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Isolation of the Most Therapeutically Active Ingredient Was Obvious Where the Ingredient Was Present in a Mixture in the Prior Art

06-1530
September 11, 2007

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Last Month at the Federal Circuit - October 2007

Judges: Mayer, Linn (author), Robertson (District Judge sitting by designation)

[Appealed from: E.D. Va., Judge Doumar]

In Aventis Pharma Deutschland GmbH v. Lupin, Ltd., Nos. 06-1530, -1555 (Fed. Cir. Sept. 11, 2007), the Federal Circuit reversed the district court and held that the subject matter of the asserted claims of U.S. Patent No. 5,061,722 (“the ’722 patent”) was invalid as obvious over various prior art references.

Aventis Pharma Deutschland GmbH (“Aventis”) was issued the ’722 patent directed to the pharmaceutical compound ramipril in a formulation “substantially free of other isomers.” Ramipril, like many complex organic molecules, is one of a family of stereoisomers. An isomer of a compound is a separate compound in which each molecule contains the same constituent atoms as the first compound, but with those atoms arranged differently. A stereoisomer is an isomer in which the same atoms are bonded to the same other atoms, but where the configuration of those atoms in three dimensions differs.

In the structural formula that represents ramipril, there are five carbon atoms that may take either of two orientations—or five “stereocenters,” as such atoms are known. To differentiate among members of the family of stereoisomers, each member’s stereocenters are labeled either “R” or “S,” depending upon its configuration. The five stereocenters in ramipril are expressly oriented in the “S” configuration and, as a result, it is known  as an “SSSSS” or a “5(S)” stereoisomer. Ramipril is in the family of drugs known as “Angiotensin-Converting Enzyme inhibitors,” or “ACE inhibitors.” ACE inhibitors are useful for treating high blood pressure because they inhibit a biochemical pathway that constricts blood vessels. Enalapril is the ACE inhibitor that immediately preceded ramipril. Enalapril has three stereocenters.

Ramipril is marketed as a blood pressure medication under the name Altace® by King Pharmaceuticals, Inc. (“King”), the exclusive licensee of the ’722 patent. After Lupin, Ltd. and Lupin Pharmaceuticals, Inc. (collectively “Lupin”) filed an ANDA seeking approval for a generic version of ramipril, Aventis and King sued Lupin for infringement of the ’722 patent. After a bench trial on validity, the district court concluded that the ’722 patent was neither anticipated nor obvious.

On appeal, the Federal Circuit first rejected an Aventis challenge to the prior art status of U.S. Patent No. 5,348,944 (“the ’944 patent”) because Aventis had not raised the issue below. The Federal Circuit also found that Dr. Elizabeth Smith’s synthesis of a mixture called SCH 31925 qualified as prior art under 35 U.S.C. § 102(g), which affords prior art status to an invention made in the United States by another inventor who has not abandoned, suppressed, or concealed it. The Federal Circuit rejected Aventis’s argument that Dr. Smith abandoned, suppressed, or concealed SCH 31925, noting that a method similar to Dr. Smith’s method for synthesizing SCH 31925 was disclosed in a patent application filed by Dr. Smith’s employer, Schering. That application was based on the work of Dr. Smith. The Court further noted that the exact method used by Dr. Smith to synthesize SCH 31925 was disclosed in a related Schering patent, and that SCH 31925 was developed in the course of extensive ongoing research and development and concurrent ongoing patent prosecution.

Turning to the question of obviousness, the Court noted that the key question is whether the 5(S) stereoisomer of ramipril, in a form substantially free of other isomers, would have been obvious over the prior art at the time of the ’722 patent’s priority date. The Court further noted that the district court found that it was a close case, but held that Lupin failed to meet its burden of proof by clear and convincing evidence that a person of ordinary skill in the art would have been motivated to purify 5(S) ramipril into a composition substantially free of other isomers.

The Federal Circuit pointed out that after the date of the district court’s decision, the Supreme Court decided KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727 (2007), which counsels against applying the teaching, suggestion, or motivation (“TSM”) test as a rigid and mandatory formula. The Federal Circuit explained that it remains necessary, however, to show “‘some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness,’ but such reasoning ‘need not seek out precise teachings directed to specific subject matter of the challenged claim.’” Slip op. at 13 (quoting KSR, 127 S. Ct. at 1741). The Federal Circuit concluded that “[r]equiring an explicit teaching to purify the 5(S) stereoisomer from a mixture in which it is the active ingredient is precisely the sort of rigid application of the TSM test that was criticized in KSR.” Id. at 13-14.

In the chemical arts, the Court noted that it has long been held that “structural similarity between claimed and prior art subject matter, proved by combining references or otherwise, where the prior art gives reason or motivation to make the claimed compositions, creates a prima facie case of obviousness.” Id. at 14 (citation omitted). The Federal Circuit explained that the necessary “reason or motivation” may be established by showing that “the claimed and prior art compounds possess a ‘sufficiently close relationship . . . to create an expectation,’ in light of the totality of the prior art, that the new compound will have ‘similar properties’ to the old.” Id. (quoting In re Dillon, 919 F.2d 688, 692 (Fed. Cir. 1990) (en banc)). Once a prima facie case of obvious has been established, it is the burden of the applicant or patentee to rebut it by showing, for example, that the claimed compound has unexpected properties.

The Court explained that the analysis is similar where, as here, 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, the Court elaborated, “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.” Id. at 15. If it is known how to perform the isolation of the compound of interest, the Court explained, doing so “is likely the product not of innovation but of ordinary skill and common sense.” Id. (quoting KSR, 127 S. Ct. at 1742).

Having laid out the legal framework, the Court turned to analysis of the prior art in the case. The Court concluded that the record suggested that when Dr. Smith synthesized SCH 31925—a prior art mixture of 5(S)-configuration ramipril and its SSSSR stereoisomer—she understood that the 5(S) form of ramipril was the mixture’s therapeutically active ingredient. Even if she did not, the Court said, other prior art provides a sufficient reason to look to the 5(S) configuration. Several pieces of prior art suggested that the S configuration is more potent than the R configuration. For example, a prior art article taught that the SSS configuration of enalapril is 700 times as potent as the SSR form. Moreover, the Court noted, prior art U.S. Patent No. 5,348,944 (“the ’944 patent”) specifically taught that stereoisomers of ramipril can be separated by conventional methods. The Court concluded that, Aventis’s protestations notwithstanding, there was no evidence that separating 5(S) and SSSSR ramipril was outside the capability of an ordinary skilled artisan. Aventis attempted to rebut the prima facie case of obviousness by asserting that 5(S) ramipril exhibited unexpected results in the form of increased potency over the next most potent isomer, the RRSSS form. The Federal Circuit rejected this comparison, noting that Aventis had to show unexpected results not over all of the stereoisomers, but over the SCH 31925 mixture disclosed in the prior art. The Court found that all of the evidence suggested that potency varies with the absolute amount of 5(S) isomer in a mixture, and the potency of pure 5(S) ramipril was precisely what one would expect. Thus, the Court concluded that the asserted claims of the ’722 patent were invalid as obvious over the SCH 31925 mixture, the ’944 patent, and the enalapril references in the prior art.

Finally, the Court addressed asserted claims 4 and 5 of the ’722 patent, noting that it must evaluate obviousness on a claim-by-claim basis. The additional limitations of claim 4, concerning a hypotensively effective amount, and claim 5, concerning a method for reducing blood pressure by administering the compound of claim 1, appeared almost verbatim in virtually all of the prior art patents. The Federal Circuit found claims 4 and 5 identified a manner of using ACE inhibitors that was well understood by ordinarily skilled artisans and held both claims also to be invalid as obvious.