Spectrum Pharms., Inc. v. Sandoz, Inc.

The substantially pure claimed compound was obvious when both the 50/50 mixture and the pure compound were known in the art; the ANDA product also does not infringe the patent when the dosage strength is well below the claimed amount.

January 22, 2016

GENERICally Speaking: A Hatch Waxman Litigation Bulletin

Case Name: Spectrum Pharms., Inc. v. Sandoz, Inc., 2015-1407, 2015 U.S. App. LEXIS 17313 (Fed. Cir. Oct. 2, 2015) (Circuit Judges Lourie, Wallach, and Hughes presiding; Opinion by Lourie, J.) (Appeal from D. Nev., Navarro, J.)

Drug Product and Patent(s)-in-Suit: Fusilev® (levoleucovorin); U.S. Patent No. 6,500,829 (“the ’829 patent)

Nature of the Case and Issue(s) Presented: Leucovorin is a compound used to ameliorate the toxic effects of methotrexate, a chemotherapy treatment; to treat folate deficiency; and to enhance the efficacy of a 5-fluorouracil cancer treatment. Due to an asymmetric C6 carbon, leucovorin may exist as a 50/50 mixture of two diastereoisomers, the (6S) and (6R) isomers. The (6S) diastereoisomer is also known as levoleucovorin and is the isomer with the desired biological activity.

Spectrum is the exclusive licensee of the ’829 patent and holds the NDA for Fusilev. Sandoz submitted an ANDA seeking approval from the FDA for a drug product that will be imported in the form of single-use vials with 175 mg or 250 mg of levoleucovorin indicated for methotrexate rescue at doses of 7.5-75 mg per dose. The asserted claims were directed to compositions comprising a mixture of (6S) and (6R) isomers, with at least 92% or 95% of the (6S) isomer. The patent discloses, but does not claim, a process for purifying the (6S) isomer from a 50/50 mixture using a chiral auxiliary group. The district court construed the term “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” as having its plain and ordinary meaning.

After claim construction, the district court granted summary judgment of non-infringement in favor of Sandoz because Sandoz’s 250 mg product would not satisfy the claim limitation of at least two doses of 2000 mg. The district court also held that Spectrum was precluded from asserting infringement under the doctrine of equivalents. After a bench trial, the court found the asserted claims invalid as obvious. Spectrum appealed the district court’s non-infringement and obviousness holdings. No party appealed the district court’s claim construction. The Federal Circuit affirmed.

Why Sandoz Prevailed: Spectrum argued that the district court improperly used hindsight to provide a reason or motivation to modify the prior art pure (6S) isomer compound to obtain a slightly impure compound. The Federal Circuit framed the issues as follows: “whether a substantially pure compound would have been obvious when both the 50/50 mixture and the pure compound were known in the art.” The Federal Circuit agreed with the district court’s obviousness finding for two reasons. Firstly, if it is known that the desired activity all lies in one isomer, surely, it is better, and there is generally motivation to try to obtain the purest compound possible. Secondly, if the pure material is known, no reason has been shown why one would want to have an impure material. Put another way, “because the desirable properties of the prior art 50/50 mixture are attributable to only one component, and that slightly impure mixture—one that contains the substantially pure (6S) isomer in an amount of at least 92-95%--has not been shown to possess unexpected advantages over the prior art pure material, the less-than-pure material, and any others of similar concentration, cannot be found to have been nonobvious.” Moreover, the record evidence showed that other research groups had responded to the motivation to obtain a pure isomer and were pursuing purified (6S) leucovorin prior to the priority date of the ’829 patent. Next, the Federal Circuit agreed that Spectrum had not adequately presented objective indicia of non-obviousness, in particular long-felt need, which was the only secondary consideration raised on appeal. There was no long-felt need because the purified (6S) isomer compound was clinically interchangeable with the 50/50 mixture.

Turning to the issue of infringement, the Federal Circuit compared Sandoz’s ANDA product to the ’829 patent claims. There could not be literal infringement in this case. The 7.5-75 mg dosage strength related to Sandoz’s ANDA product would be far less than the claimed “at least two doses of 2000 mg each” limitation. And Spectrum was precluded from arguing infringement under the doctrine of equivalents because of prosecution amendments and arguments it made to overcome rejections issued by the PTO. Those statements were clear and unmistaken expressions of the applicants’ intent to surrender coverage of quantities of the compound in lower doses.

Oren D. Langer


Managing Partner, New York Office

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