court found that a 40 mg GA dose was explicitly disclosed in the prior-art references, specifically Cohen, Pinchasi, and Forte. The district court also found that a POSA would have known that daily injections were difficult to tolerate based on the FDA’s statements, Fletcher, and Khan. Based on trial testimony, the district court found that a POSA would have been familiar with adverse reactions, pain, and treatment-adherence problems and would have been motivated to pursue less-frequent dosing with a reasonable expectation of success. The district court therefore concluded that it would have been obvious to try a 40 mg GA 3x/week dosage. The court also considered objective indicia of nonobviousness and concluded that none of them warranted a finding of non-obviousness.

Teva argued on appeal that the district court erroneously construed certain claim terms as non-limiting and disregarded them for non-obviousness purposes. The district court construed certain claim terms (“sufficiency,” “reduced frequency of relapse,” and “effectiveness”) to be non-limiting statements of intended effect, based on Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368 (Fed. Cir. 2001). The Federal Circuit agreed, finding no error in the district court’s construction.

Teva next argued that the district court erred in finding the claimed 40 mg-GA-3x/week-dosing regimen obvious. Specifically, Teva argued the district court used impermissible hindsight and an improper “obvious to try” analysis, and analyzed obviousness of individual claim elements rather than analyzing the claims as a whole. The Federal Circuit held that this case fell into neither of the two categories it recognizes as impermissible “obvious to try” analyses, which include (i) to vary all parameters or try every available option until one succeeds, where the prior art gave no indication of critical parameters and no direction as to which of many possibilities is likely to be successful; or (ii) to explore a new technology or general approach in a seemingly promising field of experimentation, where the prior art gave only general guidance as to the particular form or method of achieving the claimed invention.

Here, the Federal Circuit found that 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. Only two dose sizes had been shown to be effective and the prior art encouraged POSAs to pursue a less-frequent-than-daily dosing regimen. A POSA had only a limited number of permutations of dose and frequency to explore, and a 40-mg-GA-3x/week regimen would result in a total weekly dose very close to the already approved 20 mg daily regimen. Thus, a POSA would have had a reasonable expectation of success in terms of effectiveness, patient adherence, and FDA approval.

The Federal Circuit further held that the district court did not use hindsight analysis as there was plenty of evidence on which to find a 40-mg-GA-3x/week regimen obvious to try. The Federal Circuit explained that while the universe of doses is theoretically unlimited, there were only two dosages in the prior art that had clinical support: 20 mg and 40mg. Further, the prior art clearly indicated that less-frequent doses should be explored. The Federal Circuit also explained that it found no merit in Teva’s argument that the district court separately analyzed the 40 mg dose limitation and the 3x/week limitation. The district court spent considerable time discussing why the combination of dose and frequency was obvious to try.

The Federal Circuit next addressed Teva’s challenges to the district court’s factual findings, finding them unpersuasive. Finally, the court addressed Teva’s argument based on In re: Cyclobenzaprine, 676 F.3d 1063 (Fed. Cir. 2012), holding that it did not establish a rule that categorically precluded obviousness findings without pk/pd data. Further the court distinguished the case because there, the obviousness proof relied entirely on bioequivalence of certain pk profiles. Here, bioequivalence was not argued and obviousness was shown through human clinical studies that established safety and efficacy of GA doses and dose frequencies similar to the claimed regimen.

The Federal Circuit therefore held that the 40mg-GA-3x/week regimen was obvious in light of the prior art, and found no clear error in the conclusion that a POSA would have been motivated to combine the 40 mg dose, which was proven effective, with a 3x/week frequency, which was desirable for increased patient adherence while maintaining efficacy.

Certain claims required that the 40 mg GA 3x/week dosing regimen reduce the frequency of injection reactions relative to the 20 mg daily regimen. Other claims required that the claimed regimen improve tolerability relative to the 20 mg daily regimen.

Teva argued that the prior art did not lead POSAs to expect improved tolerability and reduced frequency of injection reactions from the claimed regimen. The Federal Circuit disagreed, stating that the prior-art references demonstrated that improved tolerability and less-frequent injection reactions were expected from a less-frequent regimen than 20 mg daily.

Certain claims contain additional limitations requiring that the 40-mg-GA-3x/week regimen reduce severity of injection-site reactions as compared with the 20mg daily regimen. Teva argued that the district court erroneously conflated frequency of injection reactions with severity of injection reactions and that evidence of reduced frequency of injection reactions cannot prove reduced severity. The Federal Circuit agreed that the two concepts were distinct, but concluded that in certain instances they are related, and thus the district court did not err. The Federal Circuit held that the prior art showed that reducing the frequency of injections from daily to every other day resulted in “significantly less lipoatrophy,” a severe injection reaction. The court explained that the statement could mean that the lipoatrophy either occurred less frequently with less-frequent injections or that the expression of lipoatrophy itself was less severe. Either way, it was not unreasonable for the district court to conclude that POSA would think it obvious that the 40-mg-GA-3x/week regimen, with its less-frequent injections, would result in reduced severity of at least one injection-site reaction.

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