Hoffmann La-Roche Inc. v. Apotex Inc.
Addressing the validity of a dosing regimen patent in Abbreviated New Drug Application (ANDA) litigation, the U.S. Court of Appeals for the Federal Circuit affirmed a lower court’s summary judgment of invalidity of two patents, finding that a combination of prior art references does not need to describe the efficacy of a specific dosage regimen, only that there is a reasonable expectation of success. Hoffmann La-Roche Inc. v. Apotex Inc., Case No. 13-1128 (Fed. Cir., Apr. 11, 2014) (Bryson, J.) (Newman, J., dissenting).
After Apotex made an ANDA filing, Hoffmann La-Roche (Roche) sued for infringement of patents directed to methods of treating osteoporosis. Roche then moved for a preliminary injunction. The district court denied the motion, finding that Roche had failed to prove it was likely to succeed on the merits in view of Apotex obviousness defense. Roche appealed, and the Federal Circuit affirmed the denial of preliminary injunction.
While that appeal was pending, the district court granted summary judgment of invalidity based on obviousness. The lower court found that once-monthly oral dosing was established in the prior art and that the dosage level of 150 mg per month was suggested in a combination of several prior art references, or at least indicated as obvious to try. The district court found that Roche’s evidence of objective considerations of non-obviousness was insufficient to defeat Apotex motion for summary judgment. Roche appealed again.
The Federal Circuit reviewed the issue of obviousness of the dosage limitations and concluded that the prior art taught the desirability of a relatively infrequent dosing schedule. The Court rejected Roche’s argument that the art taught away from once-monthly dosing because it was widely believed as of the date of the invention that a bisphosphonate regimen with a dose-free interval longer than one or two weeks would not be effective. Roche argued that the prior art did not conclusively prove efficacy at the claimed once monthly dose. The Federal Circuit found, however, explained that Roche was trying to apply the wrong standard and that “conclusive proof of efficacy [at the claimed dosing interval] is not necessary to show obviousness.” Rather, all that is required is a reasonable expectation of success.
The Federal Circuit concluded that, in accordance with the total-dose concept, efficacy depends on the total oral dose given rather than the dosing schedule and that this taught by the prior art, which provided substantial guidance as to the total dose. One need only scale up a known-effective dose from a shorter interval regimen, stated the Court. The Federal Circuit confirmed that the evidence showed the total-dose concept can be used as an effective rule of thumb by a person of ordinary skill deciding how to scale to an efficacious intermittent dose.
Roche argued that there were disputed issues of fact as to whether the claimed dosage level and frequency were safe, noting a prior art study showed a higher incidence of diarrhea and number of dropouts with a daily 5 mg dose (which scales up to about 150 mg/month). However, the Federal Circuit stated the study taught that the side effect profile seemed to be safe. The Court found that there was no genuine issue of fact suggesting that the references taught away from the monthly 150 mg dose.
Roche also argued that the record showed that the 150 mg once-a-month dose was more effective than the 2.5 mg daily dose and that the superior effectiveness of the 150 mg and the drug’s nonlinear bioavailability at the claimed dosage level were unexpected. While the evidence supported superior efficacy at 150 mg monthly dose, as compared to 2.5 mg daily dose, the Federal Circuit found that the evidence did not rebut a strong showing that the prior art disclosed monthly dosing and provided a reason to set that dose at 150 mg. The Court also found that prior art suggested that there was a reasonable expectation of success with the 150 mg monthly dose. Using the same reasoning the nonlinear bioavailability of the drug did not rebut the prima facie showing of obviousness of a once month 150 mg dose. Specifically, Roche did not show that the increased level of bioavailability was responsible for improved osteoporosis treatment efficacy at the higher dose.
Judge Newman dissented, arguing that there is no suggestion in the prior art of record (showing a wide range of dosages and conditions) that showed or suggested the claimed combination of a single 150 mg once-a-month dose, nor the effectiveness and safety of this combination. Judge Newman stated that the majority adopted the argument that 150 mg is 30 times the daily dose of 5mg, but ignored the fact that the FDA refused to approve the 5 mg dose due to its toxic side-effects, a fact that lead away from the obviousness of a single dose 30 times larger.