After refusing to die easy on its bid to put out a generic version of Plavix, Apotex was handed its hat by the district court. Sanofi-Synthelabo v. Apotex Inc., 02cv2255, U.S. District Court, Southern District of New York.

Granting a permanent injunction, U.S. District Judge Sidney Stein held that Apotex failed to prove by clear and convincing evidence that the Sanofi-Synthelabo patent on Plavix — U.S. Pat. 4,847,265 — is invalid or unenforceable on any of the grounds asserted.

Plavix® (clopidogrel bisulfate) is a platelet aggregation inhibiting agent used to reduce thrombotic events such as heart attacks and strokes. The active ingredient in Plavix® is the bisulfate salt of the d-enantiomer of the free base methyl alpha-5-(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)-(2-chlorophenyl) acetate (MATTPCA), which is specifically recited in claim 3 of the ’265 patent.

Apotex had filed an Abbreviated New Drug Application (“ANDA”) pursuant to the Hatch-Waxman Act seeking FDA approval to manufacture and sell a generic version of clopidogrel bisulfate. When Apotex filed a Paragraph IV certification with its ANDA asserting that the ‘265 patent is invalid, Sanofi sued Apotex on the ‘265 patent.

The parties had negotiated a settlement agreement that provided for actions in the event that the settlement failed to receive regulatory approval. But, after state attorneys general said they would not approve the settlement, litigation resumed.

Pursuant to the agreement, Apotex launched its generic clopidogrel bisulfate product on and Sanofi filed for a preliminary injunction and requested a recall of Apotex’s products that were already distributed. The district court granted the motion for injunctive relief but denied the request for recall even though Apotex had already shipped a six-month supply of its product to distributors in the US.

Apotex counterclaimed, asserting that the ‘265 patent was invalid for three separate reasons and unenforceable as well:

  1. That the ‘265 patent is anticipated pursuant to 35 U.S.C. § 102(b) by an earlier patent held by Sanofi that covered a genus of chemical compounds called thienopyridines, within which clopidogrel bisulfate falls.
  2. That pursuant to 35 U.S.C. § 103, the subject matter claimed in the ‘265 patent would have been obvious to a person of ordinary skill in the art at the time the invention was made.
  3. That the patent is invalid under the judicial doctrine of obviousness-type double patenting.
  4. That the ‘265 patent is unenforceable on the basis of Sanofi’s alleged inequitable conduct before the U.S. Patent and Trademark Office, i.e., failing to name Dr. Jean-Pierre Maffrand as an inventor, making false statements to the PTO regarding the unexpected pharmacological properties of clopidogrel bisulfate, failing to disclose relevant prior research that Sanofi had conducted on a similar chemical compound, and failing to disclose a journal article that Apotex alleges is a material prior art reference.

The court came down hard on Apotex and let them know that none of these assertions would fly. In its findings, the court stated:

Having conceded infringement, Apotex bears the burden of proof because “[a] patent shall be presumed valid,” and “[t]he burden of establishing invalidity of a patent or any claim thereof shall rest on the party asserting such invalidity.” 35 U.S.C. § 282. To overcome this presumption of validity at trial, “the party challenging a patent must prove facts supporting a determination of invalidity by clear and convincing evidence.”

The court noted that this is a “heavy burden,” … because clear and convincing evidence “proves in the mind of the trier of fact ‘an abiding conviction that the truth of [the] factual contentions [is] highly probable.'” The burden of showing invalidity is “especially difficult” when “the infringer attempts to rely on prior art that was before the patent examiner during prosecution.” … Here, not only was the prior art patent – the ‘596 patent – before the patent examiner during the prosecution of the ‘265 patent, but also the very same patent examiner, Bernard Dentz, approved both the ‘596 patent and the ‘265 patent.

In its decision affirming this Court’s grant of a preliminary injunction in favor of Sanofi, the Federal Circuit found that “the plain language of claim 2 [of the ‘596 patent] only recites the free base, MATTPCA, and does not expressly describe the dextrorotatory or levorotatory enantiomers or any salt. Because claim 2 [of the ‘596 patent] fails to describe each and every limitation of claim 3 [of the ‘265 patent] on its face, claim 2 does not anticipate claim 3.” Sanofi-Synthelabo v. Apotex, Inc., 470 F.3d 1368, 1376 (Fed. Cir. 2006), reh’g denied, 2007 U.S. App. LEXIS 2807 (Fed. Cir. Jan. 19, 2007). Nothing in the trial record changes the plain language of the patents, and this Court therefore reaches the same conclusion on a complete record as this Court and the Federal Circuit reached on a more limited record: Claim 2 of the ‘596 patent does not expressly describe clopidogrel or its bisulfate salt. The Court also finds that Example 1 does not expressly describe clopidogrel bisulfate – there is no explicit reference to the enantiomers of PCR 4099 in that example and the particular salt described is the hydrocholoride, not the bisulfate.

The more difficult question is whether the additional limitations – namely the dextrorotatory enantiomer and its bisulfate salt – are inherently described elsewhere in the ‘596 patent. “Inherent anticipation requires that the ‘missing characteristic is necessarily present, or inherent, in the single anticipating reference.'”

Claim 1 of the ‘596 patent claims a general formula and specifies that the compounds covered by that formula include: their addition salts with pharmaceutically acceptable mineral or organic acids . . . including both enantiomeric forms or their mixture. ‘596 patent at col. 13, ll. 8-19. The parties have stipulated that clopidogrel bisulfate is a compound within the genus of Claim 1 of the ‘596 patent.

Claim 8, which is also relevant, reads as follows: A therapeutic composition having blood-platelet aggregation inhibiting activities and anti-thrombotic activities containing an effective amount of a compound of claim 1, or an addition salt thereof with a pharmaceutically acceptable mineral or organic acid or with mineral bases, or one of the two enantiomers or their mixture and a pharmaceutically acceptable carrier.

In the end, the court held that:

Apotex’s argument, however, is ultimately unpersuasive. First, it is undisputed that “[a] prior art reference that discloses a genus still does not inherently disclose all species within that broad category.” Metabolite Labs., Inc. v. Lab. Corp. of Am. Holdings, 370 F.3d 1354, 1367 (Fed. Cir. 2004); see also Atofina, 441 F.3d at 999. In essence, patentability is not precluded by the fact that an inventor has identified or selected a single compound with particularly desirable qualities from a large class of previously patented compounds.

Although clopidogrel bisulfate concededly falls into the broad genus disclosed by Claims 1 and 8 – a genus which includes millions of possible compounds – a person of ordinary skill in the art would need to engage in impermissible “mechanistic dissection and recombination” of those disparate elements to arrive at the particular combination that is clopidogrel bisulfate.

The Court also refused to buy Apotex’ argument that clopidogrel bisulfate was rendered obvious by the ‘596 patent because, after gaining familiarity with that patent, a person of ordinary skill in the art would have viewed as obvious the active enantiomer of PCR 4099 in the form of each of the three salts used for ester compounds in the examples of the ‘596 patent – namely, the hydrochloride, bisulfate and hydrobromide.

Apotex tried arguing that the results were not unexpected and urged that the recent decision of the Federal Circuit, Pfizer, Inc. v. Apotex, 480 F.3d 1348 (Fed. Cir. 2007), would yield a different conclusion in this case. The Court, however, distinguished the present case from Pfizer since after obtaining that patent, Pfizer discovered that the maleate salt, for unforeseen reasons, was not suitable for the commercial manufacture of tablets due to stickiness and tablet degradation. The chemists at Pfizer attributed those problems to the particular chemical structure of the maleate salt – a reactive double bond in the maleate anion – which made the salt susceptible to degradation. In this case, there were no structural features that would have guided selecting any specific acid.

While Apotex will surely file an appeal with the federal circuit, it doesn’t seem likely that the outcome will change. The federal circuit already found a “a reasonable likelihood of its success on the merits” in favoring issuance of a preliminary injunction.

See the full opinion here:  Sanofi v. Apotex Opinion

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