In Allergan, Inc. v. Sandoz, Inc., the Federal Circuit affirmed the district court decision that upheld the validity of the Allergan patents relating to Lumigan® 0.01% glaucoma eye drops. This decision shows that it is still possible to defend a patent to a pharmaceutical formulation, at least when it is associated with truly unexpected results. 

The Lumigan® Products

As described in the Federal Circuit decision, Lumigan® 0.01% is an improvement over Lumigan® 0.03%, which was approved in 2001 for the treatment of open angle glaucoma and ocular hypertension. Lumigan® 0.03% includes 0.03% by weight of bimatoprost and 50 parts per million (“ppm”) benzalkonium chloride (“BAK”). In contrast, Lumigan® 0.01% includes 0.01% bimatoprost and 200 ppm BAK.

The active ingredient in both products is bimatoprost, a prostaglandin analog that is effective to reduce intraocular pressure but can cause hyperemia (eye redness) that led many patients to discontinue use of Lumigan® 0.03%. The other ingredient at issue, BAK, is an effective preservative for ophthalmic solutions, but was known to cause side effects. Thus, Lumigan® 0.01% has one third the amount of active ingredient and four times the amount of BAK as Lumigan® 0.03% and yet:

Lumigan 0.01% has similar efficacy to Lumigan 0.03%, viz., IOP-lowering within 0.5 mmHg of that of Lumigan 0.03%, but it causes less frequent and severe hyperemia than Lumigan 0.03%.

The Lumigan® 0.01% Patents At Issue

The patents at issue were U.S. Patent Nos. 7,851,504; 8,278,353; 8,299,118; 8,309,605; and 8,338,479, which stemmed from the same application and are listed in the Orange Book for Lumigan® 0.01%. The Federal Circuit cited Claim 2 of the ’504 patent as representative of the Group I composition claims:

2. A composition having a pH of about 7.3 which comprises about 0.01% bimatoprost, about 200 ppm benzalkonium chloride, citric acid monohydrate, a phosphate buffer, and NaCl wherein said composition is an aqueous liquid which is formulated for ophthalmic administration.

The defendants asserted that the claims were invalid as obvious over eight prior art references, and also invalid for lack of written description and enablement. After a bench trial, the district court upheld the asserted claims and found them to be infringed.

The Federal Circuit Decision

The Federal Circuit decision was authored by Judge Lourie and joined by Judges Linn and Hughes.

establishing non-obviousness within a prior art range 

Of interest for other cases is the court’s discussion of what it may take to withstand an obviousness challenge when the prior art discloses ranges that encompass the claimed amounts:

In Galderma [Laboratories, L.P. v. Tolmar, Inc. (Fed. Cir. 2013)], where there is a range disclosed in the prior art, and the claimed invention falls within that range, a relevant inquiry is whether there would have been a motivation to select the claimed composition from the prior art ranges. … In those circumstances, “the burden of production falls upon the patentee to come forward with evidence that (1) the prior art taught away from the claimed invention; (2) there were new and unexpected results relative to the prior art; or (3) there are other pertinent secondary considerations.”

The Federal Circuit cited In re Peterson (Fed. Cir. 2003), for the proposition that there can be situations where “the disclosed range[s are] so broad as to encompass a very large number of possible distinct compositions” … such that they do not teach any specific amounts or combinations and that the burden of producing evidence of teaching away, unexpected results, and other pertinent secondary considerations [does] not shift,” but did address whether this was such a case.

Turning to the case before it, the Federal Circuit found no error in the district court’s findings that the prior art taught away from using 200 ppm BAK, and that “the claimed formulation exhibited ‘unexpected results,’ which differed in kind, not just in degree, from the prior art.” Indeed, the court cited two “unexpected results”: that BAK enhanced the permeability of bimatoprost and that bimatoprost was effective and exhibited less hyperemia at 0.01%.

Those results exhibited by the claimed formulation thus constitute an unexpected difference in kind, viz., the difference between an effective and safe drug and one with significant side effects that caused many patients to discontinue treatment.

inherent properties support nonobviousness when they differ in kind

The Federal Circuit also rejected arguments based on inherency:

[W]e reject the Appellants’ argument that the that the unexpected results do not support nonobviousness because they are merely the inherent properties of an otherwise obvious formulation. As indicated, the prior art did not disclose, either explicitly or implicitly, the claimed formulation; rather, it taught away from such a formulation. …. The unexpected properties of the claimed formulation, even if inherent in that formulation, differ in kind from the prior art, thereby supporting a conclusion of nonobviousness.

This is not a case where the claims merely recite the unknown properties of an otherwise obvious formulation. …. Here, the previously unknown and unexpected properties of a new and nonobvious formulation constitute additional, objective evidence of nonobviousness.

The Federal Circuit therefore affirmed the district court’s finding that the patents had not been shown to be obvious, and also affirmed its other findings.

Patentability Of Pharmaceutical Formulations

While patent owners may welcome this decision upholding pharmaceutical formulation patents, they also may wonder if the court has set too high a bar. The primary reference cited against the Allergan patents was Woodward, which disclosed a composition comprising 0.001%–1% bimatoprost and 0–1000 ppm of a preservative, including BAK. It seems clear from the discussion of the side effects of both bimatoprost and BAK that Woodward embraces both ineffective and dangerous formulations. Yet, precedent that supports a presumption that all embodiments disclosed in a patent are enabled shifts the burden to the patent owner to prove otherwise.