Patent for multiple sclerosis drug Gilenya was correctly invalidated as obvious


April 12, 2017

The Patent Trial and Appeal Board did not err in finding that all 32 claims of a patent for Gelenya, a prescription drug used to treat relapsing forms of multiple sclerosis in adults, was invalid for obviousness, the U.S. Court of Appeals for the Federal Circuit has determined. The Board did not commit a violation of the Administrative Procedure Act ("APA") by referring to the prior art reference Sakai in its Final Written Decision even though it was not one of the references cited in its Institution Decision. Moreover, in finding the patent obvious, the Board did not err in its motivation to combine analysis or in considering the objective indicia of obviousness (Novartis AG v. Torrent Pharmaceuticals Limited, April 12, 2017, Chen, R.).

Torrent Pharmaceuticals Limited ("Torrent") filed a petition asking the PTAB to institute an inter partes review (IPR) of claims 1-32 of U.S. Patent No. 8,324,283 B2 ("the ’283 patent"), owned by Novartis AG and Mitsubishi Tanabe Pharma Corp. (collectively, "Novartis"). After the PTAB instituted trial to review the patentability of the challenged claims, Apotex and Mylan filed a separate petition seeking IPR of claims 1-32. The proceedings were joined with another trial that had been instituted in a separate IPR. The Board found all original claims of the ’283 patent and Novartis’ proposed substitute claims unpatentable as obvious.

The ’283 patent relates to a solid pharmaceutical composition suitable for oral administration, comprising a sphingosine-1 phosphate (S1P) receptor agonist and a sugar alcohol, which the patent explains is useful for the treatment of certain autoimmune diseases such as multiple sclerosis. The ’283 patent also states that a "particularly preferred S1P receptor agonist of formula I is FTY720, i.e., 2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol in free form or in a pharmaceutically acceptable salt form . . . ." FTY720 is also known as fingolimod. The ’283 patent further discloses that the specific sugar alcohol used in the claimed composition "may suitably be mannitol".

Claims 1 and 19 of the ’283 patent are the only independent claims. Claim 1 is directed towards a solid oral composition comprised of the combination of one of a handful of S1P receptor agonists and any sugar alcohol, whereas claim 19 is directed towards the specific combination of fingolimod and mannitol in a solid oral composition. The dependent claims are directed towards various refinements of the composition, including for example, the addition of a lubricant. Novartis applied to the U.S. Food and Drug Administration ("FDA") for approval to sell a fingolimod-mannitol pill to treat multiple sclerosis under the "Gilenya" brand name. The FDA approved Gilenya for the treatment of multiple sclerosis in 2010.

The Board instituted review of claims 1-32 of the ’283 patent on only one, of the submitted three separate patentability challenges brought by the petitioners: claims 1–32 are unpatentable as obvious over the combination of U.S. Patent No. 6,004,565 ("Chiba") and Pharmaceutics: The Science of Dosage Form Design ("Aulton"). Chiba teaches the use of immunosuppressive compounds with fingolimod as the preferred species. Aulton teaches the use of tablets and capsules to administer drugs orally. The Board concluded that Chiba and Aulton collectively teach each limitation of claims 1–32 of the ’283 patent and Novartis appealed.

APA. Novartis’ argument that the Board violated the requirements of notice and an opportunity to respond found in the APA when it used the Sakai reference as part of its motivation to combine analysis in the Final Written Decision. According to Novartis, the Board ruled Sakai entirely out of the case in the Institution Decision, and on that basis, denied institution of the two proposed grounds based on Sakai. Novartis contended that it relied on that ruling and consequently submitted a "vastly different" record than it would have if it had known Sakai was still a live issue.

The notice and opportunity to be heard provisions of the APA have been applied to mean that an agency may not change theories in midstream without giving respondents reasonable notice of the change and the opportunity to present argument under the new theory, the court observed. The Federal Circuit first disagreed with Novartis that the Board ruled Sakai out of the case entirely in the Institution Decision. In the Institution Decision, the Board declined to read Sakai as an anticipatory reference or primary obviousness reference because Sakai does not disclose "mannitol as a ‘conventional excipient’ in solid pharmaceutical compositions, and Sakai’s stated reasons for using mannitol in liquid pharmaceutical compositions are inapplicable to its potential use in connection with solid pharmaceutical compositions".

This conclusion, however, was not contrary to the Board’s discussion of Sakai in the Final Written Decision that Sakai’s teachings would have nevertheless been relevant to one of skill in the art in deciding which excipients to use in formulating a solid oral dosage form of Fingolimod, according to the court. Having already found that Chiba and Aulton strongly suggest the combination of fingolimod and mannitol in a solid oral composition, the Board found that Sakai merely reinforced its finding.

Also rejected as unfounded was Novartis’ complaints of "surprise" and contention that, following the Institution Decision, the parties "paid Sakai scant attention in subsequent proceedings." The parties debated Sakai at length throughout the proceeding and in the same context that it was discussed by the Board in the Final Written Decision. It was quite clear that Novartis had more than sufficient notice and opportunity to be heard on Sakai’s potential relevance, and in fact actively and repeatedly attempted to distinguish Sakai to defeat the very argument relied on by the Board in the Final Written Decision.

Finally, the court also rejected Novartis’ characterization of Sakai as the "missing link" in the Board’s obviousness analysis. This was not a case where Sakai provided the linchpin of the Board’s analysis, as Novartis contended, the court said. For all these reasons, there was no violation of the APA with respect to the Board’s discussion of Sakai in the Final Written Decision.

Obviousness

Motivation to combine. Novartis argued that the Board further erred in its motivation to combine analysis because it failed to read the prior art as a whole and overlooked critical evidence of mannitol’s known disadvantages as an excipient for solid compositions. Contrary to Novartis’ contention, the record reflected that the Board considered Novartis’ arguments regarding motivation to combine, weighed them against the competing evidence and argument, and concluded that despite Novartis’ contentions, one of skill in the art would have been motivated to combine fingolimod with mannitol in a solid composition. Moreover, the Board’s consideration of mannitol’s negative properties in the Final Written Decision was at least commensurate with Novartis’ presentation of those issues to the Board in its Patent Owner Response, the court reasoned.

Finally, substantial evidence supported the Board’s finding that, despite mannitol’s potentially negative characteristics, it was nevertheless a valid consideration as an excipient for solid oral pharmaceuticals and a person of skill in the art would have been motivated to combine fingolimod and mannitol in the manner claimed by the ’283 patent. Indeed, the Board cited to multiple pieces of evidence establishing mannitol as one of a handful of excipients used in solid oral compositions and its primacy as a non-hygroscopic and compressible diluent which makes it particularly valuable in tableting. Thus, there was no legal error in the Board’s treatment of the motivation to combine evidence nor was there a lack of substantial evidence supporting its conclusion, the court held.

Objective indicia of nonobviousness. According to Novartis, the Board erred when it grouped several dependent claims with their independent claims when considering Novartis’ unexpected results evidence. The argument raised to the Board below was quite different than Novartis’ characterization of that argument on appeal, the court noted. The undeniable focus of Novartis’ arguments throughout the proceeding was the patentability of the combination of fingolimod and mannitol, as broadly recited in claim 19. Novartis did not identify the dependent claims it raised at issue now on appeal or discuss specific dosages or concentrations at all. Thus, there was no fault in the Board’s observation that Novartis offered no separate argument with respect to dependent claims 8, 10, 22, and 23, or proposed amended claims 40, 42, 54, and 55.

After finding no evidence that Novartis distinctly argued an unexpected result specific to the dependent claims Novartis now raised on appeal, that argument was waived, the court ruled.

Novartis next argued that the Board erred as a matter of law in its analysis of the "nexus" requirement with respect to the objective evidence of nonobviousness. Novartis’ nexus argument for its objective indicia evidence was based solely on a single premise—Gilenya being the first commercially-available solid oral multiple sclerosis treatment. The treatment of multiple sclerosis with a solid oral composition, however, was indisputably known in the prior art.

The fact that Gilenya was the first to receive FDA approval for commercial marketing did not overcome the fact that solid multiple sclerosis compositions were already known. Thus, the court agreed with the Board that Novartis’ proffered evidence was not probative of the nonobviousness inquiry.

The case is No. 2016-1352.

Attorneys: Robert Trenchard (Gibson, Dunn & Crutcher LLP) for Novartis AG. Joseph M. O'Malley, Jr. (Paul Hastings LLP) for Mitsubishi Pharma Corp. Michael K. Levy (Andrews Kurth Kenyon LLP) for Torrent Pharmaceuticals Ltd. Shannon Bloodworth (Perkins Coie, LLP) for Mylan Pharmaceuticals Inc. Teresa Stanek Rea (Crowell & Moring, LLP) for Apotex Inc.

Companies: Torrent Pharmaceuticals Ltd.; Mylan Pharmaceuticals Inc.; Apotex Inc.; Novartis AG

MainStory: TopStory Patent FedCirNews

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