On October 17, 2016, the PTAB declined the requests of Swiss Pharma International AG (“Swiss Pharma”) in cases IPR2016-00912, IPR2016-00915, and IPR2016-00916 to institute inter partes reviews (“IPRs”) of three patents owned by Biogen Idec MA, Inc. (“Biogen”). The patents-at-issue—U.S. Patent 8,815,236 B2 (“the ’236 patent”), U.S. Patent 8,349,321 B2 (“the ’321 patent”), and U.S. Patent 8,900,577 B2 (“the ’577 patent”)—relate to certain stable, high concentration formulations of the humanized monoclonal antibody natalizumab. Natalizumab is commercialized by Biogen as TYSABRI® for use in treating multiple sclerosis.
Claim 1 of the ’577 patent recites:
1. A stable, aqueous pharmaceutical formulation comprising from about 20 mg/ml to
about 150 mg/ml of natalizumab, polysorbate 80 present in an amount of about
0.001% to 2% (w/v), about 10 mM phosphate buffer, and about 140 mM NaCl.
The claims of the ’321 patent recite similar formulations with the narrower range of natalizumab (20 mg/ml), wherein the pH of the formulation is 6.1. The claims of the ’236 patent recite a method of treatment of multiple sclerosis using the formulation claimed in the ’577 patent.
In each of the three cases, Swiss Pharma asserted obviousness based on the same two grounds. In the first ground, Swiss Pharma asserted that the antibody formulations claimed by Biogen were obvious in view of certain prior art references that disclosed the identical claimed excipients, but for other IgG monoclonal antibodies (“mAb”) antibody formulations, in combination with references disclosing that 3 mg of natalizumab per kg of body weight is therapeutically effective in the treatment of inflammatory bowel disease. Swiss Pharma argued that it would be a “simple substitute” for a POSA to replace natalizumab for the other IgG mAbs in the prior art formulations.
In the second ground, Swiss Pharma relied on a prior art reference, which disclosed a formulation of natalizumab containing all of the claimed excipients, with the exception that it used a histidine buffer in place of the claimed phosphate buffer. Swiss Pharma argues that a person of ordinary skill in the art would have been motivated to replace the histidine buffer in this prior art natalizumab formulation with a phosphate buffer based on the teachings of the art that a phosphate buffer worked with numerous prior art IgG mAb formulations, and the replacement would represent a simple substitution of one known element for another.
With regard to the claim limitation that the formulation comprises “from about 20 mg/ml to about 150 mg/ml of natalizumab,” Swiss Pharma argued that this was nothing more than routine optimization of a result effective variable.”
In response, Biogen pointed to the “overwhelming scientific evidence” showing “in 2003, and still today, that achieving a stable liquid formulation of a monoclonal antibody was an unpredictable and highly antibody-specific challenge” and that “the art taught that stable, high concentration (e.g., 20 mg/ml) liquid antibody formulations, liked the formulations recited in the [Biogen] patent[s], were particularly difficult to achieve.” Biogen further argued that Swiss Pharma “failed to demonstrate that it would be only a matter of routine optimization to formulate natalizumab at a concentration of about 20 mg/ml to about 150 mg/ml.”
The PTAB agreed with Biogen that Swiss Pharma failed to identify any stable, high concentration antibody formulation in the prior art. Further, the PTAB found that Swiss Pharma failed to demonstrate sufficiently that the adjustment of natalizumab concentration to 20 mg/ml would have been a matter of routine optimization based on any of the cited references. In addition, in the PTAB’s opinion, the state of the art at the time of filing of the patents at issue favored Biogen’s argument that achieving a stable highly concentrated liquid formulation of a monoclonal antibody was an unpredictable and antibody specific challenge that appeared to be particularly difficult to achieve, thus voiding any reasonable expectation of success.
Accordingly, the PTAB determined that the Swiss Pharma failed to demonstrate a reasonable likelihood that it would prevail in showing the unpatentability of any of the challenged claims.