Allergan, Inc., v. Sandoz Inc.

Trial court did not err when it found that there was no motivation to pursue modified concentration of existing drug and no reasonable expectation of success in doing so, and asserted claims met the Section 112 requirements for enablement and adequate written description.

October 15, 2015

GENERICally Speaking

Case Name: Allergan, Inc., v. Sandoz Inc., Civ. No. 2014-1275, 2015 U.S. App. LEXIS 13616 (Fed. Cir. Aug. 4, 2015) (Circuit Judges Lourie, Linn, and Hughes presiding; Opinion by Lourie, J.) (Appeal from E.D. Tex., Schneider, J.)

Drug Product and Patent(s)-in-Suit: Lumigan® (0.01% bimatoprost); U.S. Patents Nos. 7,851,504 ("the '504 patent"), 8,278,353 ("the '353 patent"), 8,299,118 ("the '118 patent"), 8,309,605 ("the '605 patent"), and 8,338,479 ("the '479 patent")

Nature of the Case and Issue(s) Presented: Allergan owns the patents-in-suit, all of which were listed in the FDA’s Orange Book as covering Lumigan and its approved uses. The active ingredient in Lumigan is bimatoprost. It was originally approved by the FDA at a concentration of 0.03% for the treatment of glaucoma. That version of Lumigan also contained a preservative known as benzalkonium chloride (“BAK”) at a concentration of 50 parts per million ("ppm"). Bimatoprost is effective in lowering the interocular pressure that is typically associated with glaucoma, but one of its side effects is that it may cause hyperemia, which is otherwise known as “red eye.” Additionally, although BAK is an effective preservative, it also is known to damage cells on the ocular surface, and can cause undesirable side effects. Because of the combination of these side effects, patients who used Lumigan 0.03% often stopped using the drug without consulting their physicians, which sometimes lead to vision loss. As a result of these problems, Allergan continued to research the compound to develop a version which would be better tolerated by patients.

Allergan’s research into improving the drug paid off when it determined that lowering the bimatoprost concentration to 0.01% and increasing the BAK concentration to 200 ppm resulted in a formulation that had similar efficacy to the 0.03% version with the advantage that it caused less frequent and severe hyperemia. In 2010, the FDA approved Allergan’s NDA for Lumigan 0.01% for the same approved uses as Lumigan 0.03%. Shortly afterwards, Defendants each submitted ANDAs seeking approval to engage in the commercial manufacture, use, importation, sale, or offer for sale of generic versions of Lumigan 0.01%. Allergan sued each of the ANDA filers.

The specifications of each of the asserted patents specifically described a formulation comprising 0.01% bimatoprost and 200 ppm BAK, among other formulations, as a "best mode" of the invention. The specifications also disclosed in vitro and in vivo experimental data in rabbits, showing that increasing the concentration of BAK from 50 ppm to 200 ppm significantly increased the permeability of bimatoprost across ocular membranes. The claims that Allergan asserted against the Defendants can be divided into two groups. The first group included a claim limitation that, in addition to the 0.01% bimatoprost and 200 ppm BAK, the composition must have a pH of about 7.3. The second group did not contain the pH limitation, but required a particular clinical profile of the claimed composition as compared to a composition comprising 0.03% bimatoprost and 50 ppm BAK. The district court held a five-day bench trial in July 2013, where it rejected the Defendants’ obviousness, written description, and enablement arguments and determined that all of the asserted claims were valid and infringed. Defendants appealed, and the Federal Circuit affirmed the district court’s determination that all of the asserted claims were not obvious, enabled, and had sufficient written description, and also affirmed the district court’s determination that each of the proposed ANDA products infringed.

Why Allergan Prevailed: The Federal Circuit first addressed Defendants’ argument that the district court erred when it required them to establish a motivation to pursue the claimed formulation by modifying Lumigan® 0.03% and a reasonable expectation of success in doing so. Additionally, Defendants felt that because the claimed amounts of bimatoprost and BAK fell within prior art ranges, the proper obviousness inquiry should have focused only on teaching away, unexpected results, and other objective indicia. Allergan responded that the Defendants’ arguments rested entirely on disputed factual issues, and that the district court did not err in finding those facts in Allergan’s favor.

Allergan identified several facts that indicated that the prior did teach away from the claimed invention, including finding that the prior art taught that (i) 0.01% bimatoprost would be less efficacious than 0.03% bimatoprost; (ii) BAK would decrease the permeability of bimatoprost; and (iii) 200 ppm BAK would be unsafe for chronic use with bimatoprost. The Federal Circuit found that the prior art clearly taught away from the claimed concentrations of bimatoprost and BAK. The Federal Circuit did note that although the prior art did not teach the specific claimed concentrations of bimatoprost and BAK, the claimed amounts did fall within prior art ranges. The Federal Circuit found that in such a case, the relevant inquiry was 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 on the patentee to come forward with evidence that (i) the prior art taught away from the claimed invention; (ii) there were new and unexpected results relative to the prior art; or (iii) there are other pertinent secondary considerations. The Federal Circuit agreed that Allergan had met its burden with respect to each of the three elements. Such findings included prior art that higher concentrations of BAK generally decreased the permeability of bimatoprost across cell membranes. So it constituted a “unexpected result” when a concentration of 200 ppm of BAK increased permeability in comparison with its predecessor version which was concentrated at 50 ppm of BAK. Additionally, prior art also taught that lower concentrations of bimatoprost generally resulted in lower efficacy. It was therefore unexpected when Allergan’s reformulated version of the drug concentrated at 0.01% bimatoprost was about as equally effective as 0.03% bimatoprost. In light of this evidence, the Federal Circuit affirmed the district court’s non-obvious finding.

Next, the Federal Circuit considered Defendant’s argument that the asserted patents were invalid for lack of an adequate written description. The Defendants argued that the group two claims were not adequately described because the specification did not disclose any efficacy or hyperemia data of a formulation comprising 0.01% bimatoprost and 200 ppm BAK. Allergan responded that the specification met that requirement because it identified the exact formulation of Lumigan 0.01% as a best mode of the invention. Allergan also argued that the permeability data and the constructive example were relevant to the written description inquiry as they would allow the skilled artisan to predict the clinical performance of Lumigan 0.01%. The Federal Circuit sided with Allergan for the reasons it set forth. The Federal Circuit did however find that the district court erred in relying on an undisclosed clinical protocol to support its written description determination. The clinical protocol was not part of the specifications of the asserted patents, and should not have formed the basis for meeting the written description requirement.

Finally, the Federal Circuit addressed Defendants’ enablement arguments. Defendants argued that the asserted claims were not enabled because the specifications contained no actual efficacy and hyperemia data; they merely provided a research proposal. Defendants argued that the skilled artisan would not accept without doubt the asserted utility of the claimed formulation, i.e., comparable efficacy as Lumigan 0.03% and less hyperemia. Defendants also argued that if the claims were not obvious, then they must be invalidated as not enabled because the district court found that ophthalmic formulations were unpredictable. Allergan argued that the specifications disclosed the exact formulation of Lumigan 0.01% and the permeability data of test formulations, which enabled the skilled artisan to make and use the claimed invention. Allergan also countered that in view of the patents’ disclosures, a skilled artisan would not have questioned the utility of the claimed formulation. The Federal Circuit reasoned that efficacy data are generally not required in a patent application. Only a sufficient description enabling a person of ordinary skill in the art to carry out an invention was needed. The Federal Circuit also stated that Defendants’ argument that the claims could not be enabled if they were found not obvious was nonsensical.

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