Cyclosporine – USA

On Oct. 16, 2017, Judge Bryson of Eastern District of Texas issued an opinion & found Restasis® (Cyclosporine) patents invalid as obvious.

Restasis is an emulsion consisting of various components, including the active ingredient cyclosporin A, an immunosuppressant, which is dissolved in castor oil, a fatty acid glyceride. Restasis, is protected by six related patents, which are listed in orange book (OB) & are expiring on same date ie. Aug 27, 2024. The six Restasis patents are U.S. Patent Nos. 8,629,111 (“the ’111 patent”), 8,633,162 (“the ’162 patent”), 8,642,556 (“the ’556 patent”), 8,648,048 (“the ’048 patent”), 8,685,930 (“the ’930 patent”), and 9,248,191 (“the ’191 patent”). The defendants, Teva,  Akorn and Mylan are generic drug manufacturers that wish to manufacture and sell generic drug before expiration of OB listed patents.

A limitation that is common to all of the claims is the formulation for Restasis, which is an emulsion “comprising cyclosporin A in an amount of about 0.05% by weight; castor oil in an amount of about 1.25% by weight; polysorbate 80 in an amount of about 1.0% by weight; acrylate/C10-30 alkyl acrylate cross-polymer in an amount of about 0.05% by weight; glycerine in an amount of about 2.2% by weight; sodium hydroxide; and water”.

Invalidity Based on Obviousness:

The issue before court was whether the asserted claims of the Restasis patents would have been obvious in light of various combinations of prior art references, including the Ding I and Ding II patents and Sall.

The obviousness dispute in this case centered on Allergan’s assertion that the Restasis formulation exhibited unexpected results compared to the prior art. Allergan stated that the Ding I patent discloses ranges of amounts of cyclosporin (0.05% to 0.40%) and castor oil (0.625% to 5.0%) that cover Restasis. Allergan arguesd however, that the particular combination in Restasis of 0.05% cyclosporin and 1.25% castor oil is a critical value that produces unexpected results far better than would be expected for the range of values disclosed in Ding I. For that reason, Allergan contended that the critical value of 0.05% cyclosporin with 1.25% castor oil is patentable, even though it falls within the ranges disclosed and claimed in Ding I.

During the prosecution of the ’857 application Allergan “concede[d] [to the PTO] that it would have been obvious to modify examples 1A-1E of the Ding reference to arrive at Composition II [the Restasis formulation] of the present application.”  Allergan explained that the differences between Examples 1A-1E of the Ding I patent and the Restasis formulation “are insignificant”; that one of ordinary skill in the art “would readily envisage” the Restasis formulation; and that “there would have been a reasonable expectation of success” with the Restasis formulation. More than four years later, while prosecuting what became the Restasis patents, Allergan withdrew its concession and argued that the applications claiming the Restasis formulation were patentable over the Ding I patent because they showed unexpected results for the Restasis formulation as compared to the ranges claimed in Ding I and the particular examples disclosed in the specification of Ding I. As evidentiary support for that position, Allergan submitted Dr. Schiffman’s declaration to the examiner.

The Court found that statistical significance is an important component in establishing the reliability of the clinical data for a person of skill in the art. Stevenson’s paper, the published account of the Phase 2 results sponsored by Allergan, demonstrated the importance of statistics in drawing conclusions. Stevenson reported that there was no observed dose response, concluded that all tested concentrations performed effectively and safely, and counseled a person of skill to investigate both the 0.05% and 0.1% cyclosporin formulations. That peer-reviewed paper does not go so far as to say that the 0.1% formulation did best, or even that the 0.1% formulation did better than 0.05%.

Stevenson’s conclusions were corroborated by other persons of skill in the art, including Allergan’s own drug developers. Upon presenting the Phase 3 results to the FDA, Allergan explained that the performance of the 0.05% cyclosporin formulation was not surprising because the lack of a dose response—i.e., the similar level of efficacy for formulations containing 0.05% or more of cyclosporin—was observed earlier in Phase 2. After presenting the FDA with its plan to test the 0.1% formulation in Phase 3, Allergan acknowledged that “[b]ecause we did not show a clear differentiation in effect among the doses [in Phase 2], it was recommended [by the FDA] that we include a lower concentration [0.05% cyclosporin] in one Phase 3 clinical trial to confirm that we have chosen the lowest effective concentration.”

For those reasons, the Court found that a person of skill reviewing Stevenson alone, or even Stevenson in combination with all the underlying Phase 2 data, would not conclude that the 0.1% cyclosporine /1.25% castor oil formulation was more effective than the 0.05% cyclosporin/0.625% castor oil formulation. A person of skill reviewing those papers would come to the conclusion that neither formulation was more effective than the other in Phase 2. That person of skill would reach the same conclusion for Phase 3.

Court further said that to the extent Allergan relies on Dr. Schiffman’s presentation to the PTO, it found that the presentation made to the examiner in 2013, including Dr. Schiffman’s declaration and the accompanying exhibits, painted a false picture of the comparative results of the Phase 2 and Phase 3 trials. Also the FDA’s Medical Review does not support Allergan’s claim of unexpected results & the success of Restasis would not have been surprising to a person of skill in the art in 2003.

Allergan had also pointed to evidence of objective considerations such as commercial success and long-felt unmet need, however the force of that evidence is considerably blunted by the fact that, based on protection from a succession of patents, Allergan was able to foreclose competition in cyclosporin/glyceride emulsion formulations from the early 1990s until 2014. And the issuance of the Restasis patents has barred any direct competition for Restasis since then. The evidentiary value of the objective consideration evidence has thus been considerably weakened by the existence of blocking patents during the critical period.

Thus court finally held that based on the extensive amount of pertinent prior art and the Court’s factual assessment of Allergan’s showing of unexpected results, the Court has concluded that Allergan is not entitled to renewed patent rights for Restasis in the form of a second wave of patent protection. The Court therefore holds that while Allergan has proved by a preponderance of the evidence that the defendants have infringed the asserted claims of the Restasis patents, the defendants have proved by clear and convincing evidence that the asserted claims of the Restasis patents are invalid for obviousness.