In In re Copaxone Consolidated Cases, the Federal Circuit affirmed the district court decision finding four patents directed to a specific dosing regimen for using COPAXONE® 40 mg/ml to treat patients with relapsing multiple sclerosis invalid as obvious. One thing that caught my attention was the use of originally confidential statements to FDA as evidence of the state of the art that supported the obviousness holding.

The COPAXONE® Patents At Issue

The patents at issue were U.S. Patent Nos. 8,232,250, 8,399,413, 8,969,302, and 9,155,776, which are four of the five patents listed in the Orange Book for Copaxone® (glatiramer acetate) 40 mg/ml. (The fifth patent, U.S. Patent No. 9,402,874, issued later and is the subject of separate litigation.)

The Federal Circuit deemed claim 1 of the ‘250 patent representative:

1. A method of alleviating a symptom of relapsing-remitting multiple sclerosis in a human patient suffering from relapsing-remitting multiple sclerosis or a patient who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis comprising administering to the human patient a therapeutically effective regimen of three subcutaneous injections of a 40 mg dose of glatiramer acetate over a period of seven days with at least one day between every subcutaneous injection, the regimen being sufficient to alleviate the symptom of the patient.

Thus, the claimed methods relate to a 3x/week dosing regimen said to be associated with reduced side effects as compared to treatment with Copaxone® 20 mg/ml administered daily.

The Federal Circuit Decision

The Federal Circuit decision was authored by Judge Reyna and joined by Judges Bryson and Stoll.

The Federal Circuit reviewed the asserted prior art, and noted that it included:

• an understanding that the 20 mg/ml dose had not been optimized
• suggestions to explore optimal dosing
• recognition that daily injections were problematic for patients
• studies of alternate daily dosing of 20 mg/ml
• studies of daily dosing of 40 mg/ml (including the “FORTE” study)
• studies of alternate daily dosing of 40 mg/ml*

*As noted by the court, this differs from the claimed regimens by one dose over a two week period.

The district court found the claimed regimen obvious based on an “obvious to try rationale” where there was “a finite number of predictable solutions that a person of ordinary skill in the art would have good reason to pursue.” The Federal Circuit affirmed, agreeing that the prior art revealed a motivation to pursue less frequent dosing, a limited number of permutations of dose and frequency to explore, and a reasonable expectation of success because “thrice-weekly 40mg injection would result in a total weekly dose very close to that in the already-approved daily 20mg injection—120mg/week versus 140mg/week.”

In a companion case, the court affirmed the USPTO Patent Trial and Appeal Board Inter Partes Review (IPR) decisions that found three Copaxone patents invalid as obvious.

The “State Of The Art” References

The Federal Circuit decision discusses “two additional references” published after the priority date but nevertheless deemed to be relevant to “the state of the art.”

One was a 2009 study (“Khan 2009”). The Federal Circuit notes that Khan 2009 was “published three weeks after … the priority date of the Copaxone patents, but the study began two years earlier.” The abstract stated, “[t]here is considerable interest in studying a more patient friendly dosing regimen of GA that may be as efficacious and better tolerated than daily GA.” The Khan 2009 study compared 20mg GA 2x/week to 20mg GA daily.

The PTAB’s treatment of Khan 2009 in the IPRs and the Federal Circuit’s comments thereon will be addressed in a separate article.

The other was Teva’s own Phase III trial of the product at issue (40mg GA 3x/week), referred to as “Glatiramer Acetate Low-frequency Administration” (“GALA”). The district court accepted statements in Teva’s FDA submission as an “admission by Teva to inform on the motivations of those having ordinary skill in the art at the time of the invention.” The district court and Federal Circuit cited the following statements to FDA:

[After the FORTE study demonstrated that the 40mg dose was equally effective as the 20mg dose,] the natural next step [was] to reduce the dosing regimen of GA and find the optimal regimen that [would] improve the convenience of treatment and reduce the burden and adverse events associated with daily subcutaneous injections.

[Results of previous studies] demonstrated effects in relapse rate reduction which were comparable to daily injections of GA 20mg, suggesting a lower injection frequency can be considered.

[O]ne may certainly expect a reduction in the frequency of such [side effect] reactions with this new dose regimen, further enhancing subject adherence to treatment.

The Federal Circuit approved the district court’s reliance on these statements as “confirmation of how a POSITA would understand FORTE, which is prior art.”

The courts’ reliance on these post-filing statements to FDA are concerning, because most clinical trial protocols include an explanation of the scientific rationale underlying the study, including a justification for the dose and dosing regimen, and Investigational New Drug Applications must include a summary of previous human trials with the drug and how they relate to “the safety of the proposed investigation or to the investigation’s rationale.” The courts appear to have lost sight of the fact that these explanations were provided by the investigator and informed by hindsight with knowledge of the invention.

I also bristled at the Federal Circuit’s comment that these two references “do not qualify as statutory prior art”—as if there is some other category of “prior art” that doesn’t quite qualify under the statute but nevertheless can be cited against the novelty or non-obviousness of a patent.