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Purified stereoisomer of compound in known mixture obvious in light of expected potency
September 11, 2007

In a decision today, the Federal Circuit reversed a district court's pre-KSR decision of nonobviousness. The claims were directed toward a particular isomer of a compound that was "substantially free" of other isomers. The prior art included a mixture that included the claimed isomer as well as a different isomer.

The court found the claims obvious because it was known in related compounds that the particular isomer had an increased therapeutic effect, and methods of isolating the particular desired isomer were known in the art at the time of the invention. This combination provided sufficient "reasoning with some rational underpinning to support" a conclusion of obviousness post-KSR.

This case relates to a patent covering the compound ramipril, marketed under the name Altace®. The drug is an ACE inhibitor used to treat high blood pressure. Ramipril's structure is depicted below:

Ramipril

The carbon atoms indicated by the asterisks are chiral, meaning that each of these atoms may produce a different stereoisomer of ramipril. As there are 5 such atoms with two possible configurations each, there are a total of 32 possible stereoisomers. The claimed compound has the "S" enantiomer (as opposed to the "R" enantiomer, more explanation here) at each of the 5 chiral carbons, and can be referred to as either the SSSSS or 5(S) stereoisomer.

The parties disputed the scope of the prior art, but there were a few key pieces of prior art used by the Federal Circuit. First, the immediately preceeding ACE inhibitor known in the art was enalapril. This was developed by making structural modifications to viper venom, known as BBP5a. Both enalapril and BBP5a had the S enantiomer at each chiral center, with enalapril having three chiral centers and BBP5a six. The scientists that developed enalapril noted that the SSS stereoisomer had 700 times the potency of the SSR isomer.

Also known in the prior art was a mixture of two stereoisomers of ramipril, the 5(S) and SSSSR isomers. It was also undisputed that one of ordinary skill would know how to isolate one of the stereoisomers from the other.

Against this backdrop, the Federal Circuit had no trouble finding the claims obvious. It was known in the prior art that using all-S stereoisomers of related compounds produced the best results, it was known in the art that the 5(S) stereoisomer existed in a mixture with one other stereoisomer, and the method of isolating one stereoisomer from another was also known in the art. Given these facts, the 5(S) stereoisomer was obvious. As stated by the court (internal quotations and citations omitted):

[H]ere, a claimed composition is a purified form of a mixture that existed in the prior art. Such a purified compound is not always prima facie obvious over the mixture; for example, it may not be known that the purified compound is present in or an active ingredient of the mixture, or the state of the art may be such that discovering how to perform the purification is an invention of patentable weight in itself. However, if it is known that some desirable property of a mixture derives in whole or in part from a particular one of its components, or if the prior art would provide a person of ordinary skill in the art with reason to believe that this is so, the purified compound is prima facie obvious over the mixture even without an explicit teaching that the ingredient should be concentrated or purified. Ordinarily, one expects a concentrated or purified ingredient to retain the same properties it exhibited in a mixture, and for those properties to be amplified when the ingredient is concentrated or purified; isolation of interesting compounds is a mainstay of the chemist’s art. If it is known how to perform such an isolation, doing so is likely the product not of innovation but of ordinary skill and common sense.

. . .

[T]he prior art provides a sufficient reason to look to the 5(S) configuration. The SCH 31925 composition contained only the 5(S) and SSSSR stereoisomers of ramipril. Importantly, these forms differ by the configuration of only one carbon atom, and that atom is not one of the “bridgehead” carbons. Rather, that carbon atom is in the part of the ramipril molecule that is common to the enalapril molecule. In enalapril, as in captopril and BPP5a before it, all of the stereocenters are in the S configuration; the Merck article taught that the SSS configuration of enalapril is 700 times as potent as the SSR form. The close structural analogy between 5(S) and SSSSR ramipril and SSS and SSR enalapril would have led a person of ordinary skill to expect 5(S) and SSSSR ramipril to differ similarly in potency. Moreover, the '944 patent specifically taught that stereoisomers of ramipril "can be separated by conventional chromatographic or fractional crystallization methods."

Accordingly, the district court's finding of nonobviousness was reversed.

This case provides some useful guidance for pharmaceutical and chemical inventions post-KSR, in that it provides examples of how to rebut a prima facie case of obviousness based on structural similarity. One example is difficulty in purifying a compound, such as in a case from last week (interestingly, making this case the second case in five days regarding stereoisomers).

To read the full decision in Aventis Pharma Deutschland GmbH v. Lupin, Ltd., click here.

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