CAFC Finds Substantially Pure Isomer Obvious From Prior Art 50/50 Mixture

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Federal Circuit Review No. 72-1.
Substantially Pure Isomer is Obvious From Prior Art 50/50 Mixture

Spectrum Pharmaceuticals, Inc., v. Sandoz Inc., No. 2015-1407, 2015 U.S. App. LEXIS 17313 (Fed. Cir. Oct. 2, 2015) (Before Lourie, Wallach, and Hughes, J.) (Opinion for the court, Lourie, J.).  Click Here for a copy of the opinion.

Spectrum Pharmaceuticals, Inc. (“Spectrum”) holds the approved New Drug Application (NDA) for a (6S) leucovorin formulation indicated for methotrexate rescue, folate deficiency, and use in 5-fluorouracil combination therapy. U.S. Patent No. 6,500,829 is listed in the FDA’s, Approved Drug Products with Therapeutic Equivalence Evaluations (“Orange Book”) as covering the leucovorin drug product. Claims 1-2 of the patent are directed to a pharmaceutical composition consisting of a mixture of 92% – 95 % by weight of the (6S) leucovorin to the (6R) diastereoisomer. Claims 5-9 of the patent also require that the composition is “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.” Sandoz submitted an Abbreviated New Drug Application (“ANDA”) seeking approval of a generic version of the drug in the form of single-use vials with 175 mg or 250 mg of (6S) leucovorin. Sandoz’s ANDA also certified that the ‘829 patent was invalid or not infringed.

Spectrum timely filed suit against Sandoz alleging that Sandoz’s ANDA infringed the ‘829 patent. After claim construction and on summary judgment, the district court granted Sandoz’s motion of non-infringement of claims 5-9. The court subsequently determined at trial that claims 1-2 were invalid as obvious over the prior art. Spectrum appealed.

The issue on appeal was whether a mixture comprising at least 92% of the (6S) isomer of leucovorin would have been obvious when both the 50/50 mixture of isomers and the pure (6S) isomer were known in the art. Affirming the district court, the Federal Circuit agreed that “one of skill would have been motivated to modify the prior art 50/50 mixture to make the claimed mixture,” especially when it was known that the desired activity lies with the (6S) isomer. The Court found no evidence indicating that the claimed mixture “possess[ed] unexpected advantages over the prior art pure material” so as to overcome obviousness. The Court rejected Spectrum’s long felt but unmet need argument, because studies demonstrated that purified (6S) leucovorin and a 50/50 mixture of isomers are clinically interchangeable. Further, a person of ordinary skill “would not have expected there to be any differences in the biological properties between purified (6S) leucovorin with or without a small amount of (6R) leucovorin.”

The Federal Circuit also affirmed the district court’s non-infringement conclusion with respect to claims 5-9. Sandoz’s product was described as “single-use vials with 175 mg or 250 mg of substantially pure [(6S]leucovorin,” which was far less than “at least two doses of 2000 mg each” as construed by the district court. The Court also agreed that Spectrum was estopped from invoking the doctrine of equivalents. During prosecution, Spectrum overcame prior art rejections by amending the claims to include specific quantities and pointing to these limitations as distinguishing features from the prior art. Applicants further argued that the prior art, which only produced experimental quantities, “does not teach, suggest, or otherwise render obvious the claimed compositions in the quantity specified” in claims 5-9. These statements were “clear and unmistakable expressions of the applicants’ intent to surrender coverage of quantities of the compound in lower doses.”