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The Plavix appeal decision could draw from recent precedents, but one should be wary in predicting the outcome on enantiomer patent litigation post KSR, a number of litigation lawyers told Pharmawire.
The KSR v. Teleflex case in April this year set a new standard for a less stringent test to challenge and invalidate a patent on the grounds of obviousness. Recent precedents which could be applied to Plavix could include decisions in cases such as Lexapro, Levaquin and Lipitor, where patents were challenged by generic players on the grounds of obviousness, but were found instead to be unobvious and therefore valid by the courts, lawyers agreed.
The Plavix appeal process is currently ongoing and it is understood that generic Apotex has already filed its appeal brief and that France based Sanofi-Aventis was due to file a brief 17 October 2007.
However, following the KSR decision, the outcome of enantiomer patent cases are not easy to predict as standards of obviousness are still being set, a source with knowledge of the situation and a lawyer agreed. While courts want to be seen to be adhering to the Supreme Court ruling in KSR, he said, which somewhat lowered the standard of proof needed to invalidate a patent on the grounds of obviousness, a line will need to be drawn as to what is obvious in deriving a salt of an enantiomer from a known racemic compound. Plavix could very much be the case that sets this precedent and which is distinguished from Lexapro, the source added.
Recently and in the aftermath of KSR, King Pharmaceutical’s Altace (ramipril) patent and Pfizer’s Norvasc (amlodipine besylate) patent were held to be invalid on the grounds of obviousness. Forest Labs’ Lexapro patent, on the other hand, was held to be valid on the grounds that (a) a previous scientific article did not anticipate claim 1 of the ’712 patent even though ”it discusse[d] and analyze[d] the efficacy of various drug enantiomers and predict[ed] that one citalopram enantiomer will be more potent [..] than the other”; and because (b) prima facie obviousness of obtaining racemic citalopram was rebutted ”by the evidence demonstrating the difficulty of separating the enantiomers and the unexpected properties of (+)-citalopram”.
According to a previous report Judge Lourie, who upheld the validitiy of the Lexapro patent, will also be sitting on the Plavix case. The source suggested that the appeal will likely hinge on the argument of obviousness rather than on proving previous enabling disclosure. In his December 2006 Plavix opinion, which affirmed the preliminary injunction against Apotex, Judge Lourie conceded found that the district court had ruled correctly in finding that a person of ordinary skill in the art would not easily have discovered the bisulfate salt as a racemate of clopidogrel in Plavix. Similarly in Lexapro the court found ”that many methods were tried without success before scientists finally hit on the right one” on how to separate the enantiomers of citalopram.
Although so far in Lexapro and in Plavix the courts held that the previous disclosure was not enabling, and obtaining the salts of an enantiomer of a previously known racemic compound, such as citalopram in Lexapro and the bisulfate salt in Plavix, was not a process deemed to be obvious, the source questioned what standard obviousness will be given going forward in cases where there are known techniques of separating enantiomers from their racemates.
So far, the source suggested, the courts have taken the position that enabling disclosures - such as naming particular enantiomers, may constitute ”a prior art”, but is per se not enough. More importantly, he suggested, the courts have relied on the obviousness of the the activity of a particular enantiomer and on the obviousness of actually separating and testing the enantiomer and deriving active substances from it. The less obvious the process, the more credibility the patent is seen to have.
In a pre-KSR opinion affirming preliminary injunction against Apotex not to market generic forms of Plavix, Judge Lourie noted that referring to the enantiomers of a large class of compounds and their racemic mixtures is not enough; one needs to go beyond and see how you can formulate the salt - which requires proof of many attempts without success before hitting the right one. Once the salt has been obtained, Judge Lourie appears to say that proof that it is a more potent or purer form than other salts, is what renders the patent unobvious.
Whether Judge Lourie will depart from this rationale and take into account the decision in the Altace (ramipril) patent which was invalidated based on rejecting a rigid application of the Teaching, Suggestion, or Motivation (TSM) test criticized by KSR, is yet to be seen, the source said. To give context, in the ramipril case it was found that a person of ordinary skill in the art would have been motivated to purify 5(S) ramipril into a composition substantially free of other isomers, and the patent was thereby obvious.
Another lawyer pointed out that there is a body of case law which effectively states that if there is a racemic mixture disclosing an enantiomer, then separation of this is prima facie obvious. Re Adamson is one such case and was used by Apotex in the appeal Plavix case, but the courts distinguished it on two grounds: first, a previous patent (a ”prior art”) did not disclose bisulfate salt of the d-enantiomer of clopidogrel; secondly, it was held that for the skilled artisan separation of the racemate ”was not mere routine experimentation and [..] it was unexpected that the desirable activity of [the active ingredient] clopidogrel would be found only in the d-enantiomer.”
The standards being applied are not necessarily correct, the lawyer pointed out and there is no indication that case law precedents on enantiomer patents have been overruled by KSR.
It is understood that Apotex is expected to appeal to the Supreme Court if it loses on this case.
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