In Hoffmann-La Roche Inc. v. Apotex Inc., Nos. 13-1128, -1161, -1162, -1163, -1164 (Fed. Cir.
Apr. 11, 2014), the Federal Circuit affirmed the district court's grant of SJ that claims 1-8 of U.S. Patent No. 7,718,634 ("the '634 patent") and claims 1-10 of U.S. Patent No. 7,410,957
("the '957 patent") are invalid as obvious.

Hoffmann-La Roche Inc. ("Roche") owns the '634 and '957 patents, which are directed to methods of treating osteoporosis through the once monthly administration of about 150 mg of a salt of ibandronic acid.  Roche markets ibandronate, a salt of ibandronic acid, in a 150 mg dose as once monthly Boniva® for the treatment of osteoporosis.  Apotex Inc. and the other defendants (collectively "the defendants") submitted ANDAs with the FDA, seeking approval to engage in the manufacture and sale of generic versions of Boniva® prior to the expiration of Roche's patents, and Roche sued for patent infringement.

The defendants moved for SJ of invalidity of claims 1-8 of the '634 patent, and the district court raised on its motion the issue of SJ of invalidity of claims 1-10 of the '957 patent.  The district court concluded that all of the claims-at-issue were invalid as obvious.  Roche appealed.

"The evidence of superior efficacy does nothing to undercut the showing that there was a reasonable expectation of success with the 150 mg monthly dose, even if the level of success may have turned out to be somewhat greater than would have been expected."  Slip op. at 17.

On appeal, the Federal Circuit stated the issue as "whether it would have been obvious at the time of invention to select a once monthly oral dosing regimen of ibandronate to treat osteoporosis and to set that dose at 150 mg."  Slip op. at 8.  The Court first determined that the prior art established at least a reasonable expectation that once monthly dosing of ibandronate could successfully treat osteoporosis and reduce fracture risk.  The Court noted that "[a] relatively infrequent dosing schedule has long been viewed as a potential solution to the problem of patient compliance stemming from the inconvenience of oral bisphosphonate regimens," pointing to a prior art bisphosphonate product and several prior art references.  Id.

The Court rejected Roche's argument that the art taught away from once monthly dosing, which Roche primarily based on its alleged failure in its intravenous ibandronate study and a prior art article describing it.  The Court reasoned that the study was a "failure" only in the sense that the reduction in fractures was statistically insignificant given the large number of patients that would have been required to reach a statistically significant conclusion about the relative rates of fractures in the control and subject groups.  The Court stated that "[the study's] failure to generate statistically significant results points to a fault in the study; it does not teach that infrequent ibandronate dosing is ineffective in treating osteoporosis."  Id. at 10.

The Court next found that the prior art pointed to a monthly treatment of 150 mg of ibandronate, stating that, "[a]t the very least, the 150 mg dose was obvious to try."  Id. at 13.  The Court reasoned that a person skilled in the art looking to scale the known-effective daily dose to a monthly dose was faced with a very limited set of possibilities, and would have expected that a 150 mg monthly dose would have equivalent success to the 5 mg daily dose taught in the prior art.

The Court rejected Roche's argument that findings by the FDA taught away from further development of the 5 mg daily dose (and its total-dose equivalents).  The Court reasoned that even though the FDA approved a 2.5 mg daily dose of ibandronate instead of a 5 mg daily dose, the FDA never made any findings contrary to the 5 mg daily dose and was never asked to approve that dose.  The Court also rejected Roche's argument that the district court misinterpreted and misapplied the total-dose concept from the prior art.  The Court explained that the evidence before the district court showed that the total-dose concept could be used as an effective rule of thumb by a person skilled in the art deciding how to scale an efficacious intermittent dose of ibandronate.

The Court next addressed Roche's argument that there were disputed issues of fact as to whether it would have been obvious to administer once monthly doses of 150 mg in light of alleged safety concerns about the adverse gastrointestinal effects of ibandronate and other bisphosphonates.  The Court concluded that the prior art established that doses even higher than 150 mg were considered safe, and that Roche did not point to any references to the contrary.  The Court also noted that Roche's expert was also not "aware of anything that taught that a once monthly, 150 mg dose of ibandronate would be unsafe."  Id. at 16.

Turning to Roche's argument that the 150 mg monthly dose demonstrated unexpected results, the Court held that neither the effectiveness nor the nonlinear bioavailability of the dose rebutted the prima facie showing of obviousness.  Regarding effectiveness, the Court stated that "[t]he evidence of superior efficacy does nothing to undercut the showing that there was a reasonable expectation of success with the 150 mg monthly dose, even if the level of success may have turned out to be somewhat greater than would have been expected."  Id. at 17.  The Court similarly stated that, regarding nonlinear bioavailability, "[t]he increased level of bioavailability has not been shown to be responsible for the improved osteoporosis treatment efficacy of the 150 mg dose."  Id.  Accordingly, the Court affirmed the judgment of the district court that claims 1-8 of the '634 patent and claims 1-10 of the '957 patent were invalid for obviousness.

Judge Newman dissented, stating that "[n]owhere amid the many studies of bisphosphonate osteoporosis treatments over a wide range of dosages and conditions, did any reference show or suggest the Boniva® combination of a single 150 mg dose and once-a-month administration."  Newman Dissent at 4.  According to Judge Newman, "[the majority's] primary reason, that 150 mg is thirty times the daily dose of 5 mg, does not mention that the FDA refused to approve the 5 mg dose due to its toxic side effects," and that "[s]urely this leads away from the obviousness of a single dose thirty times larger."  Id.

Judges:  Newman (dissenting), Lourie, Bryson (author)

[Appealed from D.N.J., Judge Chesler]

This article previously appeared in Last Month at the Federal Circuit, May 2014.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.