Sanofi-Synthelabo v. Apotex, Inc. (Fed. Cir. 2006)

    By Donald Zuhn --

In an appeal from a District Court decision granting a preliminary injunction in favor of Plaintiffs-Appellees Sanofi-Synthelabo, Sanofi-Synthelabo, Inc., and Bristol-Myers Squibb Sanofi Pharmaceuticals Holding Partnership (Sanofi), the Federal Circuit concluded that the District Court did not abuse its discretion in granting preliminary injunctive relief, and thus, affirmed the District Court's grant of the preliminary injunction.

Sanofi owns U.S. Patent No. 4,847,265 (the '265 patent), which relates to clopidogrel bisulfate, the active ingredient in Plavix®, a platelet aggregation inhibiting agent marketed by Sanofi for use in reducing thrombotic events such as heart attacks and strokes.  Clopidogrel is the dextrorotatory enantiomer (d-enantiomer) of the free base methyl alpha-5-(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)-(2-chlorophenyl) acetate (MATTPCA).

Seeking approval to market generic clopidogrel bisulfate, Defendants-Appellants Apotex, Inc. and Apotex Corp. (Apotex) filed an Abbreviated New Drug Application (ANDA) with the FDA.  In response, Sanofi filed suit against Apotex, alleging that the filing of the ANDA infringed the '265 patent.  Apotex counterclaimed asserting that the '265 patent was invalid and unenforceable.  Shortly before the FDA approved Apotex's ANDA, the parties began settlement negotiations.  However, after failing to receive regulatory approval for either of two settlement agreements, Apotex launched its generic clopidogrel bisulfate product.  In response, Sanofi filed a motion for a preliminary injunction.

Following an evidentiary hearing, the District Court granted Sanofi's motion for injunctive relief, finding that Apotex failed to establish a likelihood of proving invalidity at trial.  In particular, the District Court rejected Apotex's anticipation, obviousness, and obviousness-type double patenting defenses, and determined that Apotex failed to raise a substantial question with regard to the enforceability of the '265 patent.  Apotex then appealed the District Court's grant of the preliminary injunction.

With regard to its anticipation defense, Apotex argued on appeal that because a skilled artisan would interpret claim 2 of U.S. Patent No. 4,529,596 (the '596 patent) as disclosing not only the racemate free base of clopidogrel, but also its dextrorotatory and levorotatory enantiomers and pharmaceutically acceptable salts, the '596 patent anticipated the '265 patent.  Apotex also argued that the holdings in In re May, 574 F.2d 1082 (C.C.P.A. 1978), In re Petering, 301 F.2d 676 (C.C.P.A. 1962), and In re Schaumann, 572 F.2d 312 (C.C.P.A. 1978) mandated a finding of anticipation in the instant case.

Finding that the '596 patent discloses only the free base of clopidogrel, and does not expressly describe the dextrorotatory and levorotatory enantiomers or any salt, the Federal Circuit determined that the '596 patent fails to describe each and every limitation of claim 3 of the '265 patent.  The Federal Circuit also rejected Apotex's argument that the '596 patent inherently discloses the bisulfate salt of clopidogrel, determining that the District Court did not clearly err in finding that a skilled artisan reading the '596 patent would believe that the hydrochloride salt, rather than the bisulfate salt, was the preferred salt of clopidogrel.

The Federal Circuit also found that the facts in the instant case could be distinguished from those in May, Petering, and Schaumann.  In contrast with May, the Federal Circuit noted that in the instant case, the '596 patent contained no clear statement that the bisulfate salt is "especially suitable" for administering compounds of the genus including clopidogrel.  Unlike in Petering, where "specific preferences" in an anticipatory reference were found to narrow a broad generic formula to a more limited class of twenty compounds, the Federal Circuit determined that no such "pattern of preferences" could be found in the '596 patent that limited the broad generic formula to a limited class including clopidogrel bisulfate.  Finding no error in the District Court's determination that the '596 patent does not inherently disclose clopidogrel bisulfate or its determination that clopidogrel bisulfate is not a species of the genus disclosed in the '596 patent, the Federal Circuit concluded that the District Court did not clearly err in finding that Apotex's anticipation defense lacked substantial merit.

With regard to its obviousness defense, Apotex argued on appeal that it would have been obvious to one of ordinary skill in the art to prepare clopidogrel bisulfate based on the disclosure of the '596 patent.  Apotex also argued that the unexpected results upon which Sanofi relied to establish clopidogrel bisulfate's nonobviousness would not have been unexpected to a skilled artisan.  Apotex further argued that the District Court erred by failing to consider In re Adamson, 275 F.2d 952 (C.C.P.A. 1960), in its obviousness analysis.

Noting that a party alleging invalidity due to obviousness cannot "merely identify each element in the prior art to establish unpatentability of the combined subject matter as a whole," but rather, "must articulate the reasons one of ordinary skill in the art would have been motivated to select the references and to combine them to render the claimed invention obvious," the Federal Circuit concluded that "nothing [in the '596 patent] directed a chemist to the particular enantiomer and salt, clopidogrel bisulfate, which is the limited subject matter of claim 3 [of the '265 patent]."  The Federal Circuit also concluded that the District Court had not clearly erred in evaluating the evidence relating to the unexpected results obtained with clopidogrel bisulfate.  Finally, the Federal Circuit determined that the instant case could be distinguished from Adamson since the '596 patent does not disclose the bisulfate salt of the d-enantiomer of MATTPCA, resolution of MATTPCA would not yield the unnamed bisulfate salt, and it was unexpected that the desirable activity of clopidogrel would be found only in the d-enantiomer.  The Federal Circuit, therefore, concluded that the District Court did not clearly err in finding that Apotex failed to raise a substantial question in its obviousness defense.

Sanofi-Synthelabo v. Apotex, Inc. (Fed. Cir. 2006)
Panel: Circuit Judge Lourie, Senior Circuit Judge Clevenger, and Circuit Judge Bryson
Opinion by Circuit Judge Lourie

Comments

[Jake]

"the Federal Circuit concluded that "nothing [in the '596 patent] directed a chemist to the particular enantiomer and salt, clopidogrel bisulfate, which is the limited subject matter of claim 3"

I'm going to go out a limb here and say I find it wholly unplausable that someone competent in the art (chemistry) would overlook the enantiomer to absolutely anything they've made. Forcing them to file such in a patent app would force the orgo world to double their apps for virtually every organic compound.