Can a method of treatment claim be inherent in the prior art if neither the formulation nor the method of using the formulation twice a day were in the prior art? Earlier today, the Federal Circuit determined in Allergen v. Sandoz that a claimed method for treating glaucoma (which differed from the three-times-a-day dosage regimens required of the individual components) was not inherently obvious, and thereby prevented a group of generic challengers from being able to market their own versions of Combigan® before the expiration of the patent containing the claimed method. However, Judge Dyk, dissenting-in-part, found no difference between the instant case and Federal Circuit precedent -- although the precedent relied upon was all directed to inherent anticipation. Nevertheless, the majority and dissent agreed that the claims directed to the formulation itself were obviousness in view of the prior art, and therefore reversed the lower court's finding of validity of all the claims.
This case involved Allergan's formulation for a combination eye-drop product marketed as Combigan®, a product which combines a well-known alpha2-agonist Alphagan® (0.2% brimonidine) and a well-known beta-blocker Timoptic® (0.5% timolol). Allergan had found that by co-formulating these drugs, patient compliance increased because the drugs could now be administered at the same time, and because (unexpectedly) the number of daily administrations could be dropped from 3 to 2. The inventors obtained four patents on this formulation and methods of its use, all stemming from an application filed on April 19, 2002, which Allergan listed in the Orange Book. For the purposes of the appeal, the parties treated almost all of the asserted claims as one group, referring to claim 1 of U.S. Patent No. 7,323,463 ("the '463 patent") as the representative claim, which read:
1. A composition comprising about 0.2% timolol by weight and about 0.5% brimonidine by weight as the sole active agents, in a single composition.
The only other asserted claim was claim 4 of U.S. Patent No. 7,030,149 ("the '149 patent"), which read:
4. A method of reducing the number of daily topical ophthalmic doses of brimondine administered topically to an eye of a person in need thereof for the treatment of glaucoma or ocular hypertension from 3 to 2 times a day without loss of efficacy, wherein the concentration of brimonidine is 0.2% by weight, said method comprising administering said 0.2% brimonidine by weight and 0.5% timolol by weight in a single composition.
Sandoz Inc., Alcon Laboratories, Inc., Alcon Research Ltd., Alcon, Inc., and Falcon Pharmaceuticals, Ltd. (collectively, "Sandoz"), and the other defendants Apotex Inc. and Apotex Corp., and Watson Laboratories, Inc., each filed Abbreviated New Drug Applications with the FDA seeking to market generic versions of Combigan®. In turn, Allergan sued them under 35 U.S.C. § 271(e)(2)(A). After a claim construction determination, the lower court granted summary judgment of non-infringement as to claims 1-3 of the '149 patent, and the parties stipulated to infringement of the remaining claims. After a bench trial, the District Court found all of the claims nonobvious over the prior art. The defendants appealed.
The Formulation Claims – Claim 1 of the '463 Patent as Representative
The lower court had rejected an invalidity allegation that Claim 1 of the '463 patent was obvious primarily in view of U.S. Patent No. 5,502,052 ("DeSantis"). This reference taught the use of a combination of alpha2-agonists and beta-blockers for treating glaucoma, but did not teach that brimonidine could be one of those alpha2-agonists. Nevertheless, DeSantis incorporated by reference a publication by Timmermans, which disclosed brimonidine and its tartrate salt. Also, even if not mentioned by name, the ranges of the components of claimed formulations fell within the ranges as taught by DeSantis -- 0.02 to 2.0% alpha2-agonist and 0.01 to 3.0% beta-blocker. Also in the art was a reference that taught the topical administration of 0.2% brimonidine with 0.5% timolol in combination, although spaced five minutes apart, and the fact that it was common to dose the serial application of these two drugs twice a day. Moreover, there were only three known pharmaceutically acceptable alpha2-agonists at the time for the treatment of glaucoma -- clonidine, apraclonidine, and brimonidine. The Federal Circuit did not necessarily disagree with any of the factual findings of the lower court related to obviousness, but instead reversed because it believed that the facts instead supported a finding of obviousness.
Motivation to Combine
The lower court relied heavily on the fact that there would be no motivation to develop fixed combination products, even though such formulations might improve patient compliance, because the FDA does not consider patient compliance as a factor when approving new formulations. The Federal Circuit noted that FDA approval might be a factor in an obviousness determination, for example when determining whether there was motivation to develop a drug or whether there was skepticism regarding efficacy. However, it also noted that motivation to combine may be found in many different places, not just in the rationale used by the FDA as a basis for its approvals. In view of the overwhelming amount of prior art related to the claimed formulation, the Federal Circuit thought there was sufficient support to find a motivation to combine, notwithstanding the FDA's approval process. Somewhat lacking in the analysis, however, was how the FDA's position regarding patient compliance does factor into the obviousness determination.
Reasonable Expectation of Success
The lower court found that the unpredictability in the chemical arts weighed in favor of a finding of nonobviouness. As a factor, the District Court considered Allergan's challenges formulating Combigan®. The Federal Circuit did not agree, because some degree of unpredictability is fine, provided there is a reasonable probability of success. In this case, DeSanits provided that reasonable probability. Moreover, Allergan's formulation difficulties stemmed from the fact that it was attempting to use a proprietary preservative. There is no record of continued difficulties once its scientists switched to a commonly used preservative. The fact that the claims were not drawn to the precise formulation Combigan® was important, because there is no requirement that there be a reasonable expectation of success in formulating Combigan®.
The lower court had found factors that taught away from the claimed formulation, including the potential side effects, differing dosing regimens, and disparate half-lives of brimonidine and timolol. However, as the Federal Circuit explained, the District Court did not consider the impact that these factors would have on the clear motivation to combine (probably because it did not find a motivation to combine). Interestingly, the Federal Circuit pointed out that the lower court did not find that the prior art as a whole taught away from the claimed invention. The Court, therefore, accepted the factual findings from below, but concluded that they did not render the invention nonobvious.
Finally, the Federal Circuit accepted all the lower court's factual findings with regard to secondary considerations of nonobviousness, but still found that they did not weigh heavily enough to overcome obviousness of the claims. With regard to long-felt need, the District Court's findings were apparently entirely conclusory. With regard to unexpected results, the lower court had found that the claimed formulations were able to overcome previous difficulties in treating patients with twice-per-day dosage regimens. The Federal Circuit thought this was somewhat irrelevant. The Court did agree that these results were unexpected. However, while such results might be meaningful to method of treatment claims, they were not as relevant to the formulation claims.
The Method-of-Treatment Claim – Claim 4 of the '149 Patent
As shown above, the treatment claim has a couple of relevant limitations, including the above-referenced formulation of brimonidine and timolol, and the use of this formulation twice a day with the same efficacy as brimonidine administration three times a day. The problem with administering brimonidine only twice a day was that efficacy would drop eight to nine hours after administration, in a phenomenon referred to as "afternoon trough." The majority found that the defendants did not establish by clear and convincing evidence that the claimed method would have been obvious. Importantly, the defendants apparently did not argue that the "efficacy limitation" is inherent to all fixed combination products containing brimonidine and timolol, or that a dose reduction would inherently flow from the obvious formulation included in the claims. And, the defendants' citation to the success in using timolol with other non-alpha2-agonist ophthalmic drugs with reduced doses was found to be irrelevant, because there was no reason why the use of these unrelated drugs would make the claimed method obvious.
Judge Dyk, in dissent, disagreed -- he would have also reversed the finding of nonobviousness of this claim. He relied heavily on his belief that the method claim only contained one step -- applying a fixed combination of 0.2% brimonidine and 0.5% timolol twice a day. It was not explained, however, why he considered two administrations to be a single step. Nevertheless, Judge Dyk believed that the twice-a-day dosing of a formulation that was not in the prior art would have nonetheless been obvious to one skilled in the art, and that the alleged avoiding-"loss of efficacy" limitation was just the result of the claimed method. As support for this proposition, Judge Dyk cited to three Federal Circuit cases: Abbott Labs. v. Baxter Pharm. Prods., 471 F.3d 1363 (Fed. Cir. 2006); In re Cruciferous Sprout Litig., 301 F.3d 1343 (Fed. Cir. 2002), and Bristol-Myers Squibb Co. v. Ben Venue Labs., 246 F.3d 1368 (Fed. Cir. 2001). However, each of these cases relates to inherent anticipation, not inherent obviousness. It is not self-evident that the reasoning behind allowing the inherent result flowing from the use of a prior art composition or method to anticipate a claim would apply with equal force to a composition or method that was only obvious in view of the prior art. In other words, citation of these cases, without more, is like comparing apples with oranges.
Moreover, Judge Dyk does not appear to consider the fact that there were two limitations that were not taught in the prior art -- the formulation and its method of use. It should not be sufficient to conclude that, just because a formulation was obvious, any method of using it must also be. Granted, this case would have been completely different if the claimed formulation was taught in the prior art, and the only potentially obvious limitation was its use twice a day. In such a case, it is possible that its use might have been obvious, and the "efficacy" result that flowed from it could therefore have been inherent. This is, perhaps, why the majority agreed in footnote 1 that "the inherency doctrine may apply to an otherwise obvious claim" in some situations. Nevertheless, this was not the case and, without more, the majority's position was more grounded in the facts of the case, and in the Court's precedent.
Allergan, Inc. v. Sandoz Inc. (Fed. Cir. 2013)
Panel: Circuit Judges Dyk, Prost, and O'Malley
Opinion for the court by Circuit Judge Prost; opinion concurring-in-part and dissenting-in-part by Circuit Judge Dyk