A new twist on the chiral switch

Patents covering Sanofi-Synthelabo/BMS's oral antiplatelet chiral drug Plavix (clopidogrel bisulfate) are under legal fire in the United States from generics companies, Apotex and Dr Reddy's Laboratories. Plavix was approved by the FDA in 1997 as the (+)-enantiomer, and its five-year exclusivity period, granted for all New Chemical Entities, expired last year. The first patent — US 4,529,596, which was filed in 1983 and expires in July 2003 — claims both enantiomers and their mixture, whereas a later patent — US 4,847,265, due to expire in 2011 — claims only the (+)-enantiomer. Interestingly, although the case might be played out as if it were a chiral switch1, this drug has never been marketed as a racemate, so the switch is operating at the level of the intellectual property. The likely crux of the generic challenge is that the '265 patent for the single enantiomer does not satisfy the key requirements of being novel and inventive.

Is the '265 patent novel — that is, not part of the prior art? The earlier patent claimed, but did not describe, the (+)- and (−)-enantiomers, although it states that “the invention relates both to each enantiomer and their mixture”. In the description of the activities of each enantiomer in the '265 patent, data show that the (+)-enantiomer is pharmacologically superior in activity and less toxic than both the (−)-form and the racemate. However, this is not listed in the claims section of the patent. Even if it were, the court would need to decide if these differences were large enough to qualify as novel and inventive.

Israel Agranat and Hava Caner, The Hebrew University of Jerusalem. Analysis based on data taken from To Market, To Market in Annual Reports in Medicinal Chemistry, Vols 19–37 (1984–2002) (eds Bristol, J. A. & Doherty, A. M.); and Frantz, S. & Smith, A. Data of New Drug Approvals for 2002 (by the FDA and EMEA). Nature Rev. Drug Discov. 2, 95–96 (2003).

Was the development of Plavix as a single enantiomer in the 1980s non-obvious — that is, was there an inventive step? In the years 1983–1987, before the 1988 filing of the '265 patent, the distribution of worldwide approved drugs was 30% single enantiomers, 29% racemates and 41% achirals (see below: Israel Agranat and Hava Caner, The Hebrew University of Jerusalem). One fact that will undoubtedly come into play during the deliberations is that, in the 1980s, single enantiomers were already a significant and important component of approved drugs.

These issues have been assigned to Judge Robert Sweet of the Southern district of New York, who is not expected to make a decision until mid-2004, and the outcome could have far-reaching implications for the chiral switch strategy. WEB SITE US States Patent and Trademark Office