Asenapine - USA

On Nov 15, 2018, Delaware court found that Sigmapharma’s ANDA infringes claim 1 of U.S. Patent No. 5,763,476 which covers Saphris®.

The ’476 patent, relates to “Sublingual or Buccal Pharmaceutical Composition” & claims composition which disintegrates within 30 seconds. Forest sets its specification as that it can release a batch of its drug product if: (1) the number of sample tablets that disintegrate within 30 seconds is less than 3/6 tablets or between 4 – 15/18 tablets; and (2) the number of sample tablets that disintegrate within 55 seconds is 6/6, 16/18, or 17/18. Dr. Kupiec (Sigmapharma’s expert) concluded that there were no 6/6 test results from two of Sigmapharm’s batches. However, court found testing method unreliable & called it questionable. First, Dr. Kupiec only measured the temperature of the water once, before putting the basket in the water, and he did not check the temperature during or after his experimentation. Second, Dr. Kupiec testified that he did not probe all of the remaining cores, only a “majority” or a “fair amount.” Third, Dr. Kupiec’s lab notebook provides insufficient details, especially compared to Dr. Myers’ (Plaintiff’s expert) lab notebook. Finally, after careful examination of each expert’s background and experience, court concluded that Dr. Kupiec did not have the same level of expertise with USP as Dr. Myers.

With respect to internal testing in SIgmapharma, CEO, Dr. Spiridon Spireas, testified that only 2 tablets out of the 564 total tablets tested across the 94 runs disintegrated within 30 seconds. In other words, Dr. Spireas contends that for all but a couple of runs, zero tablets (0/6) disintegrated within 30 seconds. But court did not find this testimony credible because Dr Spireas did not perform or supervise the test results. Also the lab notebooks do not state how many tablets out of 6 remained after 30 seconds. Instead, the lab notebooks simply report, with few exceptions, “At 30 Seconds: Fails.” Under the Sigmapharm monograph governing these testing procedures, “fails” means a test result of 0/6, 1/6, 2/6, or 3/6. In other words, many more than zero tablets could have disintegrated within 30 seconds, and the internal scientist would have been in compliance with the Sigmapharm monograph by recording “At 30 Seconds: Fails.” Thus, how many tablets actually disintegrated within 30 seconds is simply unknown. Moreover, both Dr. Spireas and the internal scientists (whose testimony was heard via video deposition) admitted that they were at times not conducting disintegration tests in accordance with USP<701>. In addition, one scientist indicated that she was not palpating any remaining cores to determine if it was hard or soft. These practices all undermine the reliability of the internal test results.

Court said that Sigmapharm’s current specification has two disintegration tests: a “30-Seconds Test,” in which the tablets must “fail” USP at 30 seconds, and a “55-Seconds Test,” in which the tablets must “pass” USP at 55 seconds. But claim 1 does not literally claim a pharmaceutical composition that “passes” USP at 30 seconds. Rather, it claims a pharmaceutical composition that “disintegrates within 30 seconds in water at 37°C.” At no time has the court construed “disintegrates within 30 seconds in water at 37°C” to mean that tablets must “pass” USP<701>. This means that, in order to prove infringement, Forest must prove that Sigmapharm’s generic sublingual asenapine tablets will “disintegrate within 30 seconds in water at 37°C.” Sigmapharm can attempt to undermine this proof by showing that the tablets will not “disintegrate within 30 seconds in water at 37°C.” But Sigmapharm cannot short-cut the infringement analysis by focusing only on whether its tablets “pass” or “fail” USP<701>. The problem is that “failing” USP<701> is not sufficient proof that a batch of tablets will not disintegrate within 30 seconds in water at 37°C, meaning “failing” is not proof of non-infringement. Experts from both sides agreed that a test designed to show that a batch of tablets will not disintegrate within 30 seconds—and therefore not infringe claim 1—requires a higher standard of proof than just “failing” USP<701> . Specifically, to establish non-infringement, experts from both sides required 0/6 tablets to completely disintegrate within 30 seconds, meaning there is some hard core remaining for all 6 tablets. If a hard core remains for only 4 or 5 tablets, then the experts would proceed to stage-two testing on an additional 12 tablets. After stage-two testing, and again to establish non-infringement, a hard core must remain for 16 or 17 out of the 18 total tablets tested. Thus, consistent with the procedure established by USP<701> , the experts would require anywhere between 89% and 100% of the sample tablets to not disintegrate within 30 seconds in order to impute the characteristics of those samples onto an entire batch.

On the other side, Forest has proven by a preponderance of the evidence that Sigmapharm’s accused product literally infringes claim 1 of the ’476 patent, because Sigmapharm’s accused product disintegrates within 30 seconds in water at 37°C. Forest has proven that 6/6 tablets disintegrated within 30 seconds for at least one run each from representative batches PD0054:43, PD0054:44, and PD0054:33.

Thus, court held that Forest has proven by a preponderance of the evidence, that Sigmapharm infringes claim 1 of the ’476 patent.