IP Law Daily Invalidation of patent for prostate cancer drug ZYTIQA clears path for generic versions
Thursday, November 1, 2018

Invalidation of patent for prostate cancer drug ZYTIQA clears path for generic versions

By Cheryl Beise, J.D.

A patent directed to methods for treating metastatic prostate cancer co-owned by Janssen Biotech and BTG International is invalid as obvious, the federal district court in Newark, New Jersey, has ruled, following a bench trial in a consolidated Hatch-Waxman case brought against drug manufacturers seeking to sell generic versions of the plaintiffs’ prostate cancer treatment drug ZYTIQA. It would have been obvious to a person familiar with the prior art to combine the androgen inhibiting enzyme abiraterone acetate with the steroid prednisone for treating metastatic castration-resistant prostate cancer as of the patent’s 2006 priority date. The objective indicia of nonobviousness, such as ZYTIQA’s commercial success, did not alter that conclusion. The court also determined the patent-in-suit contained an adequate written description. Finally, the court found that if the patent had been valid, the defending generic manufacturers’ accused product labels would give rise to induced or contributory infringement liability (BTG International Ltd. v. Amneal Pharmaceuticals LLC, October 26, 2018, McNulty, K.).

The case involved consolidated Hatch-Waxman actions against several generic drug manufacturers brought by Janssen Biotech, Inc.; Janssen Oncolor, Inc.; Janssen Research & Development, LLC (collectively, "Janssen"); and BTG International Ltd. ("BTG"). Janssen and BTG co-own U.S. Patent No. 8,822,438 ("the ’438 patent"), issued September 2, 2014, and entitled "Methods and Compositions for Treating Cancer." The ’438 patent has 20 claims and is directed to methods for the treatment treats metastatic castration-resistant prostate cancer ("mCRPC") by administering various dosages of abiraterone acetate in combination with one other therapeutic agent, such as an "anti-cancer agent or steroid," such as prednisone. A first-line treatment for metastatic prostate cancer is androgen deprivation therapy. Abiraterone, which inhibits the 1 7c-hydroxylase/ Ci 7,20-lyase ("CYP1 7") enzyme, is a second-line therapy. In 2011, the FDA approved the plaintiff’s New Drug Application (NDA) to market ZYTIQA in combination with prednisone for the treatment of mCRPC. The FDA also approved three medication product labels in connection with ZYTIQA.

The defendants filed Abbreviated New Drug Applications (ANDAs) seeking FDA approval to manufacture or sell abiraterone acetate 250 mg tablets, generic versions of the plaintiffs’ branded drug, ZYTIGA. The plaintiffs filed suit, asserting that the defendants infringed claims 4, 8, 11, 19, and 20 the ’438 patent, all of which depend from independent claim 1. The defendants argued that the asserted claims were invalid for obviousness and for lack of a written description. On January 17, 2018, the Patent Trial and Appeal Board (PTAB), in three inter partes proceedings, found the patent invalid. A motion for reconsideration remains pending. The court in this case conducted a bench trial in late July and early August, and the parties submitted post-trial briefing. In this ruling, the court concluded that the ’438 patent satisfies the written description requirements of 35 U.S.C. §112 but is invalid for obviousness under 35 U.S.C. §103. For completeness, the court also ruled that if the patent were valid, the defendants’ proposed labels for marketing generic products would infringe, on either an induced infringement or contributory infringement theory.

Written description. The court found that the ’438 patent clearly sets forth the metes and bounds of the invention. It teaches the administration of a specified dosage of two specified drugs for the treatment of a specified condition in a specified, narrow class of patients, i.e., those suffering from mCRPC. Not even minimal adjustment or experimentation is suggested; a skilled practitioner (assuming regulatory approval) would need little if any additional instruction to practice the method.

The defendants argued that the specification is inadequate because it fails to disclose test results showing that prednisone itself provides an anticancer benefit and failed to provide sufficient information to permit a person of ordinary skill in the art (POSA) to understand that both agents, abiraterone and prednisone, "treat" prostate cancer. The court disagree, finding that the specification of the ’438 patent sufficiently identifies prednisone as an agent that "treats" cancer. Prednisone is an antibiotic agent and the specification defines "anti-cancer agent" to include antibiotic agents. The specification also expressly includes prednisone in a list of steroids to be administered "in an amount that is sufficient to treat [a mammal having] cancer."

Obviousness. The defendants argued that the combination therapy claimed in the ’438 patent would have been obvious to a person of ordinary skill in the art (POSA) as of August 25, 2006, the patents’ priority date. Specifically, a POSA familiar with the prior art would have been motivated to combine abiraterone acetate with prednisone with a reasonable expectation of success because of prednisone’s (1) anti-cancer effects; (2) palliative properties, and (3) ability to mitigate abiraterone’s side effects.

By the priority date, abiraterone had been identified in the art as a treatment for mCRPC. It was understood that abiraterone selectively inhibited the CYP17 enzyme. In addition, more than one study suggested that prednisone could cause reduced PSA levels, a marker of anti-cancer effect. The court also agreed that prednisone’s known effects as a palliative and a side-effect minimizer would have furnished a powerful motivation to combine it with abiraterone. "And the idea for such a combination, even if initially motivated only by those two effects," would lead to the practice of the claimed invention. Moreover, prior art suggested that adrenal androgen synthesis can be inhibited by low doses of steroids, or through inhibition of key enzymes using either abiraterone or ketoconazole, and that combining drugs could improve outcomes.

Regarding objective considerations, the plaintiffs raised several arguments related to ZYTIGA’s commercial success, failure of others, skepticism, long-felt need, professional approval and industry praise, and unexpected results. Although ZYTIGA had yielded billions of dollars in sales, its commercial success was in large part due to the exclusionary effect of an earlier "blocking patent," which gave Janssen the exclusive right to market abiraterone between 1997 and 2006, the court explained. Between 2004 and 2006, Cougar Biotechnology was the exclusive licensee for abiraterone. The evidence also suggested that abiraterone/prednisone combination therapy did not yield unexpected results, but merely represented an incremental improvement over prior treatment options.

Balancing the prior art and the other indicia, the court concluded that the patented combination at issue "was well foreshadowed in peer-reviewed articles" and that this factor outweighed all others. The defendants met their burden of rebutting the presumption of validity of the ’438 patent by clear and convincing evidence.

Infringement. Assuming arguendo that the ’438 patent was valid, it would be infringed by the defendants. The defendants’ ANDA label—which specified indications and proper use of the abiraterone/prednisone combination therapy—would induce physicians’ direct infringement of the method claimed in the ’438 patent. The ZYTIGA Indications and Usage section encompassed the administration of abiraterone plus prednisone for the treatment of mCRPC. The defendants’ proposed product labels were substantively identical to the approved ZYTIQA label, except that the chemical name "abiraterone acetate" was substituted for the trademark "ZYTIQA." The labels clearly expressed an intent that physicians be authorized to prescribe abiraterone plus prednisone for the treatment of mCRPC, and thereby, to practice the ’438 patent.

In addition to liability for inducement of infringement, the defendants’ labels also gave rise to contributory infringement liability, in the court’s view. The court was not persuaded by the defendants’ argument that prednisone had a substantial non-infringing use as a glucocorticoid replacement. The court observed that every administration of prednisone as a glucocorticoid replacement to treat mCRPC would factually duplicate the patented method. Thus, there was no practical distinction between infringing and non-infringing use.

This case is No. 2:15-cv-05909-KM-JBC.

Attorneys: Donald A. Robinson (Robinson Miller LLC) for BTG International Ltd., Janssen Biotech, Inc. and Janssen Oncology, Inc. James S. Richter (Winston & Strawn, LLP) for Amneal Pharmaceuticals LLC and Amneal Pharmaceuticals of New York, LLC. Michael E. Patunas (Patunas Law LLC) for Teva Pharmaceuticals USA, Inc. Sarika Singh (McNeely, Hare & War LLP) for Amerigen Pharmaceuticals, Inc. and Amerigen Pharmaceuticals Ltd.

Companies: BTG International Ltd.; Janssen Biotech, Inc.; Janssen Oncology, Inc.; Amneal Pharmaceuticals LLC; Amneal Pharmaceuticals of New York, LLC; Teva Pharmaceuticals USA, Inc.; Amerigen Pharmaceuticals, Inc.; Amerigen Pharmaceuticals Ltd.

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