The Patent Trial and Appeal Board ( Board ) has heard numerous petitions for

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1 BIOTECH BUZZ Biotech Litigation APRIL 2018 Contributor: Laura W. Smalley Recent Sandoz Inc. Petitions against AbbVie Result in Grant of Inter Partes Review of Patents Covering Methods of Treatment using Humira. Humira, used for the treatment of autoimmune diseases such as Crohn s disease and rheumatoid arthritis, was the number one selling drug in the world in Because of the drug s success, several competitors have sought to enter the market by developing biosimilars, including Amgen Inc. ( Amgen ), Boehringer Ingelheim and Samsung Bioepis. AbbVie Biotechnology Ltd. ( AbbVie ) has assembled a shield of over 100 patents covering different formulations, methods of production and dosages of the drug. 2 While biosimilars to Humira have been approved by the Food and Drug Administration, they have not yet come to market in the United States. Settlements with Amgen and Samsung Bioepis have delayed the marketing of their Humira biosimilars in the United States until The Patent Trial and Appeal Board ( Board ) has heard numerous petitions for inter partes review ( IPR ) relating to Humira. Coherus BioSciences, Inc. filed ten IPR

2 petitions from November 2015 through March 2017 two were dismissed; five denied institution and three resulted in determinations of unpatentability, which are on appeal to the United States Court of Appeals for the Federal Circuit. 4 Boehringer Ingelheim also had two IPRs result in successful patentability challenges, which are also on appeal. 5 AbbVie thereafter sued Boehringer Ingelheim for patent infringement. Amgen filed two unsuccessful challenges against Humira patents, and thereafter settled patent infringement litigation over its biosimilar. 6 Sandoz Inc. ( Sandoz ) filed eight IPR petitions against AbbVie in The Board denied institution in four of these proceedings. On February 9, 2018, the Board denied Sandoz s petition on U.S. Patent No. 9,512,216, disclosing a method of treating plaque psoriasis by subcutaneously administering a specific regimen of adalimumab (the active ingredient in Humira ). On the same day, the Board denied Sandoz s petition on U.S. Patent No. 8,802,100, which discloses stable aqueous pharmaceutical formulations comprising an anti-tnfα antibody. On March 9, 2018, the Board denied institution of IPR and IPR , which sought to challenge U.S. Patent Nos. 8,911,737 and 8,974,790. These patents, titled Methods of Administering Anti-TNFα Antibodies, claimed, respectively, a method of treating Crohn s disease by administering adalimumab and a method of treating ulcerative colitis by administering adalimumab. The Board, however, granted Sandoz s petitions in IPR and IPR , finding that Sandoz had demonstrated a reasonable likelihood that it would prevail on demonstrating unpatentability of certain claims of the challenged patents. The first proceeding involved U.S. Patent No. 9,090,689 B1 ( the 689 patent ), titled Use of TNFα Inhibitor for Treatment of Psoriasis, which related to methods of treating disorders in which tumor necrosis factor alpha (TNFα) activity is detrimental by administrating the TNFα inhibitor adalimumab. The second proceeding involved U.S. Patent No. 9,067, Id. 6 Id.

3 B2 ( the 992 patent ), entitled Use of TNFα Inhibitor for Psoriatic Arthritis, which also related to methods of treating disorders in which TNFα activity is detrimental by administrating adalimumab. IPR Challenging Method of Treating Moderate to Severe Chronic Plaque Psoriasis The 689 patent discloses a method where the TNFα inhibitor is used to treat skin and nail disorders, such as psoriasis. The patent disclosed a study demonstrating that adalimumab administered for 12 weeks was effective in treating moderate to severe chronic plaque psoriasis. The independent claims of the 689 patent disclose a method of administering adalimumab for the treatment of moderate to severe chronic plaque psoriasis, comprising filling the adalimumab into vessels and subcutaneously administrating 40g of adalimumab to the patient every other week. Sandoz argued that the claimed methods of treatment were obvious under 35 U.S.C The cited prior art references disclosed, among other things: (1) the results of a dose-ranging study showing that adalimumab administered subcutaneously in combination with methotrexate to rheumatoid arthritis patients every other week was better than a placebo; (2) describing studies demonstrating that TNFα targeted therapies (already shown to be a success with rheumatoid arthritis) were a new therapeutic option for patients with psoriatic arthritis and psoriasis; (3) describing a clinical trial demonstrating that treating psoriatic arthritis and psoriasis patients with another TNFα inhibitor improved their conditions; and (4) disclosing that patients with moderate or severe plaque psoriasis treated with another TNFα inhibitor experienced a higher decree of clinical benefit from the baseline. Based on the references, the Board held that one of ordinary skill in the art would have had a reasonable expectation of success in using adalimumab in treating moderate to severe chronic plaque psoriasis and in using 40g of adalimumab administered every other week to treat moderate to severe chronic plaque psoriasis. The record indicated that a person of ordinary skill in the art: (1) knew that TNFα was implicated in the pathogenesis of chronic inflammatory diseases, including rheumatoid arthritis and

4 psoriasis ; (2) were using TNFα inhibitors to treat rheumatoid arthritis and to treat psoriasis based on the known role of TNFα in those conditions ; and (3) would have predicted success in using adalimumab one of the handful of TNFα inhibitors already known to treat rheumatoid arthritis in treating moderate to severe chronic plaque psoriasis based on the successes [of other such drugs] in treating both rheumatoid arthritis and psoriasis. Further, the record demonstrated that a person of ordinary skill in the art would have had a reason to use the same dose of adalimumab to treat both rheumatoid arthritis and moderate to severe chronic plaque psoriasis based on the prior art s disclosure of using the same or similar doses and dosing regimens to effectively treat both disorders. IPR Challenging Method of Treating Psoriatic Arthritis The 992 patent discloses a method where the TNFα inhibitor is used to treat disorders in which TNFα activity is detrimental, such as psoriatic arthritis. The patent disclosed a study demonstrating that adalimumab administered for 24 weeks was effective in treating erosive polyarthritis and radiographic disease progression in patients with psoriatic arthritis. The independent claims of the 992 patent disclose a method of administering adalimumab for the treatment of moderate to severe psoriatic arthritis, comprising subcutaneously administrating 40g of adalimumab to the patient every other week. Sandoz argued that the claimed methods of treatment were anticipated under 35 U.S.C. 102 and/or obvious under 35 U.S.C The cited prior art references disclosed, among other things: (1) the results of a study showing that adalimumab administered subcutaneously to psoriatic arthritis patients every other week was better than a placebo, and that a majority of the patients achieved an ACR20 response at week 24 and that a significant number of patients achieved an ACR70 response at week 24; (2) the results of a dose-ranging study showing that adalimumab administered subcutaneously in combination with methotrexate to rheumatoid arthritis patients every other week was better than a placebo; (3) describing studies demonstrating that TNFα targeted therapies

5 (already shown to be a success with rheumatoid arthritis) were a new therapeutic option for patients with psoriatic arthritis and psoriasis; (4) describing a clinical trial demonstrating that treating psoriatic arthritis and psoriasis patients with another TNFα inhibitor improved their conditions; (5) describing a clinical trial involving another TNFα inhibitor which demonstrated that the drug was effective in treating psoriatic arthritis; and (6) disclosing several clinical studies where the patients were administered adalimumab which halted the damage of psoriatic arthritis. Even though the Board held that the outcome limitations recited in the wherein clauses (that the patient achieves an ACR50 or ACR70 score at week 24 of the treatment) were entitled to patentable weight, it nevertheless held that the claims of the 992 patent were anticipated by the first reference. The Board also held that one of ordinary skill in the art would have had a reasonable expectation of success in using adalimumab in treating psoriatic arthritis and in using 40g of adalimumab administered every other week to treat psoriatic arthritis. The record indicated that a person of ordinary skill in the art: (1) knew that TNFα was implicated in the pathogenesis of chronic inflammatory diseases, including rheumatoid arthritis and psoriatic arthritis ; (2) were using TNFα inhibitors... to treat rheumatoid arthritis and to treat psoriatic arthritis based on the known role of TNFα in those conditions ; and (3) would have predicted success in using adalimumab one of the handful of TNFα inhibitors already known to treat rheumatoid arthritis in treating psoriatic arthritis based on the successes of [other such drugs] in treating both rheumatoid arthritis and psoriatic arthritis. The current record demonstrates that a person of ordinary skill in the art would have had a reason to use the same dose of adalimumab to treat both rheumatoid arthritis and psoriatic arthritis based on the prior art s disclosure of using the same or similar doses and dosing regimens to effectively treat both disorders.

6 Nothing herein should be construed as legal advice or legal representation. Laura W. Smalley Harris Beach PLLC 99 Garnsey Road Pittsford, NY 14534