Accorda Therapeutics v. Roxane Labs ($-aminopyridine)
Edward D. Pergament, Esq.
The case Accorda Therapeutics v. Roxane Labs came down from the Federal Circuit on September 10, 2018. Federal Circuit invalidated 4 patents directed to a 600 million drug.
4-aminopyridine (dalfampridine) is a 102 year old drug. Research into the use of 4-AP in multiple sclerosis has been ongoing since 1970s. 5 patents has been the patents-in-suit. The broader patent assigned to Elan claims the use of sustained release formulation of 4-AP in multiple sclerosis. Elan patent expired on July 30, 2018. The 4 Accorda patents with longer expiration times claims methods of administration of 4-AP in patients with MS 1) in a dose of 10 mg twice daily, 2) at that stable dose for the entire treatment period of at least two weeks, 3) to achieve serum level of 4-AP of 15-35 ng/ml, and 4) to improve walking. The examples of the specific asserted claims will be set forth later herein below.
Stefoski investigated intravenous formulation of 4-AP to determine efficacy in MS. Doses from 2 mg to 35 mg were given to patients. 10 of 12 patients in the study showed mild to marked improvement. Improvements were seen at doses as low as 2 mg. Gait ( a measure of walking ability) improved in 5 patients.
Davis investigated oral, immediate release formulation of 4-AP in MS patients. Doses from 10 mg to 25 mg were given. David reports improvement in gait. Davis also reports that no serious or bothersome side effects were observed at doses of up to 25 mg.
Polman reports a study of long-term efficacy and safety of 4-AP in patients with MS.. Patients took stable doses (without escalation and titration) of 10 to 50 mg immediate release formulation of 4-AP. Overall, 23 patients continued active treatment for 6 to 32 months with daily doses ranging 15-40 mg. Polman reported: “ Although a placebo effect cannot be excluded the dynamics of response in relation to the intake of the medication and the deterioration and subsequent improvement in functioning during drug free interval and subsequent restarting of therapy are, in our view, highly suggestive of a real effect being induced by the 4-AP.”
Beaver I reference
Beaver reports the results of a double blind, placebo controlled trial of immediate release oral formulation of 4-AP in 8 MS patients. Study aimed to compare the effects of low (30-59 ng/ml) and high (60-100 ng/ml) peak concentrations of 4-AP in the blood. Beaver I concluded that the therapeutic response was not concentration-related as between two ranges tested. Beaver I reports: “because the high-serum concentration arm produced much greater toxicity than the low without any obvious therapeutic advantage, it seems likely that clinically useful serum concentration would be in the 30 to 59 ng/ml range.”
Beaver II reference
Beaver II is a review article of the use of 4-AP in MS. The article concluded that 4-AP is effective in some MS patients. As to toxicity, Beaver II states that “seizures are common at higher doses but 4-AP “rarely causes seizures at the doses used in MS trials.” Beaver II suggested that controlled release formulation would be useful in addressing toxicity.
Elan study (1994) and Schwid (1997)
Elan study was not published and is not prior art. Elan developed sustained release formulation of 4-AP. Elan conducted a double-blind, placebo controlled clinical trials of controlled release formulation of 4-AP in 161 patients. Elan trial showed no statistically significant improvement in the composite score for MS but showed a statistically significant improvement in secondary outcomes of lower extremities motor score, a measure of muscle strength in the legs. Elan also conducted a smaller trial of controlled release formulation of 4-AP in 10 patients reported in 1997 article by Schwid. Schwid reported that the larger trials did not find statistically significant improvement in the composite score for MS but noted that the composite score may have been an inadequate measure of efficacy. In the Schwid study, ten patients were given 17.5 mg sustained release formulation of 4-AP twice daily and measured timed gait (a measure of walking ability) among other endpoints.. Schwid reported a statistically significant improvement in timed gait.
Accorda tested 10 mg, 15 mg, 20 mg, and 25 mg sustained release formulation of 4-AP in patients with spinal cord injuries. The average serum concentration for 10 mg twice daily dose was 20.8+-5 ng/ml.
Accorda clinical trial and Goodman references
In 2000-2001, Accorda conducted a study of Elan’s controlled release formulation of 4-AP in MS patients. Patients received 10 mg 4-AP twice daily for a week, then higher dosages, which increased weekly in 5 mg increments, reaching 40 mg twice daily. Most of the results of this study were published by Dr. Goodman in two abstracts and a poster in late 2002. Dr. Goodwin was Accorda expert at trial. Dr. Goodwin reported: “Doses above 50 mg per day added little benefit and increased adverse effects. There was significant improvement in measures of mobility and muscle strength.” The Goodwin poster reported that observed adverse event, including seizures, were associated with higher peak plasma concentrations and rapid plasma concentration changes caused by immediate release 4-AP. The Goodwin poster reported a graph of dose response on 25 ft walk. The graph showed that the total time for the walk decreased significantly between the placebo and 20 mg/day range and stayed essentially the same for higher doses. The Conclusion section had six bullet points. They reported significant benefit on timed walking and significant benefit on lower extremity strength. The Goodwin poster reported little added benefit and increased adverse events at doses above 50 mg/day.
Representative asserted claim 6 of the Accorda patent recites:
6 A dosing regimen method for providing a 4-aminopyridine 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-aminopyridine by orally administering to said human a sustained release composition of 10 milligrams of 4-aminopyridine twice daily for a day without a prior period of 4-aminopyridine titration, and then,
Maintaining administration of 4-aminopyridine by orally administering to said human a sustained release composition of 10 milligrams of 4-aminopyridine twice daily; without a subsequent period of 4-aminopyridine titration,
Whereby an in vivo CmaxSS:CminSS ratio of 1.0 to 3.5 and CavSS of 15 ng/ml to 35 ng/ml are maintained in the human.
District court held that a relevant skilled artisan would have been motivated to administer a stable dose of 10 mg of 4-AP twice daily and had a reasonable expectation of success in the objective to improve walking. The district court also found that the pharmacokinetics parameters of the claims would have been inherent. Finally with respect to secondary considerations of non0obviousness, the court held that commercial success of Apryra, as well as long felt need are not probative of non-obviousness since the Elan patent (“blocking patent”) block the competition from entering the field even if the claims were obvious.
Accorda makes 3 arguments on appeal. First, Accorda contents that the district court erred in finding that a ordinary artisan would have a motivation to combine the prior art. Second, Accorda challenges court’s determination that pharmacokinetics limitation (15 ng.ml to 35 ng/ml) are inherent. Third, Accorda argued that the court improperly applied a categorical rule that a blocking patent (Elan patent) negates any finding in Accorda favor on secondary considerations, such as commercial success, long felt need, etc.
The use of 4-AP to improve walking in MS patients is disclosed in Stefoski, Davis, Schwid and Goodman references. Goodman specifically teaches that gait (measure of walking ) improves while cumulative parameters is not improving.
The use of 4-AP in a stable formulation (level administration of the same dose over long time) is disclosed in Polman and Schwid. Expert for the generic testified at trial that goal of any drug development is to administer a stable dose. The expert further testified : “Obviously, it is a lot easier to take one pill, the same pill twice a day than to have to figure out, well, this morning I need this much. That much. But with pills, it is almost impossible to titrate easily.”
Several references suggests the use of low dose 4-AP. Goodwin poster in the graph reported that time to walk decreased from placebo to 20 mg/day and then stays the same at higher doses which side effects are observed at higher doses. Beaver I specifically looked at high versus low serum concentration of 4-AP and concluded that higher concentrations provide little benefit and lead to side effects, including seizures. 10 mg twice daily is specifically disclosed in Polman, Heyes, and Goodwin references.
The blood serum level of between 15 and 35 ng/mg is disclosed in Hayes, which teaches administration of 10 mg 4-AP twice daily to patients with spinal cord injuries. The court found this limitation inherent every time 10 mg dose is administered in the prior art. According to the court, “an obvious formulation cannot become nonobvious simply by administering it to a patient and claiminh the resulting serum concentration” Sl Op. at 43.
The Federal Circiot found the claims prima facie obvious over the prior art as a whole. The remaining issue was secondary consideration of non-obviousness, namely commercial success and long-felt need. The Federal Circuit held that the risk of liability from the blocking Elan patent would have provided an independent incentive for a potential competitor not to develop the invention of the Accorda patents even if they were obvious. For this reason, the Federal circuit discounted evidence of commercial success and long-felt need and found all asserted claims of the Accorda patent obvious.
Judge Newman, who never seen an invalid pharma patent, dissented. The essence of her dissent is that there had been long term failures in the attempt to develop 4-AP for MS and this indicates non-obviousness. Judge Newman could not point to one limitation that was not taught or suggested by the prior art.
In essence, Accorda made a mistake publishing the results of the Phase II study in Dr. Goodwin abstracts and a poster. Without this evidence, the Accorda patents would have been upheld.Previous Post Next Post
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