Canada: Federal Court Declares Clopidogrel Patent Invalid For Lack Of Utility/Sound Prediction

The Federal Court of Canada recently issued a decision (2011 FC 1486) concerning the drug Plavix, known generically as clopidogrel bisulfate. An impeachment action, under Section 60 of the Patent Act, was launched by Apotex Inc. ("Apotex") against Canadian Patent 1,336,777 (the "777 Patent") alleging that the 777 Patent was invalid on various grounds, namely inutility, lack of demonstrated utility/sound prediction, obviousness, anticipation and double patenting (Court Docket T-644-09). Sanofi-Aventis and a related entity (collectively "Sanofi") subsequently launched an action against Apotex asserting that Apotex had infringed the 777 Patent by manufacturing clopidogrel-containing products in Canada for export to other countries (Court Docket T-933-09). Both cases were consolidated and a decision was rendered by Justice Boivin in which he ruled that the 777 Patent was invalid for lack of utility/sound prediction, and dismissed Sanofi's infringement action.

At 271 pages in length, Justice Boivin's decision is quite extensive and deals with a variety of issues. The focus of this article is on Justice Boivin's decision in respect of utility and sound prediction.

THE 777 PATENT

The 777 Patent was filed on February 2, 1988 and, if valid, would expire on August 22, 2012. As noted by the Court, the 777 Patent has eleven claims which can be grouped as follows: clopidogrel and its salts, a process for preparing clopidogrel and its salts, and pharmaceutical compositions containing clopidogrel and its salts.

PROMISE OF THE PATENT

Justice Boivin stated that the promise of a patent is for a court to decide through the eyes of a skilled person and with the assistance of expert evidence. He cited Eli Lilly Canada Inc. v. Novopharm Ltd., 2010 FCA 197 ("Eli Lilly") regarding the role of promise of the patent with respect to utility:

"[76] Where the specification does not promise a specific result, no particular level of utility is required; a 'mere scintilla' of utility will suffice. However, where the specification sets out an explicit 'promise', utility will be measured against that promise... The question is whether the invention does what the patent promises it will do."

Apotex argued that the promise of the 777 Patent relates to humans; Sanofi submitted that the promise merely relates to "potential use" in humans. After reviewing the expert evidence, Justice Boivin concluded that the skilled person would find the promise of the 777 Patent to be the use of the invention (clopidogrel bisulfate) in the treatment of humans.

UTILITY AND SOUND PREDICTION

Apotex argued that Sanofi had not demonstrated or soundly predicted the utility of clopidogrel by the Canadian filing date. In its evidence on utility, Sanofi cited a human clopidogrel study entitled P-1062, conducted for the purposes of assessing, inter alia, blood platelet activity. Evidence was adduced that the P-1062 study was a double-blind study and was not completed until March 1988, shortly after the filing date of the 777 Patent. Apotex's experts opined that given the nature of the study, the double-blind would not have been broken until study completion and investigators would not have known the identity of the drug by the filing date of the 777 Patent. Furthermore, the study was carried out mostly on healthy individuals and very few patients, and that no conclusions could be drawn to demonstrate utility. Justice Boivin agreed and concluded that the P-1062 human study did not demonstrate the utility of the 777 Patent.

The Court, having concluded that the utility of the 777 Patent was not demonstrated by the filing date of the 777 Patent, considered whether the invention was soundly predicted by that date. Citing the decision from Apotex Inc. v. Wellcome Foundation Ltd., 2002 SCC 77 and Eli Lilly above, Justice Boivin assessed whether there was a factual basis for the prediction, a sound line of reasoning and a proper disclosure in the 777 Patent. With respect to factual basis, Justice Boivin considered evidence that Sanofi had been working with thienopyridine compounds (the general class to which clopidogrel belonged) for quite some time. Sanofi's work had shown that ticlopidine (an early thienopyridine) was active but had an unfavourable side effect profile. Subsequent racemic compounds PCR 1033, PCR 3549 and PCR 4099 were made and tested, with significant resources devoted to PCR 4099. However, undesirable side effects (e.g. convulsions) in baboon studies directed Sanofi to attempt to isolate and test the enantiomers of PCR 4099. Justice Boivin concluded that Sanofi had a factual basis for its prediction that the invention could be used in humans.

With respect to a sound line of reasoning, the Court considered the following elements in terms of whether they would provide Sanofi scientists with a line of reasoning: (1) stereochemistry: that previous, structurally-related compounds had been made and tested; (2) toxicology: that pre-clinical toxicity tests could predict clinical toxicity; (3) haematology: that ADP was produced by all animal species; (4) pharmacology: that drug behaviour in vivo was understood from prior thienopyridines; and (5) extrapolation from animals to humans: that previous thienopyridines were found to be useful in animals and humans. Justice Boivin also reiterated that a "certainty" in the line of reasoning was not required as long as it was "prima facie" reasonable. Justice Boivin agreed that Sanofi had a sound line of reasoning upon which to predict that clopidogrel had platelet inhibiting activity.

Finally, with respect to disclosure, the third requirement for establishing a sound prediction, Justice Boivin relied on Justice Hughes' decision in Eli Lilly Canada Inc. v. Apotex Inc., 2008 FC 142, affirmed 2009 FCA 97, that proper disclosure in the patent at issue was a requirement for sound prediction. The Court considered the 777 Patent as a whole and found that neither the factual basis nor the sound line of reasoning were disclosed in the 777 Patent. Specifically, there was no reference to work performed with respect to ticlopidine, no reference to the findings related to PCR 4099, no reference to multiple animals used, no reference to knowledge of convulsions and no recognition of the importance of drug metabolism. Moreover, the tests disclosed in the 777 Patent were in one strain of animal, in one gender and at a single point in time. Thus, there was no basis for the skilled person to make "the leap" to predict the use of clopidogrel in humans. As a result, Justice Boivin decided that even though Sanofi had established a factual basis and sound line of reasoning, there was not sufficient disclosure in the 777 Patent to soundly predict that clopidogrel would work to treat humans. Therefore, Justice Boivin ruled that on a balance of probabilities the claims of the 777 Patent were invalid for lack of sound prediction.

Having determined that the claims of the 777 Patent were invalid because the patent lacked the required disclosure for a sound prediction, Justice Boivin dismissed Sanofi's infringement action. Sanofi has since appealed the decision (Court Docket A-7-12).

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