Aventis Pharma S.A. v. Amphastar Pharmaceuticals Inc.

• Decision Date: 08 February 2007
• Docket Number: No. EDCV03 887 MRP FLAX.,No. EDCVO4 333 MRP PLAX.,EDCV03 887 MRP FLAX.,EDCVO4 333 MRP PLAX.
• Citation: 475 F.Supp.2d 970
• Parties: AVENTIS PHARMA S.A., and Aventis Pharmaceutical, Inc., Plaintiff, v. AMPHASTAR PHARMACEUTICALS, INC., and Teva Pharmaceuticals USA, Inc., Defendant. And Related Counterclaims.
• Court: U.S. District Court — Central District of California

475 F.Supp.2d 970

AVENTIS PHARMA S.A., and Aventis Pharmaceutical, Inc., Plaintiff, v. AMPHASTAR PHARMACEUTICALS, INC., and Teva Pharmaceuticals USA, Inc., Defendant And Related Counterclaims.

No. EDCV03 887 MRP FLAX.

No. EDCVO4 333 MRP PLAX.

United States District Court, C.D. California.

February 8, 2007.

COPYRIGHT MATERIAL OMITTED

Donald R. Dunner, Allen M. Sokal, Bryan. C. Diner, Esther H. Lim, Finnegan Henderson Farabow Garrett & Dunner, Washington, DC, Michael J. McCabe II, John D. Livingstone, Robert C. Stanley, Finnegan Henderson Farabow Garrett & Dunner, Atlanta, GA, Anthony G. Brazil, Donald L. Ridge, Megan S. Wynne, Morris Polich & Purdy, Los Angeles, CA, for Plaintiffs.

Jan P. Weir, Jennifer A. Trusso, Nicole A. Varner, Steven M. Hanle, Stradling Yocca Carlson & Rauth, Newport Beach, CA, Edith Ramirez, Eugene T. Chen, Lee J. Papageorge, Quinn Emanuel Urquhart Oliver & Hedges, Los Angeles, CA, Francis C. Lynch, Laurie S. Gill, Goodwin Procter, John T. Bennett, Palmer & Dodge LLP, Boston, MA, for Defendants.

MEMORANDUM OF DECISION FINDING IN FAVOR OF DEFENDANTS AMPHASTAR PHARMACEUTICALS, INC. AND TEVA PHARMACEUTICALS USA, INC. ON THE RELATED ISSUES OF INTENT TO DECEIVE THE PATENT AND TRADEMARK OFFICE AND INEQUITABLE CONDUCT

PFAELZER, District Judge.

I. INTRODUCTION

This case was commenced before District Judge Robert J. Timlin. Aventis Pharma S.A. and Aventis Pharmaceuticals, Inc. (collectively, "Aventis"¹) brought suit against Amphastar Pharmaceuticals, Inc. ("Amphastar") and Teva Pharmaceuticals USA, Inc. ("Teva") (collectively, "Defendants") for infringement of Aventis' patent, U.S. Patent No. 5,389,618, and its replacement, U.S. Reissue Patent No. 38,743 (collectively, "the '618 patent"). The case was transferred to this Court for all further proceedings on June 27, 2006. A bench trial on inequitable conduct was held December 4 through December 8, 2006. The Court limited its inquiry to Aventis and its agents' intent in failing to disclose highly material information to the United States Patent and Trademark Office ("PTO"). Based on consideration of the evidence adduced at trial and the post-trial arguments made by counsel, the Court concludes as follows:

II. BACKGROUND

Heparin is an anticoagulant used to decrease the clotting ability of the blood. Chemically, it is a heterogeneous mixture of straight-chain anionic mucopolysaccharides having anticoagulant properties. Low molecular weight heparin ("LMWH") is synthesized by various methods of heparin fractionation or depolymerization. These methods break down heparin's long, heavy polysaccharide molecules, yielding smaller, less massive chains in more homogenous proportions. The resulting mixtures consist of shorter chains of polysaccharides having lower average molecular weights.

The '618 patent claims a range of defined LMWH mixtures. These encompass the drug formulation, enoxaparin, approved by the United States Food and Drug Administration ("FDA") as an anticoagulant in diseases featuring venous thromboses. Aventis is the international pharmaceutical company that manufactures enoxaparin, which it markets under the brand name Lovenox®. Enoxaparin was approved in France in 1987. By 1989, it had "taken the French market by storm" and achieved commercial success throughout Europe. Aventis exerted a monopoly position in the European market for enoxaparin in the 1980s by virtue of European Patent 40,144 ("EP '144"), which issued in 1984 and broadly claimed undefined LMWH mixtures invented by J. Mardiguian.

Serious challenges to EP '144 soon threatened this position. Opposition proceedings initiated in the mid-1980s before the European Patent Office to revoke EP '144 as devoid of novelty had, by 1989, proved successful — the opposition was allowed, and the revocation of EP '144 became effective in October 1990. Enoxaparin did not have patent coverage in the U.S. at this time. Aventis had been forced to abandon its U.S. counterpart application to EP '144 in 1984 when it had no argument to oppose the PTO's prior-art rejections. Notwithstanding this deficit, Aventis filed its New Drug Application ("NDA") with the FDA in July 1991 to obtain marketing approval for enoxaparin in the U.S. In concert, Aventis sought to protect enoxaparin in the U.S. with an EP '144 successor: a formulation of enoxaparin invented by Roger Debrie (the "Debrie" or "'618" product).² This was the subject of the '618 prosecution. The high cost of FDA approval generated substantial pressure on Aventis to succeed. Internal Aventis documents reveal its commitment of "significant financial and human resources" to the "enoxaparin USA-patent situation."

The '618 prosecution involved successive rounds of rejection and appeal. The Patent Examiner ("PE") issued three Office Actions dated April 2, 1992 ("First Office Action"), October 16, 1992 ("Second Office Action"), and March 2, 1993 ("Third Office Action"). Each rejected the Debrie formulation under 35 U.S.C. & sect; 102 as anticipated by or, in the alternative, under 35 U.S.C. & sect; 103 as obvious in light of Mardiguian EP '144. The keystone of Aventis' strategy for overcoming the PE's rejections was to distinguish the Debrie LMWH based on its purportedly superior pharmacokinetic properties — particularly, its longer plasma half-life. The '618 patent discloses that "[t]he processes described in the prior art, and especially in EP '144, do not permit the production of mixtures possessing the requisite pharmacological properties for improved therapeutic applications, namely, a sufficiently long plasma half-life, a fairly high absorption rate, a high bioavailability or alternatively, a low clearance." In support of these assertions, Aventis directed the PE's attention to Example 6 of the '618 patent ("Example 6") and the half-life analysis presented therein.³ Aventis also submitted two expert declarations from its employee French scientist Dr. Andre Uzan ("Dr.Uzan"), who was responsible for the data underlying Example 6.⁴

Throughout the prosecution, Aventis and Dr. Uzan affirmatively represented that Example 6 "clearly demonstrate[d]" a significantly longer plasma half-life for the Debrie LMWH compared to Mardiguian EP '144. At no time, however, did Aventis or Dr. Uzan disclose at what dosage the half-life comparisons in Example 6 had been made. Subparagraph (3) of Example 6 omitted the experimental dose of EP '144. In his Second Declaration, Dr. Uzan presented five tables: Tables I, X, and XI referred to the '618 product, while Tables A and III referred to Mardiguian EP '144. Again, Table III failed to disclose the dose. In fact, Dr. Uzan had compared a 60 mg dose of Mardiguian EP '144 to a 40 mg dose of the Debrie product. However, comparing the 60 mg dose amount of Mardiguian EP '144 to the 60 mg dose amount of the Debrie product results in a far closer mean half-life.⁵ The difference is not statistically significant.

III. PRIOR PROCEEDINGS

Amphastar moved for summary judgment on its affirmative defense and counterclaim of inequitable conduct, arguing that Aventis and Dr. Uzan's withholding of the EP '144 dosage constituted a failure to disclose material information to the U.S. PTO and rendered the '618 patent-in-suit unenforceable. Judge Timlin agreed, finding that: (1) the EP '144 dose information was highly material, because Aventis made half-life the centerpiece of its argument for patentability, and a reasonable PE would have considered the experimental dose important in deciding whether to allow Aventis' application on that basis; and (2) the omission of the dose information supported a strong inference of intent to deceive, because the Debrie product's half-life was not significantly different from EP '144 at the same dose. Accordingly, Judge Timlin granted summary judgment in favor of Amphastar and held the '618 patent and the '743 reissue patent unenforceable. Aventis Pharma S.A. v. Amphastar Pharmaceuticals, Inc., 390 F.Supp.2d 936 (C.D.Cal.2005).

On appeal, the Federal Circuit reversed and remanded, Aventis Pharma S.A. v. Amphastar Pharmaceuticals, Inc., 176 Fed.Appx. 117 (Fed.Cir.2006), concluding that, although there were no genuine issues as to high materiality, a finding of deceptive intent was inappropriate on summary judgment. The panel conceded that Judge Timlin's inference of intent by Aventis to deceive the PTO was "reasonable," observing that "by failing to disclose that the EP 40,144 data was at a 60 mg dose, Aventis may have been painting the rosiest picture possible as to the half-life improvement of its claimed compounds in an attempt to deceive the examiner." Aventis, 176 Fed.Appx. at 123. This concession ratified Amphastar's prima facie case of intent. See Paragon Podiatry Lab., Inc. v. KLM Lab., Inc., 984 F.2d 1182, 1192 (Fed.Cir.1993) ("A party charging inequitable conduct may make a prima facie case by showing an unexplained violation of the duty of candor.").

The panel also agreed with Aventis, however. The case for deceptive intent "hinge[d] on an assessment of Dr. Uzan's credibility and an examination of the scientific rationale and facts justifying Dr. Uzan's half-life comparison at different doses." (Fed. Cir. Reply Br. 21-22.) Aventis had stated facts supporting a "plausible justification" for its material omission, but Judge Timlin had denied Dr. Uzan an opportunity to testify to it at trial. Thus, because "there [was] another reasonable inference [than intent to deceive] — namely, as Aventis argue[d], if the comparison between different doses was reasonable, the failure to disclose may have been partly due to inadvertence" — the finding of intent was premature.

Upon remand and transfer, the Court entertained pre-trial motions,⁶ considered the trial briefs of the parties, and conducted the bench trial on intent to which the present decision relates.

IV. LEGAL STANDARD

"Inequitable conduct occurs when a patentee breaches his or her duty of `candor, good faith, and honesty,'"...