By Kevin E. Noonan --
Last week the Federal Circuit affirmed a District Court's finding of invalidity and non-infringement in ANDA litigation between Spectrum Pharmaceuticals and Sandoz. In so doing, the Court deferred to the factual determinations made by the lower court for no clear error and agreed on de novo review with the District Court's legal conclusions.
The case involved leucovorin, a drug used to "ameliorate the toxic effects of methotrexate during cancer chemotherapy . . . to treat folate deficiency [] and to enhance the efficacy of 5-fluorouracil cancer treatment" and sold by exclusive licensee Spectrum Pharmaceuticals as Fusilev®. The molecule exists as a pair of diastereomers, designated 6S and 6R, in a 50/50 mixture. The 6S diastereomer, also called levoleucovorin, has the biological activity of the drug.
Spectrum, the exclusive licensee of Orange Book-listed U.S. Patent No. 6,500,829, asserted claims 1, 2 and 5-9
Claim 1. A pharmaceutical composition for therapeutic use which consists essentially of a therapeutically effective amount sufficient for the treatment of human beings for methotrexate rescue or folate deficiency, of a pharmaceutically acceptable compound which is a (6S) diastereoisomer selected from the group consisting of (6S) leucovorin (5- formyl-(6S)-tetrahydrofolic acid) and pharmaceutically acceptable salts and esters of (6S) leucovorin; wherein the compound consists of a mixture of (6S) and (6R) diastereoisomers and consists of at least 92% by weight of the (6S) diastereoisomer, the balance of said compound consisting of the (6R) diastereoisomer; in combination with a pharmaceutically acceptable carrier.
Claim 2 recites the limitation that the 6S diastereomer was 95% of the composition by weight. The specification discloses that "a typical daily dose" is up to 150 mg of the 6S isomer for use with methotrexate, 25-150 mg for use with 5-FU and 2-25 mg for treating folate deficiency.
Claim 5. A pharmaceutical composition for therapeutic use for the treatment of human beings comprising:
a pharmaceutically acceptable composition which is a (6S) diastereoisomer selected from the group consisting of (6S) leucovorin (5-formyl-(6S)-tetrahydrofolic acid) and pharmaceutically acceptable salts and esters of (6S) leucovorin, wherein the composition consists of a mixture of (6S) and (6R) diastereoisomers and consists of at least about 92% by weight of the (6S) diastereoisomer, the balance of said composition consisting of the (6R) diastereoisomer; and a pharmaceutically acceptable carrier; and
said composition being of a quantity at least sufficient to provide multiple doses of said mixture of (6S) and (6R) diastereoisomers in an amount of 2000 mg per dose.
(Claims 6-9 recited additional limitations that the opinion states were not relevant to the issues on appeal.)
The claims were rejected during prosecution as being anticipated or obvious over a prior art reference disclosing synthesis of levoleucovorin, which the applicants addressed by adding claims 5-9 and "emphasizing the specific claim limitations relating to quantities of the specified mixture, which were allegedly not disclosed by the prior art." When this was unsuccessful the inventors appealed, and the claims were eventually granted inter alia on the grounds that the quantity limitations could not be met by the cited art.
Sandoz's generic version of the drug was specified as "single-use vials with 175 mg or 250 mg of levoleucovorin, indicated for [use with] methotrexate [] at doses of 7.5–75 mg per dose." On this basis the District Court granted summary judgment of non-infringement of claims 5-9, on the ground that Sandoz's product would not provide a minimum of 2000 mg per dose and rejected Spectrum's argument that Sandoz would import in aggregate "at least two doses of 2000 mg per dose."
The District Court also held that Spectrum was barred by prosecution history estoppel from relying on the doctrine of equivalents based on statements made during prosecution. Specifically, Sandoz argued that applicants had distinguished the prior art based on the "more stringent quantity limitations" of their claims. The District Court held that these arguments amounted to "a clear and unmistakable surrender of subject matter covering pharmaceutical composition quantities less than what is required to provide two or more doses of, at minimum, 2000 mg per dose of the mixture."
With regard to Sandoz's validity challenge of claims 1 and 2, the District Court found that the prior art disclosed "(i) leucovorin as a mixture of (6R) and (6S) diastereoisomers; (ii) that the therapeutic usefulness of leucovorin derives wholly from the (6S) isomer; and (iii) a rationale for investigating a purified (6S) isomer product for use in 5-FU combination therapy." That prior art included references not considered by the Office, that disclosed methods for making purified levoleucovorin (the 6S diastereomer), and that these methods would "invariably" produce a mixture of the 6S and 6R diastereomers but also "a highly pure 6S isomer." Finally, the District Court held that the prima facie obviousness determination was not rebutted by secondary considerations because Spectrum did not provide a nexus between any of the factors (including long-felt need and commercial success as evidenced by successful licensing) and the invention.
The Federal Circuit affirmed, in an opinion by Judge Lourie joined by Judges Wallach and Hughes. The validity question, according to the opinion, rested on the balance between the motivations set forth in KSR v. Teleflex (wherein "'design need or market pressure or other motivation' may provide a suggestion or motivation to combine prior art elements in the manner claimed") and impermissible hindsight reconstruction of the invention. Here, Spectrum argued (somewhat bizarrely) that the question the Court should consider was whether there was any motivation in the art to contaminate purified (100%) preparations of the 6S diastereomer with small amounts of the 6R diastereomer. Sandoz countered that the District Court correctly considered whether the skilled worker would have been motivated to increase the percentage of the 6S diastereomer from 50/50 mixtures of leucovorin, and that "it had no burden to show a motivation to contaminate the prior art pure (6S) isomer compound" (emphasis in opinion). The Court noted that typically arguments related to purified diastereomers (or enantiomers) related to pharmaceuticals were centered on whether it would have been obvious to purify one of the isomers from a mixture, citing several ANDA cases. This case, in contrast, revolved around "whether a substantially pure compound would have been obvious when both the 50/50 mixture and the pure compound were known in the art," and agreed with the District Court that it would.
The Federal Circuit found no clear error in the District Court's factual determination that the skilled worker would have been motivated by the knowledge that the biological activity of leucovorin resides in one diastereomer to differentially purify that isomer from a mixture, stating that "there is always in such cases a motivation to aim for obtaining a pure, resolved material." And similarly, the Court found that there would be no motivation (or reason) to contaminate a purified isomer to obtain an "impure" mixture. But this argument, advanced by Spectrum, was not persuasive on the issue of non-obviousness because the "slightly impure (92%-95%) mixture was not shown to have any "unexpected advantages over the prior art pure material, the less-than-pure material, and any others of similar concentration." In addition, the Federal Circuit agreed with the District Court that the motivation to purify the biologically active 6S isomer would apply to "substantially pure" preparations as well as "pure" levoleucovorin. The opinion asserted that the evidence showed than "numerous" researchers had recognized the 6S isomer as possessing the biological activity had undertaken the effort to purify that isomer from the mixture and many succeeded (whether prior to the '829 patent's priority date or after was unclear in the opinion).
This motivation, and the evidence of a reasonable expectation of success as shown by the success of these "numerous" other researchers, was enough to satisfy the panel that the District Court did not err in finding claims 1 and 2 to be obvious. The opinion also stated that Spectrum did not show "any" evidence of unexpected results based on the substantial clinical equivalence of purified 6S leucovorin and preparations that are 92-95% pure.
The opinion also held that whether or not the prior art at issue before the District Court was enabling did not change its conclusion, based on "the whole spectrum of prior art available before the invention was made" which would have enabled the skilled worker to prepare substantially pure levoleucovorin (despite the rubric that enablement is not a requirement for a prior art reference to render a claim obvious).
Finally, the panel agreed with the District Court that Spectrum did not establish any of the objective indicia of non-obviousness sufficient to rebut the prima facie case, based on the equivalence of the prior art mixtures and the substantially pure levoleucovorin as claimed in claims 1 and 2 of the '829 patent.
With regard to non-infringement, the Federal Circuit also affirmed, based on its agreement with the District Court that Sandoz would be entitled by FDA approval of its ANDA to sell "single-use vials with 175 mg or 250 mg of substantially pure levoleucovorin" for the methotrexate indication for which the approved administered dose would be limited to 7.5-75 mg. This was "far less" than the "at least two doses of 2000 mg each" recited in claims 5-9 of the '829 patent, and thus Spectrum had not established literal infringement. As for infringement under the doctrine of equivalents, the panel opinion found that the "claim amendments and distinguishing statements on the prior art during prosecution" estopped Spectrum from asserting infringement under the doctrine. The opinion notes that the prosecution history contained several instances where the dosage was relied upon to distinguish the prior art by amendment and argument, including arguments made to the Board on appeal.
Spectrum Pharmaceuticals Inc. v. Sandoz Inc. (Fed. Cir. 2015)
Panel: Circuit Judges Lourie, Wallach, and Hughes
Opinion by Circuit Judge Lourie