Sanofi-Synthelabo et al. v. Apotex, No. 2007-1438 (Fed. Cir. 2008)
In an opinion released last Friday, the Federal Circuit affirmed the decision of the U.S. District Court for the Southern District of New York, following a 2007 bench trial, that Sanofi's U.S. Patent No. 4,847,265 is not invalid for anticipation or obviousness. The '265 patent covers clopidogrel bisulfate, the active ingredient in Sanofi and Bristol-Myers Squibb's blockbuster heart medication Plavix. A botched settlement of the case in 2006 led to Apotex's at-risk launch of its generic Plavix, followed by a preliminary injunction against Apotex, and ultimately the departure of executives from BMS.
Claim 3 of the '265 patent is directed to clopidogrel bisulfate: "Hydrogen sulfate of the dextro-rotatory isomer of methyl alpha-5(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)(2-chlorophenyl)-acetate substantially separated from the levo-rotatory isomer." Apotex stipulated to infringement and argued that claim 3 is invalid as anticipated by and obvious over Sanofi's U.S. Patent No. 4,529,596, which describes the racemate that includes clopidogrel.
For anticipation, Apotex argued that the '596 patent describes not only the racemate ("PCR 4099"), but also its addition salts and enantiomeric forms. The district court found that although the racemate is in the prior art, the dextrorotatory enantiomer and salt in claim 3 of the '265 patent are not described, either explicitly or inherently, in any reference. The court reasoned that the '596 patent would not have guided a person of ordinary skill in the art to either the dextrorotatory enantiomer of PCR 4099 or its bisulfate salt. On appeal, according to the Federal Circuit, Apotex argued that the district court "erred in law, and that it suffices that the reference shows the specific racemate PCR 4099 and states that the compounds in the reference have enantiomers and that the enantiomers are included in the invention."
The Federal Circuit, however, explained in its opinion that Apotex's view "is not the correct view of the law of anticipation, which requires the specific description as well as enablement of the subject matter at issue. To anticipate, the reference must not only disclose all elements of the claim within the four corners of the document, but must also disclose those elements arranged as in the claim." Distinguishing the classic cases of In re Petering (CCPA 1962) and In re Schaumann (CCPA 1978), the court stated, "PCR 4099 is shown in the references as one of several compounds with desirable biological properties, but the district court did not clearly err in finding that the reference disclosure would not have led one of ordinary skill to recognize either an explicit or inherent disclosure of its dextrorotatory enantiomer, as well as the bisulfate salt." Similarly, consistent with Forest Labs v. Ivax, the court discerned no clear error in the district court's finding that the asserted prior art does not enable one to separate the enantiomers of PCR 4099 without undue experimentation.
With respect to obviousness, the district court "held that the unpredictable and unusual properties of the dextrorotatory enantiomer, and the therapeutic advantages thereby provided, weighed in favor of nonobviousness, and that Apotex had not met its burden of establishing otherwise." On appeal, Apotex argued "that the only features of clopidogrel bisulfate arguably not explicit in the prior art -- the separation of the dextro- from the levorotatory enantiomer and its preparation as a bisulfate salt -- required no more than well-known chemical techniques." Apotex cited known examples of other chiral compounds that exhibit stereoselectivity and that even if some experimentation was required, upon separation of the enantiomers, "routine testing would have revealed the favorable allocation of properties in the dextrorotatory isomer."
In affirming the district court's holding of nonobviousness, the Federal Circuit cited numerous instances where Apotex's expert witnesses appeared to admit the unexpected properties of clopidogrel. For example, according to the court, Sanofi determined that the enantiomers of PCR 4099 had the "rare characteristic of 'absolute stereoselectivity': the dextrorotatory enantiomer provided all of the favorable antiplatelet activity but with no significant neurotoxicity, while the levorotatory enantiomer produced no antiplatelet activity but virtually all of the neurotoxicity. The experts for both sides agreed that while it was generally known that enantiomers can exhibit different biological activity, this degree and kind of stereoselectivity is rare, and could not have been predicted." In addition, "the experts of both parties agreed that whether a pharmaceutically suitable crystalline salt will form from a particular acid-base combination is unpredictable." Moreover, "here Sanofi presented evidence that the prior art taught away from the use of sulfuric acid with an enantiomer, for strong acids could encourage re-racemization."
When Apotex launched its generic version of Plavix in 2006, it was able to ship a six-month supply of its generic drug before the district court preliminarily enjoined further sales. Thus, potential damages could run into the billions of dollars. Accordingly, it would not be surprising for Apotex to appeal the Federal Circuit decision to the Supreme Court.