Sanofi Synthelabo v Apotex Inc clopidogrel bisulfate

Case History: Apotex received Food and Drug Administration (FDA) approval to sell, and commenced selling, generic Plavix (i.e., the dextrorotatory enantiomer of clopidogrel bisulfate). Sanofi attempted to stop Apo-tex's clopidogrel bisulfate sales by suing Apotex in district court. Sanofi, in its suit, asserted that Apotex, by selling clopidogrel bisulfate, infringed upon U.S. Patent No. 4,847,265 ('265). Sanofi won at the district court level and upon appeal the decision was affirmed by the Federal Circuit [15].

Analysis: This case presents an example where superior and unexpected results associated with a molecule (one enantiomer) conveyed patentability to the enantiomer over its previously disclosed (prior art) racemate. The case also introduces another mechanism through which patents can be defeated by demonstrating that the claimed subject matter is obvious.

One of the requirements for obtaining a patent is that the claimed subject matter in the patent not be obvious in view of prior art (previously disclosed patents and publications). Obviousness [16] and prior art [17] are legally codified in Title 35 of the United States Code.

A basic, or prima facie, case of obviousness, which would otherwise defeat patentability, may in turn be defeated by one or more "secondary considerations [18]." One of the most commonly employed secondary considerations is a "superior and unexpected result [18]." At trial, Apotex argued that the dextrorotatory enantiomer of clopidogrel bisulfate, found in Plavix , was prima facie obvious in view of the prior art combined with generally available knowledge. Sanofi countered in part with superior and unexpected results and won.

Apotex, in establishing its prima facie case of obviousness, first asserted the following facts:

  1. A prior art Sanofi patent disclosed the racemate that the dextrorotatory enantiomer found in Plavix was separated from.
  2. The prior art Sanofi patent made statements concerning enantiomers and addition salts.
  3. It was generally known that racemates can be separated into their component enantiomers.
  4. Techniques for separating enantiomers from racemates were generally known.
  5. Separated enantiomers can differ as to biological properties.
  6. In the future, it was possible the FDA would require separation and testing of enantiomers.

Apotex wove these facts into a prima facie case of obviousness as follows: It would be obvious to separate an enantiomer from a known racemate using generally known techniques. Furthermore, there was motivation [19] to do so because enantiomers can have different properties from those displayed by the racemate, and because of a possible future FDA regulatory requirement for separation of enantiomers. Additionally, there was a reasonable expectation of success [20] in achieving the separation because techniques for separating enantiomers from racemates are known. And finally, it would be obvious to form an addition salt of the enantiomer to optimize selected physical properties. Thus, concluded Apotex, dextrorotatory clopidogrel bisulfate was obvious, it is therefore unpatentable, and this renders the '265 patent invalid.

Sanofi skillfully countered every point argued by Apotex. Sanofi first noted that their scientists had previously separated enantiomers from racemates in the same molecular class as clopidogrel, but found that the enantiomers showed no advantages over the racemates. For example, in one of the separations, "one of the enantiomers was more biologically active but also [was] more neurotoxic than the racemate [21]." Sanofi then presented data showing that when enantiomers of racemic clopidogrel were separated, 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 [21]." Experts from both Sanofi and Apotex 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 be predicted" and that "in the usual case, if one enantiomer is more biologically active than the other, that activity includes the adverse as well as the beneficial properties [21]."

Thus, Sanofi had two superior and unexpected results that (1) the dextrorotatory enantiomer separated from racemate PCR 4099 contained substantially all of the antiplatelet activity and (2) was essentially devoid of the neurotoxicity associated with PCR 4099.

Evidence was further presented that "eventual success [in separating the enantiomers] came only after several failures using known strategies for enantiomer separation" and that it "could be ... difficult to separate the enantiomers of PC 4099 ... because it would be understood by chemists that the methyl ester substituent in PCR 4099 could make it more susceptible to re-racemizations, and thus resistant to successfully obtaining a separated product [22]." Accordingly, "neither the chemists at Sanofi nor a person of ordinary skill in the art could have reasonably expected that the separate enantiomers of PCR 4099 could be obtained . and if obtained, by what method and configuration [22]." Thus, Apotex's contention that separating the enantiomers was obvious was also refuted.

Concerning the bisulfate salt, Sanofi presented evidence that "the prior art taught away from the use of sulfuric acid with the claimed enantiomer, for strong acids could encourage re-racemization [23]." "Teaching away" from, a separate secondary consideration trending toward patentability, is discussed in more detail in Section 7 of this chapter.

Finally, concerning the possible FDA mandate, the court concluded that "Sanofi undertook this separation [of enantiomers] in order to study adverse neurological effects of [the racemate that the dextrorotatory enantiomer found in Plavix was separated from], and not because of a possible future regulatory requirement [24]."

In summary, Sanofi presented two superior and unexpected results, in the form of a highly significant combination of properties [associated with one enantiomer], as part of a point-by-point rebuttal of Apotex's arguments in its prima facie obviousness case. By doing so, Sanofi retained patent protection for Plavix . Superior and unexpected results can thus overcome a basic case of obviousness and confer patentability, even in the close case of an enantiomer compared to a racemate.

Suggested Best Practices for Chemists: 1. Throughout the course of a discovery program, molecules are tested against multiple targets. Selectivity for a given target over other targets, degree of inhibition of key isozymes, blockage of key ion channels, toxicity, carcinogenicity, and mutagenicity are all examined. Thus, there are many opportunities to discover superior and unexpected results associated with specific discovery program molecules. Each superior and unexpected result should be assigned to its corresponding molecule and recorded in the laboratory notebook.

  1. A listing of all superior and unexpected results and their associated molecules should be provided as part of each invention disclosure to the patent department.
  2. Often, the biggest obstacle to obtaining a patent is a company's own prior art. Thoughtful consideration as to the content and timing of disclosures can remove or minimize self-created obstacles to obtaining patent protection. Discuss the content of proposed patent applications and publications with your patent professional.
  3. For each discovery program, a company should formulate and adhere to a patent and publication strategy. Make sure that you have a strategy and that you understand how to apply it.
  4. Molecules that are structurally similar (e.g., enantiomers) to previously known molecules (e.g., racemates) may, in a fact-dependent fashion, be patentable. Work with your patent professional early in the process to determine if such molecules are worth pursuing as program targets.

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