Addressing the issue of the obviousness of a compound that is purified from a mixture of related chemical compounds, the U.S. Court of Appeals for the Federal Circuit reversed a district court’s pre-KSR finding of non-obviousness for Aventis’ leading ACE inhibitor, Altace®. Aventis Pharma Deutschland GMBH and King Pharmaceuticals, Inc. v. Lupin, Ltd., Case Nos. 06-1530, -1555 (Fed. Cir., Sept. 13, 2007) (Linn, J.).
ACE inhibitors are a group of pharmaceutical compounds used primarily in the treatment of hypertension and congestive heart failure. Aventis and its competitor Schering created new ACE inhibitors, including ramipril. Ramipril has five carbon atoms, each of which can be spatially oriented in two different ways, designated either “R” or “S” depending on its configuration. SSSSR and SSSSS (also known as “5(S)”) are stereoisomers of each other—the fifth carbon atoms are simply configured differently.
Schering synthesized a mixture of 5S ramipril and its SSSSR stereoisomer, which became known as SCH 31925. Schering’s work led to two issued patents: U.S. Patent Nos. 4,587,258, which issued on May 6, 1986, and 5,348,944, which issued on September 20, 1994: the ’258 and ’944 patents, respectively. The two related patents and parent application disclosed ramipril, but did not describe the configuration of its stereoisomers. Aventis’ U.S. Patent No. 5,061,722 (the ’722 patent), which issued on October 29, 1991, claims ramipril in the S-configuration, known as “SSSSS” or “5(S)” stereoisomer.
After Schering’s ’258 patent expired on January 27, 2005, Lupin filed an Abbreviated New Drug Application (ANDA), seeking approval for a generic version of ramipril. Aventis sued Lupin for infringement of the ’722 patent. In a pre-KSR bench trial, the district court concluded that the prior art, including Schering’s patents, neither taught ramipril “substantially free of other isomers,” nor would a person of ordinary skill in the art been motivated to isolate ramipril in the 5(S) configuration substantially free of other isomers. Notably, the district court held that the ’722 patent was neither anticipated nor obvious under the standard of clear and convincing evidence with the caveat that the ruling might have been in Lupin’s favor under a preponderance of evidence standard. Lupin appealed.
Noting that the “teaching, suggestion, or motivation” test was not meant to be applied as a “rigid and mandatory formula,” the Federal Circuit held that, in the chemical arts, the “reason or motivation” need not be an explicit teaching that the claimed compound will have a particular utility. The Court focused on whether a purified compound is prima facie obvious over a mixture that existed in the prior art. The Court focused on whether it is known that the purified compound is present in the mixture, whether the purified compound has similar properties to the mixture and whether one of ordinary skill in the art at the time of the invention would have known how to perform the purification. The Court held that the prior art provided sufficient reason to isolate the claimed purified compound from Schering’s mixture without an explicit teaching of purification of this mixture.
Practice Note: Generally, to rebut prima facie obviousness, the patentee must show that the claimed compound has unexpected properties over a mixture. As it relates to the chemical arts, it now appears that (under KSR), if the isolation of stereoisomers of a compound is known, the resulting purified product is less likely to be found innovative and more likely to be found to be the product of ordinary skill and common sense.