IP Law Daily Restasis patents invalidated for obviousness; validity of assignment to Indian tribe questioned
Tuesday, October 17, 2017

Restasis patents invalidated for obviousness; validity of assignment to Indian tribe questioned

By Thomas Long, J.D.

In a patent dispute between Allergan, Inc.—the maker of the widely prescribed brand-name treatment for chronic dry eye, Restasis—and drug companies seeking to market generic versions of the medication, the federal district court in Marshall, Texas, has held that the asserted claims of six patents for the formulation used in Restasis were invalid in light of prior art, including two expired Allergan patents. Allergan’s argument that the formulation disclosed in the six Restasis patents were novel because they had achieved unexpectedly successful results was rejected because that formulation was within the range of ratios of ingredients described in the prior art. The commercial success of Restasis, as well as its role in meeting a long-felt but unmet need, was primarily the result of Allergan’s market dominance resulting from its previous patents, the court said in finding that objective indicia of nonobviousness did not overcome the strong evidence of obviousness. In a separate ruling, the court granted Allergan’s motion to join the Saint Regis Mohawk Tribe—to which Allergan had assigned the Restasis patents—as a co-plaintiff, although the court questioned whether the assignment (and licensing back to Allergan of use rights) was valid and expressed misgivings about the wider implications of the transfer, which Allergan admitted was done tactically to avoid USPTO review of the patents (Allergan, Inc. v. Teva Pharmaceuticals USA, Inc., October 16, 2017, Bryson, W.).

Allergan held six related patents protecting Restasis. Defendants, Teva Pharmaceuticals USA, Inc.; Akorn, Inc.; Mylan, Inc.; and Mylan Pharmaceuticals, Inc., were generic drug manufacturers that wished to manufacture and sell bioequivalent drugs having the same components as Restasis. They asserted that Allergan’s patents were invalid as obvious in light of prior art.

Restasis patents. The Restasis patents—U.S. Patent Nos. 8,629,111 ("the ’111 patent"), 8,633,162, 8,642,556, 8,648,048, 8,685,930, and 9,248,191—were directed to treatments for chronic dry eye based on the active ingredient cyclosporin, an immunosuppressant medication. Cyclosporin is highly insoluble in water and is therefore very difficult to deliver in an aqueous solution. The Restasis patents solved this problem by using an oil-in-water emulsion that contained a small amount of castor oil (a hydrophobic vehicle that would dissolve the cyclosporin), together with an emulsifier and an emulsion stabilizer in water. That approach allowed small droplets of the cyclosporin/castor oil solution to be suspended in an emulsion from which the cyclosporin would be available to the target tissue. In addition, the emulsion stabilizer was able to keep the emulsion stable for long periods of time.

The patents contained a total of 157 claims, including both product and method claims. Common to all of the patent claims (with slight variations in wording) was the formulation for Restasis, consisting of 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."

Prior art patents. Allergan held two patents regarding cyclosporin/castor oil solutions, both of which were prior art to the Restasis patents. The first was U.S. Patent No. 5,474,979 ("the ’979 patent" or "the Ding I patent"), which issued in 1995 and expired in 2014. Entitled "Nonirritating Emulsions for Sensitive Tissue," the ’979 patent disclosed and claimed a pharmaceutical emulsion containing cyclosporin and castor oil, along with a stabilizer and other ingredients. The second prior art patent was U.S. Patent No. 5,981,607 ("the ’607 patent" or "the Ding II patent"), entitled "Emulsion Eye Drop for Alleviation of Dry Eye Related Symptoms in Dry Eye Patients and/or Contact Lens Wearers." The Ding II patent disclosed and claimed a method for alleviating dry eye by topically applying to ocular tissue an emulsion of a higher fatty acid glyceride, polysorbate 80, and an emulsion-stabilizing amount of the emulsion stabilizer Pemulen in water, all without cyclosporin.

Obviousness—unexpected results. Allergan asserted that the formulation it developed for use in Restasis was patentable over Ding I because the third of three phases of testing showed significantly better results for a 0.05% cyclosporin formulation, compared to a 0.1% cyclosporin formulation. According to Allergan, this result was unexpected, particularly in light of the fact that the 0.05% formulation in the Phase 3 studies contained twice the concentration of castor oil (1.25% castor oil) as that used in previous trials. However, the court noted, each of the components of the 0.05% formulation fell within the range of the components disclosed and claimed in Ding I. In addition, the defendants contended that there was no significant difference between the results of the different studies, and the Phase 3 results were not "unexpected."

The court agreed with the defendants. Based on the evidence at trial the court found that the formulation for Restasis fell within the range of values disclosed and claimed in the Ding I patent, and that the particular values for the components of Restasis did not produce unexpected results that would render the invention of Restasis nonobvious as of the priority date for the Restasis patents, September 15, 2003.

The court noted that the specification of the ’111 patent—which was representative of all six Restasis patents—acknowledged that the use of cyclosporin to treat ophthalmic conditions is well known, as illustrated by Ding I. Also, during the prosecution of one patent application ("the ’857 application"), Allergan had conceded that it would have been obvious to modify certain examples of Ding I to arrive at the Restasis formulation. At that time, Allergan told the USPTO that the differences between the examples of the Ding I patent and the Restasis formulation were "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 this 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.

According to the court, the evidence showed that the 0.05% cyclosporin/1.25% castor oil formulation did not, in fact, perform significantly better than other formulations known in 2003. The court rejected Allergan’s proffered evidence to the contrary, and found that that even if there was initial surprise regarding the performance of the Restasis formulation in the Phase 3 studies in 1999, intervening disclosures in the art would have rendered that result unsurprising to a person of skill in the art by the 2003 priority date for the Restasis patents.

Objective indicia of nonobviousness. The court also found that objective indicia of nonobviousness did not overcome the strong showing of obviousness based on the Ding patents and other prior art (a paper referred to as "Sall"). Allergan relied particularly on the commercial success of Restasis and the long-felt unmet need for a pharmaceutical that would provide effective treatment—and not just palliative relief—for dry eye, without significant side effects. While there was no doubt that Restasis had been a commercial success, and the evidence indicated that Restasis satisfied a long-felt but unmet need, the problem with this evidence, in the court’s view, was that Allergan’s patents had long blocked others from entering the space in the market that was occupied by Restasis. Allergan had patent protection for the topical administration of cyclosporin to the eye since obtaining rights under a patent issued in 1993. The Ding I patent issued shortly thereafter in 1995 and expired in 2014. Just before the Ding I patent expired, Allergan obtained the Restasis patents in late 2013 and early 2014. Where market entry by others was precluded due to blocking patents, the inference of nonobviousness from evidence of commercial success was weak. The court found that the commercial success of Restasis was attributable mainly to the patent protection Allergan had enjoyed for cyclosporin/castor oil emulsions over the past quarter century. The same analysis applied to the objective consideration of long-felt but unmet need. Although there was ample incentive to invent an appropriate ophthalmic product that would have anti-inflammatory properties, the option to invent in the area of castor oil/cyclosporin emulsions was closed to those outside of Allergan. Therefore, objective indicia of nonobviousness did not overcome the strong evidence of obviousness, the court concluded.

Motivation to combine. Finally, the court concluded that each of the other limitations in the asserted claims of the Restasis patents was disclosed in Ding I or Sall, and that there was a clear motivation to combine the prior art, based on the close relationship between the Ding I patent, the Ding II patent, and the Sall reference, as well as a motivation to select the claimed formulation from the prior art range of component values. Accordingly, the court held that the defendants satisfied their burden of showing by clear and convincing evidence that the asserted claims of the Restasis patents would have been obvious.

Joinder of Saint Regis Mohawk Tribe. Prior to ruling on the invalidity issue, the court ruled on Allergan’s motion to join the Saint Regis Mohawk Tribe as co-plaintiff. Last month, Allergan announced that it had assigned its rights to the Restasis patents to the Tribe and that the Tribe had granted Allergan an exclusive license to the patents. This transfer was effected explicitly so that the Tribe—a recognized sovereign tribal government—could move to dismiss an ongoing inter partes review (IPR) proceeding before the Patent Trial and Appeal Board.

The court stated that it had "serious concerns about the legitimacy of the tactic that Allergan and the Tribe have employed." In the court’s view, Allergan had paid the Tribe to allow Allergan to purchase—"or perhaps more precisely, to rent"—the Tribe’s sovereign immunity. "This is not a situation in which the patentee was entitled to sovereign immunity in the first instance," the court said. "Rather, Allergan, which does not enjoy sovereign immunity, has invoked the benefits of the patent system and has obtained valuable patent protection for its product, Restasis." In this way, Allergan was trying to continue to enjoy the benefits of the U.S. patent system without accepting the limits that Congress had placed on those benefits through the administrative mechanism for canceling invalid patents. The court expressed concern that, if this tactic proved successful, other companies could follow suit, thereby spelling the end of the IPR program.

However, the court said, the questions as to the validity of the assignment and exclusive license transaction and whether the Tribe was an owner of the Restasis patents within the meaning of the Patent Act did not bear on the court’s power to hear this case. The assignment did not operate as a bar to the court’s continued exercise of its jurisdiction over the matter. The case was brought by Allergan, the Tribe’s predecessor in interest, seeking affirmative relief; thus any possible immunity from suit that might be applicable to avoid litigation brought against the Tribe had no application to this action. Therefore, the court decided to adopt "the safer course" of joining the Tribe as a co-plaintiff, while leaving the question of the validity of the assignment to be decided in the IPR proceedings, where it was directly presented.

The case is No. 2:15-cv-1455-WCB.

Attorneys: Jonathan Elliot Singer (Fish & Richardson PC) for Allergan, Inc. The Saint Regis Mohawk Tribe, pro se. John Christopher Rozendaal (Sterne Kessler Goldstein & Fox PLLC) for Teva Pharmaceuticals USA, Inc.

Companies: Allergan, Inc.; The Saint Regis Mohawk Tribe; Teva Pharmaceuticals USA, Inc.

MainStory: TopStory Patent TexasNews

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