The fight is for the angiotensin-converting enzyme (ACE) – Ramipril which is used for treating high blood pressure by inhibiting a biochemical pathway that constricts blood vessels.
Aventis sued a case against Lupin for filing of ANDA (Abbreviated New Drug Application) for a generic version of the ACE inhibitor Ramipril. According to the summary of judgement provided by the District Court it is Lupin the infringer under the doctrine of equivalents and US Patent No. 5061722 is invalid for obviousness.
ACE inhibitor ramipril is one of a plurality of stereoisomers of the chemical compound and it is known as the “5(S)” or “SSSSS” enantiomer. Pharmaceutical ramipril is one of 32 different stereoisomers. Searches on Prior art for ACE inhibitor including a naturally-occurring molecule isolated from snake venom and several synthetic analogues, were structurally similar to ramipril.
The chemical compound Ramipril has multiple chiral carbon atoms where all has the S configuration. The “all S” enantiomer of the most closely-related molecule, enalapril which is produced by Merck and has been having 700 times the biological activity of the “SSR” stereoisomer, the prior art also gives information on how the SSS isomer of enalapril have been separated from the other seven stereoisomeric species of that compound.
Addition to that Schering scientist had granted patent for the ramipril’s chemical structure but that did not disclose the active stereochemical conformation of the molecule. But since the 5(S) enantiomer was not known in the prior art, Aventis’ claims were novel over this art.
Interesting is that Aventis licensed the Schering patents, and when the Patent and Trademark Office declared an interference between the Schering patents and Aventis’ applications, the interference settled on submitting reasons. However, Aventis did concede priority as to the generic ramipril structure, i.e., without specifying the stereochemical configuration of the active ramapril enantiomer.
Since Lupin had failed to submit clear and convincing evidence, The District Court found that there is a lack of obviousness.
The Federal Circuit reversed in focus of its analysis on the prior art relating to the Merck compound elanapril, and the Schering invention of the mixture of ramapril stereoisomers, including the mixture of the SSSSS and SSSSR enantiomers. The CAFC noted that the District Court’s reasoning in deciding that the claims were not obvious was based primarily on a lack of clear and convincing evidence of any motivation in the art to separate the SSSSS isomer, as required by Aventis’ patent claims in suit.
the Federal Circuit found that the two enantiomers, SSSSS and SSSSR of Schering mixture were differed at only one position, and that the earlier prior art compounds were all consistent with the “all (S)” enantiomer having the greatest potency. Schering’s prior patents significantly describes that SSS configuration as being 700-fold more potent and described the methodology of how to isolate the 5(S) enantiomer from the other stereoisomers. Moreover, the differences in potency shown for the two enantiomers of elanapril (SSS and SSR) would have lead the skilled worker to expect the activity of ramapril to reside preferentially in the SSSSS enantiomer, due to the close structural similarity between these two molecules.
This evidence was enough to convince the Federal Circuit that Aventis’ claims were obvious in view of the prior art.
Key words: Aventis, Lupin, Ramipril, Enalapril, Schering invention, sterioisomers