The Federal Circuit decision in Acorda Therapeutics, Inc. v. Roxane Laboratories, Inc. addressed several aspects of obviousness doctrine. We previously wrote about the impact of a blocking patent on consideration of objective indicia of non-obviousness. Here, we look at the court’s treatment of the requirement for a reasonable expectation of success.
The Acorda Ampyra® Patents At Issue
The Orange Book-listed patents for Ampyra® include the four Acorda patents at issue in this case—U.S. Patent Nos. 8,007,826, 8,663,685, 8,354,437, and 8,440,703—and an earlier patent licensed from Elan, U.S. Patent No. 5,540,938. Independent claim 6 of the ‘826 patent is representative for the purpose of this article:
A dosing regimen method for providing a 4-aminopyridine [(“4-AP”)] at a therapeutically effective concentration in order to improve walking in a human with multiple sclerosis in need thereof, said method comprising:
initiating administration of 4-AP by orally administering to said human a sustained release composition of 10 milligrams of 4-AP twice daily for a day without a prior period of 4-AP titration, and then,
maintaining administration of 4-AP by orally administering to said human a sustained release composition of 10 milligrams of 4-AP twice daily without a subsequent period of 4-AP titration,
whereby an in vivo CmaxSS:CminSS ratio of 1.0 to 3.5 and a CavSS of 15 ng/ml to 35 ng/ml are maintained in the human.
According to the Federal Circuit decision, Acorda demonstrated in clinical trials that by following the claimed dosing regimen, 4-AP could improve walking in humans with multiple sclerosis and avoid severe toxic side effects that had prevented clinical use of 4-AP in the past.
The District Court Decision
This appeal arose from ANDA litigation against Roxane, Mylan Pharmaceuticals Inc. and Teva Pharmaceuticals USA, Inc. The defendants challenged validity in view a number of clinical studies of 4-AP treatment of multiple sclerosis:
- Stefoski was relied on to show that 4-AP could improve walking in multiple sclerosis patients.
- Davis was relied on as showing improvement in motor tasks within 60 minutes of administering 4-AP at doses as low as 10 mg.
- Van Diemen and Polman were relied on to show long-term effects of administering a stable dose of 4-AP (since both Stefoski and Davis were one-day trials).
- Polman also was cited for teaching administering a dose of 10-50 mg/day.
- Bever I was cited for showing that a serum concentration of 30-59 ng/mL may be adequate for inducing improvements of some neurologic deficits associated with multiple sclerosis, and that 4-AP serum levels at 104 ng/mL could result in serious side effects like seizures.
- Bever II (a review article) was cited for concluding from several trials that 4-AP may cause seizures at higher doses, and therefore, that it may be useful to use controlled release formulations to minimize toxicity.
- Schwid (sponsored by Elan to test the efficacy and safety of Elan’s sustained release formulation) was relied on to show that 4-AP had a beneficial effect on motor function. The dosing regimen used in this study was 17.5 mg 4-AP sustained release twice a day for a week. Schwid concluded that 4-AP provided some improvement in timed gait, but had no significant effect on the global impression of the condition.
- Goodman I (Acorda’s own first and failed trial using 4-AP to treat multiple sclerosis) reported a study using 20-80 mg/day that found some improvement in walking, but also adverse events, including seizures, at doses above 40 mg/day.
The district court found the prior art to provide a motivation to test, with a reasonable expectation of success, a 10 mg twice-daily dose of sustained release 4-AP to improve walking in multiple sclerosis patients. In particular, the district court relied on Schwid for disclosing improvement in walking ability by administering 17.5 mg 4-AP twice daily , and Goodman for disclosing improvement in walking using 10-40 mg 4-AP twice daily. Since the Bever II review article reported that higher doses of 4-AP may cause seizures, the district court found that it would be reasonable to expect that the lower 10 mg dose of 4-AP disclosed by Goodman would be preferable.
The Federal Circuit Decision
The Federal Circuit decision was authored by Judge Taranto. Judge Dyk joined in the decision. Judge Newman filed
On appeal, Acorda challenged the finding of “a reasonable expectation of success based on Schwid and Goodman in light of the totality of the prior art.” In particular, Acorda argued that “Schwid teaches away from the claimed invention and that the prior art teaches the administration of titrated-dosing regimen rather than a stable-dosing regimen as required by the claimed invention.” Acorda pointed to Bever II and a more recent review article by Solari, which concluded that 4-AP was not a safe and effective treatment for multiple sclerosis. Acorda also emphasized that Elan, the holder of the sustained release 4-AP formulation patent, had abandoned its attempts to develop 4-AP for multiple sclerosis treatment.
The Federal Circuit rejected Acorda’s arguments, explaining that “conclusive proof of efficacy” is not required for a finding of obviousness. The Federal Circuit agreed with the district court that prior art reports that 4-AP treatment may improve walking in multiple sclerosis patients supported a reasonable expectation of success. For example, the Federal Circuit agreed with the district court that Schwid did not teach away from using 4-AP to improve walking, even though patients reported no significant improvement in global impression of their condition, because global impression “is not the issue.”
The Federal Circuit discounted Acorda’s arguments that prior art only taught titrated dosing regimens, finding that even if the studies “used a titrated-dosing scheme to avoid adverse effects caused by starting at higher doses,” the prior art as a whole did not indicated that titrated dosing was required. Rather, the prior art revealed a consensus that 4-AP does not induce seizures at lower doses. The Federal Circuit also noted expert testimony that supported a finding that a stable dosing regimen is a general goal of drug development, so a person of ordinary skill in the art would be motivated to identify a stable dose within the narrow range disclosed by the prior art.
The Federal Circuit concluded that “[t]he district court did not clearly err in finding that a person of skill would have looked to both of those references [Schwid and Goodman], considered their limits, and had a reasonable expectation of success as to the efficacy of 10-20 mg 4-AP twice daily to improve walking.” Thus, the prior art references provided “a sufficient basis for the district court’s finding of a reasonable expectation of success” even though the prior art studies never matured into an effective method of treating multiple sclerosis.
Judge Newman’s Dissent
Judge Newman criticized the majority decision for ignoring that “work with 4-AP was abandoned due to the inability to balance the compound’s potential effectiveness with its toxicity.” Judge Newman found the prior art to reveal a goal of achieving a low and stable dose of 4-AP for treating multiple sclerosis, but failed to reach this goal. Judge Newman noted that Dr. Goodman had testified at trial that the result of the timed walk test “was not at all significant,” and that while the Goodman I study showed increasing benefits as the dose was increased from 20 to 50 mg/day, it also showed that the higher doses resulted in adverse effects. In contrast, Acorda discovered that “the effect of 4-AP did not increase with increase in dosage,” and it was that breakthrough that led Acorda to conduct further studies that led to the invention. In Judge Newman’s view, the claimed invention “contradicted the teachings of all the previous studies” and should not have been held obvious.
Focusing On The Claimed Effect
In upholding the finding of reasonable expectation of success, the Federal Circuit cited prior art reports directly related to the claimed indication of improving walking and overlooked different or more general negative assessments of the usefulness of 4-AP for treating multiple sclerosis. The Federal Circuit’s conclusion that several decades of failure to develop 4-AP as a treatment for multiple sclerosis did not undermine specific positive results pertaining to improving walking highlights the limited scope of the reasonable expectation of success inquiry.