Aventis Pharma Deutschland Gmbh v. Lupin, Ltd.

• Decision Date: 11 September 2007
• Docket Number: No. 2006-1530.,No. 2006-1555.,2006-1530.,2006-1555.
• Citation: 499 F.3d 1293
• Parties: AVENTIS PHARMA DEUTSCHLAND GmbH, Plaintiff-Cross Appellant, and King Pharmaceuticals, Inc., Plaintiff-Cross Appellant, v. LUPIN, LTD. and Lupin Pharmaceuticals, Inc., Defendants-Appellants.
• Court: U.S. Court of Appeals — Federal Circuit

499 F.3d 1293

AVENTIS PHARMA DEUTSCHLAND GmbH, Plaintiff-Cross Appellant, and King Pharmaceuticals, Inc., Plaintiff-Cross Appellant, v. LUPIN, LTD. and Lupin Pharmaceuticals, Inc., Defendants-Appellants.

No. 2006-1530.

No. 2006-1555.

United States Court of Appeals, Federal Circuit.

September 11, 2007.

Joel Katcoff, Kaye Scholer LLP, of New York, NY, argued for plaintiff-cross appellant Aventis Pharma Deutschland GmbH. With him on the brief were Benjamin C. Hsing, Sapna Walter Palla, and Tatiana N. Alyonycheva.

F. Dominic Cerrito, Jones Day, of New York, NY, argued for plaintiff-cross appellant King Pharmaceuticals, Inc. With him on the brief were Daniel L. Malone, Eric Stops, and Jonathan A. Muenkel.

Deanne M. Mazzochi, Rakoczy Molino Mazzochi Siwik LLP, of Chicago, IL, argued for defendants-appellants. With her on the brief were William A. Rakoczy, Paul J. Molino, and Alice L. Riechers.

Before MAYER and LINN, Circuit Judges, and ROBERTSON, District Judge.^*

LINN, Circuit Judge.

This is a patent infringement action concerning the pharmaceutical compound ramipril, which is marketed by King Pharmaceuticals, Inc. ("King") as a blood pressure medication under the name Altace®. Lupin Ltd. and Lupin Pharmaceuticals, Inc. (collectively, "Lupin") appeal from a final judgment of infringement entered by the United States District Court for the Eastern District of Virginia in favor of King and Aventis Pharma Deutschland GmbH ("Aventis"). Aventis Pharma Deutschland GmbH v. Lupin Ltd., No. 2:05-CV-421, 2006 WL 2008962 (E.D.Va. July 17, 2006). The district court concluded at summary judgment that Lupin's filing of an Abbreviated New Drug Application (ANDA) for a generic version of ramipril infringed Aventis's U.S. Patent. No. 5,061,722 ("the '722 patent") under the doctrine of equivalents, and concluded after a bench trial that the asserted claims of the '722 patent were not invalid.¹ Lupin appeals from these decisions. Aventis cross-appeals from the district court's decision to dismiss its claim of willful infringement. For the reasons that follow, we conclude that the subject matter of the asserted claims of the '722 patent would have been obvious. Accordingly, we reverse. The cross-appeal and the remaining issues raised by the parties are deemed moot and are not addressed.

I. BACKGROUND

A. The Claimed Technology

The patent at issue in this appeal is 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. As the district court explained in greater detail in its opinion regarding validity, Aventis Pharma Deutschland GmbH v. Lupin, Ltd., No. 2:05-CV-421, 2006 WL 2008962 (E.D.Va. July 17, 2006) ("Invalidity Opinion"), 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. The following structural formula represents ramipril:

NOTE: OPINION CONTAINING TABLE OR OTHER DATA THAT IS NOT VIEWABLE

Each of the five carbon atoms marked with an asterisk can be spatially oriented in two different ways.² For example, the dashed triangle leading from the leftmost marked carbon to a hydrogen ("H") atom indicates that the hydrogen atom lies below the planes of the two five-sided rings of which the carbon atom is a part. The hydrogen atom may also lie above the planes of the rings, resulting in a structure that is a stereoisomer of ramipril. Because there are five carbon atoms that may take either of two orientations — or five "stereocenters," as such atoms are known — ramipril is one of 2⁵, or 32, stereoisomers. There are a number of different ways of naming these stereoisomers; one comparatively simple system, used by both parties and by the district court, involves labeling each stereocenter with an "R" or an "S" depending on its configuration. Using this system, all five stereocenters in ramipril are in the "S" configuration, so it is known as an "SSSSS" or "5(S)" stereoisomer. Other stereoisomers would include RRRRR, SSSSR, RRSSS, etc.

Some of the prior art references also use the terms "enantiomer" and "diastereomer." Enantiomers are stereoisomers that are mirror images of each other, like left and right hands. Diastereomers are stereoisomers that are not enantiomers.

The asserted claims of the '722 patent read as follows:

1. A compound of the formula

NOTE: OPINION CONTAINING TABLE OR OTHER DATA THAT IS NOT VIEWABLE

or a physiologically acceptable salt thereof, wherein R² is hydrogen, methyl, ethyl, or benzyl, and wherein hydrogen atoms on the ring carbon atoms in the 1- and 5-positions are in the cis-configuration relative to one another, the carboxyl group on the ring carbon atom in the 3-position is in the endo position relative to the bicyclic ring system, and the chirality centers in the chain and on the ring carbon atom in the 3-position all have the S-configuration, said compound or salt being substantially free of other isomers.

2. A compound or salt as in claim 1 which is N-(1-S-carboethoxy-3-phenyl-propyl)-S-alanyl-cis,endo-2-azabicyclo-[3.3.0]-octane-3-S-carboxylic acid or a salt thereof.

4. A hypotensive composition for reducing blood pressure comprising a hypotensively effective amount of a compound or salt as in claim 1 and a pharmaceutically acceptable excipient therefor.

5. A method for reducing blood pressure in a patient which comprises administering to said patient a hypotensively effective amount of a compound or salt as in claim 1.

Claim 1, the only independent claim, covers a small genus of compounds, each of which has a different functional group at location R². The language of the claim, "wherein hydrogen atoms on the ring carbon atoms in the 1- and 5-positions are in the cis-configuration relative to one another, the carboxyl group on the ring carbon atom in the 3-position is in the endo position relative to the bicyclic ring system, and the chirality centers in the chain and on the ring carbon atom in the 3-position all have the S-configuration," limits claim 1 (and thus all the other claims) to the 5(S) stereoisomer. When the R² functional group is ethyl, the compound of claim 1 is ramipril. This is the compound claimed specifically by claim 2.

B. The Development of Ramipril

Ramipril is one of a family of drugs known as "Angiotensin-Converting Enzyme inhibitors," or "ACE inhibitors." ACE inhibitors inhibit a biochemical pathway that constricts blood vessels and therefore are useful for treating high blood pressure. The earliest ACE inhibitors, dating back to the late 1960s, were based on the venom of the Brazilian Viper, which was known to reduce blood pressure. The active compound isolated from viper venom, known as BPP_5a, has six stereocenters, all of which are in the S configuration. Synthetic ACE inhibitors have been developed by making structural modifications to this venom and to successive generations of ACE inhibitors. For example, captopril, the first synthetic ACE inhibitor, consists of part of the BPP_5a molecule with a sulfur atom at the end. Captopril retains two stereocenters from BPP_5a, both of which remain in the S configuration.

Ramipril's immediate predecessor is an ACE inhibitor known as enalapril that was introduced by Merck in 1980. Enalapril has three stereocenters. In a published article, Merck scientists explained that the all-S (SSS) stereoisomer of enalapril was found to have 700 times the potency of the SSR stereoisomer. A.A. Patchett et al., A New Class of Angiotensin-Converting Enzyme Inhibitors, 288 Nature 280 (Nov. 20, 1980), available at J.A. 15475. The Merck article taught how to separate the all-S isomer using standard chromatography techniques.

Both Aventis and its competitor Schering sought to create new ACE inhibitors based on enalapril. Soon after enalapril's introduction, Dr. Elizabeth Smith, a chemist at Schering, conceived of the structure of ramipril and recorded it in her laboratory notebooks. Ramipril has the same overall structure as enalapril, with one distinction: where ramipril has two linked five-sided carbon rings (a "5,5 fused ring system"), depicted, in the chemical diagrams above, on the left side of the molecule, enalapril has only a single ring. The addition of the second ring gives rise to two more stereocenters than are present in enalapril; thus, ramipril has the same three stereocenters as enalapril, plus two new ones that span the fused ring system and are therefore known as "bridgehead" carbons, for a total of five as discussed above.

Based on the work of Dr. Smith, Schering filed U.S. Patent Application No. 06/199,886 ("the '886 application") on October 23, 1980. Thereafter, the U.S. Patent and Trademark Office ("PTO") granted Schering Patent No. 4,587,258 ("the '258 patent," issued May 6, 1986) and No. 5,348,944 ("the '944 patent," issued Sept. 20, 1994), both claiming priority from the '886 application via a series of continuations and continuations-in-part. The '886 application, the '258 patent, and the '944 patent disclose the structure of ramipril but do not describe how its stereocenters should be configured.

Example 20 of the '886 application discloses a method for making ramipril and is contained in the published specification of the '944 patent. '944 patent, col. 15, ll. 1-15. The title of Example 20 encompasses only eight of the 32 stereoisomers of ramipril, but there is some suggestion in the record that, in fact, Example 20 would have produced only four stereoisomers in practice. Invalidity Opinion at 22-23. The district court described one of the experts testifying on the topic as "somewhat credible" and did not make any explicit findings as to which stereoisomers Example 20 would create. Id. at 23. For...