Mesalamine – USA

On Jun 12 2019, Federal Circuit affirmed PTAB’s decision & found patent covering Salix Pharmaceuticals' ulcerative colitis treatment invalid.

Salix holds NDA for mesalamine extended release capsules (375 mg), marketed under trademark, Apriso®. U.S. Patent No. 8,865,688 (expiring on 05/01/2030) is owned by Dr. Falk Pharma GmbH (“Dr. Falk”) and exclusively licensed to Salix Pharmaceuticals. In 2015, Mylan filed ANDA & subsequently in Jun 2015 Salix and Dr. Falk filed suit alleging infringement.  On Dec. 8, 2015, after Salix and Dr. Falk sued Mylan in district court, GeneriCo and Flat Line filed a petition for IPR challenging claims 1 and 16 of the ’688 patent as obvious over certain prior art references. Following an oral hearing, the Board issued a final written decision on May 19, 2017 finding claims 1 and 16 unpatentable as obvious over the asserted references. Meanwhile in Apr 2016, Northern District of West Virginia after bench trial held that claim 1 of the ’688 patent would not be infringed. Salix & Dr. Falk Pharma appealed both the rulings.

Obviousness:

The ’688 patent relates to a method of maintaining remission of ulcerative colitis with a granulated mesalamine formulation. Patent specification explains that previous delivery methods for oral treatments known at the time of invention were problematic due to the “variation . . . in the release of mesalamine, including premature release, the possibility of dose dumping, and sensitivity to conditions that increase gastric pH and cause premature release of mesalamine. The invention of the ’688 patent purports to improve upon past methods by administering an effective amount of granulated mesalamine formulation.

Claim 1 reads as:

1. A method of maintaining the remission of ulcerative colitis in a subject comprising administering to the subject a granulated mesalamine formulation comprising four capsules each comprising 0.375 g of granulated mesalamine once per day in the morning, without food, wherein:

said method maintains remission of ulcerative colitis in a subject for a period of at least 6 months of treatment; remission is defined as a DAI score of 0 or 1; the granulated mesalamine formulation is not administered with antacids; and wherein 85% to 90% of the mesalamine reaches the terminal ileum and colon.

Board found claims 1 and 16 of the ’688 patent as obvious over certain prior art references: a September 2007 Press Release (Phase III trials), Endonurse (Phase III trials with 375 mg dose), and Davis-1985 (discusses 3 factors relevant to controlled release delivery systems among which “positioned release of drugs in the colon”), in view of either Marakhouski  or Brunner (both references compare pellet formulation with tablet formulation).

Board found that all claimed limitations, including the without food and DAI score limitations, were satisfied by the prior art and that there was a motivation to combine the asserted references with a reasonable expectation of success. Specifically, the Board found that a skilled artisan would have been motivated to combine the method of the September 2007 Press Release and Endonurse with the teachings of either Marakhouski or Brunner that the granulated mesalamine formulation could be administered without food. The Board cited as its rationale the fact that all four prior art references pertain to the same or similar granulated mesalamine formulation for treatment of the same disease and because Marakhouski and Brunner teach that an advantage of a granulated mesalamine formulation is the ability to administer the drug independent of food. The Board also found that a skilled artisan would have had a reasonable expectation of success in maintaining remission of ulcerative colitis by administering granulated mesalamine without food. The Board found that the September 2007 Press Release supports this finding because it announces a successful outcome of a Phase III trial to evaluate the safety and efficacy of the same or similar granulated mesalamine formulation for treatment of the same disease. Notably, the Board found “[t]here is no indication in the [September 2007 Press Release] that the granulated mesalamine had to be administered with food in order to obtain the reported success.”

The Board rejected Dr. Falk’s argument that a skilled artisan would need to conduct a food study to determine if the formulation should be administered with or without food. The Board reiterated that such comparative studies are not necessary in view of the evidence of record especially when the claims at issue do not recite an efficacy requirement related to the effect of food.

Federal circuit sided with Board & said that Board did not change theories on the evidence required to show obviousness of the without food limitation. Board here correctly found that the claims do not recite a food effect. In its institution decision, the Board responded to Dr. Falk’s contention that the claims impliedly contained a food effect limitation by stating that, obviousness “turns on whether administering granulated mesalamine without food would have been predictable and would have led to anticipated success.” Consistent with these statements in its institution decision, the Board stated in its final written decision that “[t]he requirement to show a reasonable expectation of success pertains to the subject matter of the claims,” and, here, because “the claims do not recite a food effect,” there was a reasonable expectation of success of arriving at the without food limitation even though none of the prior art discloses a food effect study.

Dr. Falk contended that, even if the claims do not recite a food effect, the Board still erred in disregarding Dr. Falk’s evidence because evidence relating to unclaimed features is relevant to the inquiry of a motivation to combine with a reasonable expectation of success. In support of this proposition, Dr. Falk cites to Intelligent Bio-Systems, 821 F.3d at 1367–68, in which it contends that this court found evidence relating to an unclaimed feature central to the motivation to combine inquiry and to Institut Pasteur & Universite Pierre et Marie Curie v. Focarino, 738 F.3d 1337, 1346 (Fed. Cir. 2013), in which it contends that this court similarly found that the Board erred in disregarding evidence relating to an unclaimed feature when assessing a motivation to combine with a reasonable expectation of success. Federal Circuit disagreed & said that in Institut Pasteur, we admonished the Board, not because it failed to consider evidence relevant to unclaimed features, but because it failed to consider evidence related to a feature that the Board admitted was implicit in the claims. In contrast, here, the claims do not recite any food effect—either expressly or implicitly. Therefore, Board did not disregard evidence of record, but rather correctly found Dr. Falk’s evidence as falling outside the scope of the claims.

Thus, Federal Circuit affirmed the Board’s final written decision that claims 1 and 16 of the ’688 patent are unpatentable as obvious.  Accordingly, court dismissed as moot Salix’s appeal from the district court’s judgment that claim 1 of the same patent would not be infringed.