Allergan v Sandoz: when obvious is not obvious enough!

On May 1, the US Court of Appeals for the Federal Circuit issued an interesting, yet controversial, ruling in Allergan Inc. v Sandoz Inc. et Al., examining obviousness in the context of a combination ophthalmic drug treatment. At issue were four patents (US Patent Nos. 7,642,258 - 7,320,976 - 7,323,463 - 7,030,149) related to Combigan, an eye-drop product developed by Allergan to treat glaucoma and ocular hypertension, based on a combination of 0.2% brimonidine and 0.5% timolol (and the preservative benzalkonium chloride), to be administered twice daily. Sandoz and the other defendants submitted an Abbreviated New Drug Application (ANDA) to the US Food and Drug Administration (FDA) seeking approval to market a generic version of Combigan (declaring, in a certification pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV) that Allergan's patents were invalid and/or would not be infringed by the manufacture, importation, use or sale of the generic drugs). Allergan filed suit for patent infringement, under 35 USC § 271(e)(2)(A), according to which:

(2) It shall be an act of infringement to submit:
(A) an application under section 505(j) of the Federal Food, Drug, and Cosmetic Act [Abbreviated New Drug Application] or described in section 505(b)(2) of such Act for a drug claimed in a patent or the use of which is claimed in a patent

At first instance, the Eastern District of Texas granted summary judgment of non-infringement as to claims 1-3 of the '149 patent; the parties stipulated to infringement of the other claims. The district court rejected claims of invalidity under 35 USC § 103 in relation to all the asserted claims. Sandoz appealed, challenging the district court's findings on invalidity (Allergan's cross-appeal on the same issue was dismissed on April 4, 2012). The Court of Appeals examined Sandoz's allegations of obviousness, in relation to the '463 patent and claim 4 of the '149 patent.

The '463 patent discloses a composition comprising 0.2% timolol and 0.5% brimonidine, as well as a small amount of benzalkonium chloride, and an article of manufacture comprising packaging material indicating that twice daily topical administration of that composition is useful for treating glaucoma or ocular hypertension. Sandoz argued that this patent would be invalid in light of US Patent No. 5,502,052 (DeSantis), which describes the use of fixed combinations of alpha2-agonists and beta-blockers, with formulatory ingredients such as benzalkonium chloride (BAK), for the treatment of glaucoma. The '052 patent expressly claims the use of timolol as beta-blocker; for suitable alpha2-agonists, it refers to a previous publication, which discloses both brimonidine and its tartrate salt. Moreover, it explains that administering the medication in two or more medications in separate, spaced dosages, several times a day, resulted in poor patient compliance. Sandoz also pointed to other studies, which disclosed the use of a composition comprising 0.2% brimonidine and 0.5% timolol (and BAK) in combination, spaced five minutes apart, and alleged that it was common, at the time of invention, to administer the composition twice a day (as described, for other combinations, by additional studies). At first instance, the district court had found that (1) there was no motivation to create the combination product, because the FDA did not view patient compliance as a factor for approval, (2) the formulation arts were unpredictable, (3) some teaching in the prior art taught away from the invention, and (4) secondary considerations supported non-obviousness.

The Court of Appeals reversed the district court's judgment, declaring the '463 patent invalid. With regard to (1), the court held that, although FDA approval may be relevant to the obviousness analysis (Knoll Pharm. Co. Inc. v Teva Pharms. USA Inc.), 'there is no requirement in patent law that the person of ordinary skill be motivated to develop the claimed invention based on a rationale that forms the basis for FDA approval'. Further, DeSantis' disclosure and the medical practice at the time provided enough motivation to develop a fixed combination brimonidine/timolol product. As for (2) unpredictability in the chemical arts, the judges found that 'there was a reasonable expectation of success based upon the teachings of DeSantis' and highlighted that the difficulties faced by Allergan in developing Combigan could not prove otherwise, as the claims only covered the combination of brimonidine and timolol, while Combigan contained many other elements in addition to these two. On (3) teaching away, it was noted that the district court 'did not find that the prior art as a whole taught away from the invention'. Therefore, although certain aspects of the prior art taught away from the claimed invention, they could not be deemed sufficient to demonstrate non-obviousness. Finally, the Court of Appeals turned its attention to (4) secondary factors, finding that the district court had not adequately justified its reasoning on long-felt need. It also held that, while a twice per day dosage regimen of Combigan unexpectedly eliminated the loss of efficacy which affected, several hours after administration, previous attempts of treating patients with brimonidine twice daily, the prior art still provided enough motivation to combine brimonidine and timolol, irrespective of the potential elimination of the loss of efficacy. In light of these findings, the court concluded that the claims of the '463 were invalid as obvious.

Examining claim 4 of the '149 patent, which describes the use of a combination of 0.2% brimonidine and 0.5% timolol to reduce the number of daily topical doses of brimonidine 'from 3 to 2 times a day without loss of efficacy', the judges took a different perspective. The majority observed that the record established that when brimonidine was dosed twice a day, a loss of efficacy took place in the afternoon, and held that Sandoz had 'failed to point to evidence in the prior art that would allow [the court] to conclude that the addition of timolol to brimonidine dosed twice per day would eliminate the afternoon through issue'. Addressing Sandoz's arguments pointing to studies which described the use of timolol combined with other ophthalmic drugs to treat glaucoma at a reduced dosage, the court stated that it could 'see no reason why the success of unrelated drugs would make it obvious to one of ordinary skill that a fixed combination of brimonidine and timolol could be dosed twice per day without loss of efficacy'. Further, it highlighted that, even if DeSantis taught that a combination drug achieves greater reduction in intraocular pressure than a drug administered alone, this effect could not be equated to the requisite of 'no loss of efficacy', contained in claim 4 of the '149 patent. Accordingly, the majority dismissed allegations of obviousness in relation to this claim.

Brimonidine (top) and timolol (bottom)

Judge Dyk, however, (concurred with the finding of invalidity in relation to the '463 patent, but) dissented with this conclusion. He stated that the majority's opinion was contradictory:

The majority concludes, correctly, that the composition claimed in the ’463 patent would have been obvious, even though it has the unexpected property that it can be dosed twice a day without a loss of efficacy ... Yet the majority affirms the validity of a claim drawn to the method of dosing that same composition twice a day, because the prior art did not disclose that this dosing regimen "would eliminate the afternoon trough issue." I think that the different results as between the claims of the '463 patent and claim 4 of the '149 patent cannot be reconciled.

The dissenting opinion pointed to the distinction between a new and non-obvious method of use of an existing or obvious composition, and a newly-discovered result or property of an existing or obvious method of use. While the former is patentable, the latter is not. Judge Dyk observed that the avoidance of loss of efficacy, obtained through the combination of brimonidine and timolol, was 'not a separate step, but rather a result of the claimed method'. Thus, reciting Bristol-Myers Squibb Co. v Ben Venue Labs. Inc. et Al., he concluded that claim 4 of the '149 patent should have been held invalid, as 'newly discovered results of known processes directed to the same purpose are not patentable'.

The majority agreed with the dissent 'that the inherency doctrine may apply to an otherwise obvious claim as well', but rejected the applicability of this doctrine in the case. Judge Dyk's dissent appears to rely on the concept of inherent anticipation, applied to an obvious formulation: the rationale behind this reasoning could be disputed by some, but it should not be read as an automatic equivalence between formulation's and method's obviousness. Certainly, the line between formulation/result or property/method of use is blurred in this case, as is that between obvious/non-obvious/inherent. For example, the majority is probably right in concluding that 'greater efficacy' in reducing intraocular hypertension cannot be equated to avoidance of the loss of efficacy normally occurring after several hours from administration. But the former effect may well comprise the latter. And where does the border between method of use and result or property of a method of use lie? How can we [and who should provide evidence to] establish if a therapeutic effect is inherent in the use of an obvious formulation? The majority offered an interesting perspective: '[o]f course, it may be true that the mere administration of [the brimonidine/timolol combination] twice daily in any fixed combination formulation inherently produces the claimed result ... [alternatively], it may also be true that only certain fixed-combination formulations produce this result ... [o]n the present record, we cannot draw a conclusion in favor of either proposition'!