Is stereoisomer obvious over the racemic mixture?
Altace® (Ramipril) Capsules (2006 Sales of $653 millions)
Aventis Pharma & King Pharma v. Lupin Ltd. (Fed. Cir. Sep. 11, 2007)
Parties: Generic (Lupin) v. Brand (Aventis and King); Lupin filed ANDA on March 18, 2005 Lower Court: US District Court for the Eastern District of Virginia ruled in favor of Brand companies (Generic infringed); Decision was issued on July 17, 2006. Appeal Court: Reverse district court decision in favor of Generic (Generic Prevailed); Ruling was on September 11, 2007. Issue at Appeal: whether the 5(S) stereoisomer of ramipril, in a substantially free of other isomers, would have been obvious over the prior art … to one of ordinary skill in the art at the time of the ‘722 patent’s priority date”, November 5, 1981. Ruling: Stereoisomer is prima facie obvious over a racemic mixture but it can be rebutted. Brand Strategy: Altace® tablets were approved on February 27, 2007. On September 12, 2007, King seeks rehearing at CAFC. On December 3, 2007, the rehearing is denied. |
This is a post-KSR decision. CAFC invalids the US5,016,722 patent as obvious over the prior arts. ‘722, patent which expires October 29, 2008, covers Altace®. Altace® is developed by Aventis and marketed by King.
The independent claim in the ‘722 patent stating “A compound of the formula … all have the S-configuration, said compound or salt being substantially free of other isomers.” Lupin argues that this claim is obvious over the prior arts at the time of the invention, November 5, 1981.
Ramipril is an Angiotensin-Converting Enzyme inhibitors (ACE inhibitor) for the treatment of hypertension. It has 5 stereocenters, all have S-configurations “5(S)” stereoisomer. The earliest ACE inhibitor, back in late 60s, derived from Brazilian Viper, has 6 stereocenters, all of which are in S configuration. Aventis chemist synthesized ramipril in October 1981 and filed a German application claiming priority date November 5, 1981. This application eventually results the issued of ‘722 patent.
Merck’s publication (A.A. Patchett et al., A New Class of Angiotensin-Converting Enzyme Inhibitors, 288 Nature 280 (Nov. 20, 1980))
This article describes the enalapril, ramipril’s immediate predecessor enalapril, has 3 stereocenters, all of which are in S configurations. It also taught how to separate the all-S isomer using “standard chromatograph techniques.” The SSS configuration of enalapril is 700 times more potent than the SSR form.
The district court also found that a 30 mg dose of the mixture that is 1/3 5(S) ramipril has the same effectiveness as a 10 mg dose of pure 5(S) ramipril. This indicates that the potency is directly related to the purity of 5(S) ramipril.
Structures of ramipril and enalapril are as follows,
Ramipril Enalapril
Schering U.S. Patent Nos. 4,587,258 and 5,348,944 and SCH31925 mixture
Both ‘258 and ‘944 patents claims priority of 06/199,866 application filed on October 23, 1980, “disclose the structure of ramipril but do not describe how its stereocenters should be configured.” Schering’s chemist synthesize a mixture (SCH31925) by following the process of Example 20 of ‘944 patent with slight modification. The mixture contains 5(S) and SSSSR forms of ramipril. ‘944 patent also has the following teaching: “When diastereomeric products result from the synthetic procedures, the diastereomeric products can be separated by conventional chromatographic or fractional crystallization methods.”
The prior arts disclose that the S configuration is more potent than R configuration and it can be separate from conventional chromatograph techniques. Therefore, ‘722 patent independent claim “[a] compound of the formula … all have the S-configuration, said compound or salt being substantially free of other isomers.” is obvious over these prior arts.
It is difficult to patent the stereoisomer if the racemic mixture is already disclosed. There are still two possibilities. Scientists can show that no one knows the racemic mixture is actually made up by the stereoisomers, or that the separation technique of these isomers is very difficult even when the racemic mixture was disclosed.
Federal Circuit states in the opinion,
“[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.”
Prima facie obviousness can be rebutted that the isomer “would have been difficult for a person of ordinary skill in the art to separate” as described in Lexapro® (escitalopram) decision. (Forest Labs. Inc. v. Ivax Pharmas., Inc. Fed. Cir. Sept. 5, 2007)
On September 12, 2007, King seeks rehearing at the Court of Appeals for the Federal Circuit (CAFC). On December 3, 2007, the rehearing is denied.