Saturday, October 03, 2015

The CAFC affirms D. Nev. in Spectrum case on Leucovorin

From SPECTRUM PHARMACEUTICALS, INC. v. Sandoz, concerning the
drug Leucovorin, which is used to ameliorate the toxic effects
of methotrexate.

Spectrum Pharmaceuticals, Inc. (“Spectrum”) appeals
from the decisions of the United States District Court for
the District of Nevada holding claims 1–2 of U.S. Patent
6,500,829 (“the ’829 patent”) invalid as obvious, and
finding claims 5–9 of the ’829 patent not infringed by the
submission of an Abbreviated New Drug Application
(“ANDA”) by Sandoz Inc. (“Sandoz”). Spectrum Pharm.,
Inc. v. Sandoz Inc., No. 2:12-cv-00111, 2015 WL 794674
(D. Nev. Feb. 25, 2015) (“Trial Order”); Spectrum Pharm.,
Inc. v. Sandoz Inc., No. 2:12-cv-00111, 2014 WL 7368845
(D. Nev. Dec. 29, 2014) (“Summary Judgment Order”).
Because the district court did not err in concluding that
claims 1–2 are invalid, and additionally did not clearly err
in finding claims 5–9 not infringed by Sandoz’s ANDA
product, we affirm.

<-- This case involves a molecule with optical activity: Due to an asymmetric C6carbon, leucovorin may exist as a 50/50 mixture of two diastereoisomers, the (6S) and (6R) isomers. The (6S) diastereoisomer is also known as levoleucovorin or l-leucovorin, and is the isomer with the desired biological activity. In the prosecution,
During prosecution of the application that became the ’829 patent, the examiner rejected the application’s claims as anticipated by or obvious over an article disclosing an enzymatic synthesis technique by which 0.91 grams of lleucovorin had been synthesized.

At trial:

Sandoz stipulated to infringement of claims 1 and 2, and the district court subsequently conducted a bench trial only on the validity of those claims. The 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. Trial Order at *6–8, *13–14. The court also found that preparations of purified (6S) isomer by an enzymatic synthesis method and by separation methods had been publicly reported before the ’829 patent’s priority date. Id. at *6–7. In particular, the court analyzed two related prior art references that disclosed a process for separating the diastereoisomers using the solubility differential of the (6S) and (6R) isomer salts, i.e., fractional crystallization. See id. at *11–13 (findings relating to Donna B. Cosulich, Diastereoisomers of Leucovorin, 74 J. Am. Chemical Soc’y 4215–16 (1952) and U.S. Patent 2,688,018 (collectively, “Cosulich” or “the Cosulich references”)).

The arguments in this case are a bit unusual:

Sandoz responds that the district court correctly found that one of skill would have been motivated to make substantially pure (6S) leucovorin starting with the 50/50 mixture to have a more effective pharmaceutical treatment, and would have reasonably expected to succeed in doing so. Sandoz contends that it had no burden to show a motivation to contaminate the prior art pure (6S) isomer compound, because the court’s analysis began with the 50/50 mixture and rejected Spectrum’s arguments on the inoperability of the prior art. Moreover, Sandoz argues, the court found no patentable difference between the claimed substantially pure compound and the prior art pure compound, which presented a prima facie case of obviousness that Spectrum failed to rebut.

Most issues relating to purified diastereoisomers or enantiomers involve the question whether a pure, resolved compound would have been obvious over the corresponding mixture. See, e.g., Aventis Pharma Deutschland GmbH v. Lupin, Ltd., 499 F.3d 1293, 1301–03 (Fed. Cir. 2007);


This case is unusual in involving a slightly different question, namely, whether a substantially pure compound would have been obvious when both the 50/50 mixture and the pure compound were known in the art. We agree with the district court that the claimed substantially pure compound would have been obvious over both the 50/50 mixture and the pure (6S) isomer compound in the prior art. First

Spectrum’s position here, that the 92–95% pure material was nonobvious over the known pure material—that position, despite its superficial appeal, is not persuasive.


In the face of that evidence of obviousness, Spectrum did not provide any evidence of unexpected results for the substantially pure compound as compared to the 50/50 mixture or the 100% pure compound.


We owe the district court’s factual findings considerable deference on appeal, and we see no clear error based on the record before us. Based on those findings, we affirm the district court’s conclusion that Sandoz proved by clear and convincing evidence that claims 1 and 2 of the ’829 patent are invalid as obvious.



Post a Comment

<< Home