Genentech, Inc. v. Boehringer Mannheim GmbH, Civil Action No. 96-11090-PBS.

• Decision Date: 30 December 1997
• Docket Number: Civil Action No. 96-11090-PBS.
• Citation: 989 F.Supp. 359
• Parties: GENENTECH, INC., Plaintiff, v. BOEHRINGER MANNHEIM GmbH and Boehringer Mannheim Corp., Defendants.
• Court: U.S. District Court — District of Massachusetts

Page 359

989 F.Supp. 359

GENENTECH, INC., Plaintiff, v. BOEHRINGER MANNHEIM GmbH and Boehringer Mannheim Corp., Defendants.

Civil Action No. 96-11090-PBS.

United States District Court, D. Massachusetts.

December 30, 1997.

Joseph Ferraro, Leora Ben-Ami, Philip E. Roux, Rogers & Wells, New York City, Gary W. Smith, Dennis D. Allegretti, Anthony J. Fitzpatrick, Renee Inomata, Burns & Levinson, Boston, MA, Dale A. Malone, Banner & Whitcoff, Boston, MA, Sean Johnston, Genentch, Inc., South San Francisco, CA, Gerard P. Norton, Rogers & Wells, New York City, for Plaintiff.

William L. Patton, Steven A. Kaufman, Martin J. Newhouse, Crystal D. Talley, Ropes & Gray, Boston, MA, Peter F. Felfe, Felfe & Lynch, New York City, John E. Lynch, Felfe & Lynch, New York City, J. Barry Vice Pres. and Gen. Counsel, Boehringer Mannheim Corporation — Therapeutics, Gaithersburg, MD, for Defendants.

MEMORANDUM AND ORDER

SARIS, District Judge.

INTRODUCTION

The plaintiff, Genentech, Inc. ("Genentech"), alleges that the defendants, Boehringer Mannheim GmbH and Boehringer Mannheim Corp. (collectively, "BM"), infringed five patents involving its tissue plasminogen activator ("t-PA") product. This memorandum and order addresses the issues of claims construction raised in a hearing held on June 17-18, 1997, and July 23, 1997, regarding three of Genentech's patents: United States Patent Nos. 4,432,832 ("the '832 patent"); 5,034,225 ("the '225 patent"); and 4,511,502 ("the '502 patent"). See Markman v. Westview Instruments, Inc., 517 U.S. 370, 116 S.Ct. 1384, 134 L.Ed.2d 577 (1996).

The hearings consisted of extensive and impressive testimony by experts, including: Joseph Oliver Falkinham, III, professor of microbiology at Virginia Polytechnic Institute and State University; Andrew C. Webb, professor of biological sciences at Wellesley College; Victor Gurewich, M.D., director of the vascular research laboratory and co-director of the Institute for the Prevention of Cardiovascular Disease at Beth Israel-Deaconess Medical Center, and professor of medicine at Harvard Medical School; Jeffrey V. Ravetch, M.D., professor at the Rockefeller University and head of the laboratory of molecular genetics and immunology, and adjunct professor in the department of microbiology and immunology at Jefferson Medical College and Jefferson Cancer Institute; Alexander M. Klibanov, professor of chemistry at the Massachusetts Institute of Technology (M.I.T.); and Charles L. Cooney, a professor of chemical and biochemical engineering and executive officer of the department of chemical engineering at M.I.T. In addition, the Court heard testimony of an agreed-upon court-appointed neutral expert, Connie Cepko, a professor of genetics and associate investigator of the Howard Hughes Medical Institute at the Harvard Medical School.

The parties agreed at the Markman v. Westview Instruments, Inc., 52 F.3d 967 (1995) hearing on June 18, 1997 and on July 23, 1997, that the terms in dispute were: "organically synthesized" and "gene fragments" ('832 patent); "tissue plasminogen activator," "incorporating," and "pharmaceutical composition" (225 patent); and "molecular sieve" ('502 patent). (Tr. 2-117 - 2-118.)¹ At the urging of both parties, the hearings addressed only the claims construction issues and left pending the parties' cross-motions for summary judgment.

I. FACTUAL BACKGROUND

Serious heart attacks can be caused by the presence of a thrombus, which is a blood clot in the coronary blood vessels or coronary artery. The process that dissolves a thrombus is called thrombolysis and the chemicals in the body that induce thrombolysis are called plasminogen activators. Two plasminogen activators, which are a natural part of a body's defenses, are urokinase-type plasminogen activator (u-PA or urokinase) and tissue-type plasminogen activator (t-PA).

T-PA is a chemical that makes the body's natural plasminogen become plasmin, an enzyme. Plasmin cuts through fibrin, the substance which makes up blood clots. Although the body naturally produces small amounts of t-PA, this quantity is insufficient to activate sufficient plasminogen to cut through the large clots involved in heart attacks.

In the late 1970s and early 1980s, scientists, whose research was sponsored by Genentech, successfully reproduced t-PA through recombinant DNA technology by identifying the DNA encoding t-PA — 527 amino acids with glycosylation (the attachment of sugars) — at three sites and inserting the DNA into bacteria. In July, 1979, Genentech applied for the '832 patent for its particular method of reproducing t-PA and subsequently obtained approval from the Food and Drug Administration (FDA) to sell t-PA under the brand name Activase. Genentech also obtained a patent for purifying proteins ('502 patent) in 1985 and one for increasing the solubility of t-PA in a pharmaceutical composition by incorporating arginine ('225 patent) in 1991.

Genentech claims that BM's plasminogen activator called Reteplase violates its patents.

II. THE PATENTS

A. '832 Patent

Entitled "Method of Constructing a Replicable Cloning Vehicle Having Quasi-Synthetic Genes," the '832 patent "provides a method of general applicability" for the production of useful proteins of known amino acid sequence, including antibodies and enzymes, and is "particularly suited to the expression of mammalian polypeptide hormones and other substances having medical applications." ('832 Patent, Col. 8, lines 3-11.) The inventors claim that their application represents "the first occasion upon which a medically significant human polypeptide was directly expressed microbially, rather than in conjunction with extraneous protein." ('832 prosecution history, Pl.Ex. 2, at p. 103.) To do this, the '832 patent teaches a method of making a plasmid using two types of DNA, synthetic DNA, and cDNA derived from messenger RNA. Id. (See '832 patent, Col. 10, lines 35 et seq.) Specifically, the '832 patent describes "a method of using organically-synthesized DNA to create an optimal 5' end (encoding the amino terminus of a protein) for the desired protein. The organically-synthesized DNA is joined to the cDNA to create a chimeric [or semi-synthetic] gene." (Cepko report at 1, Docket 262.)

Claim 1 of the '832 patent teaches the method of constructing the "replicable cloning vehicle" capable of expressing a gene for a particular polypeptide of known amino acid sequence by combining cDNA and synthetic DNA. Steps (a) and (b) involve "obtaining by reverse transcription from messenger RNA gene fragments" which encode less than all of the amino acid sequence of the polypeptide. Step (c) involves providing by "organic synthesis one or more synthetic non-reverse transcript gene fragments" for the remainder of the sequence. Step (d) involves joining the gene fragment of Step (c) to the gene fragment described in Steps (a) and (b) and inserting these gene fragments into a plasmid in proper reading phase.

The disputed terms in Claim 1 are in bold type:

In the method of constructing a replicable cloning vehicle capable, in a microbial organism, of expressing a particular polypeptide of known amino acid sequence wherein a gene coding for the polypeptide is inserted into a cloning vehicle and placed under the control of an expression promoter, the improvement which comprises:

(a) obtaining by reverse transcription from messenger RNA a first gene fragment for an expression product other than said polypeptide, which fragment comprises at least a portion of the coding sequence for said polypeptide;

(b) where the first fragment comprises protein-encoding codons for amino acid sequences other than those contained in said polypeptide, eliminating the same while retaining at least a substantial portion of said coding sequence, the resulting fragment nevertheless coding for an expression product other than said polypeptide;

the product of step (a) or, where required, step (b) being a fragment encoding less than all of the amino acid sequence of said polypeptide;

(c) providing by organic synthesis one or more synthetic non-reverse transcript-gene fragments encoding the remainder of the amino acid sequence of said polypeptide, at least one of said fragments coding for the amino-terminal portion of the polypeptide; and

(d) deploying the synthetic gene fragment(s) of step (c) and that produced in step (a) or (b), as the case may be, in a replicable cloning vehicle in proper reading phase relative to one another and under the control of an expression promoter;

whereby a replicable cloning vehicle capable of expressing the amino acid sequence of said polypeptide is formed.

B '225 Patent

The '225 patent, entitled "Stabilized Human Tissue Plasminogen Activator for Compositions," claims a method of increasing the solubility and stability of the protein human tissue plasminogen activator (t-PA) in a pharmaceutical composition by incorporating arginine. ('225 Patent, col. 9, 11. 32-35 - col. 10, 11. 24-25; Cepko report at 6.) Genentech alleges that BM infringes the '225 patent by adding arginine in the course of producing Reteplase.

The parties dispute three terms in the '225 patent: "tissue plasminogen activator," "pharmaceutical composition," and "incorporating," as used in the claims of the '225 patent. The claim reads as follows, with the disputed terms in bold type:

1. A method of increasing the solubility of tissue plasminogen activator in a pharmaceutical composition containing same as active principle comprising incorporating argininium ion in said composition, wherein said argininium ion is present in an amount effective to increase the solubility of said t-PA.

C. '502 Patent

The '502 patent claims a three-step process of purifying proteins. The parties dispute the meaning of the term "molecular sieve" as it is used in the claim of the '502 patent. The claim reads as follows, with the disputed term in bold type:

A process for purifying heterologous proteins which...