DCT

3:96-cv-01307

Integra Lifesciences v. Merck KGaA

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Key Events
Amended Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 3:96-cv-01307, S.D. Cal., 04/08/1998
  • Venue Allegations: The complaint alleges that venue is proper under 28 U.S.C. § 1400(b), noting that Defendant Scripps has its principal place of business in the district and Defendant Cheresh resides and works in the district.
  • Core Dispute: Plaintiffs allege that Defendants’ research activities, involving the use of specific peptide sequences, infringe five patents related to the discovery and application of the Arg-Gly-Asp (RGD) cell-adhesion motif.
  • Technical Context: The patents relate to the RGD peptide sequence, a fundamental component of extracellular matrix proteins like fibronectin that mediates cell attachment, a process critical to cell biology, tissue engineering, and drug discovery.
  • Key Procedural History: Plaintiff Integra Lifesciences I, Ltd. asserts its rights as the exclusive licensee of the patents-in-suit, having acquired the original licensee, Telios Pharmaceuticals, Inc., through a merger in December 1996.

Case Timeline

Date Event
1982-08-04 ’525 and ’997 Patents Priority Date
1985-05-24 ’621 and ’237 Patents Priority Date
1985-08-06 ’734 Patent Priority Date
1988-12-06 U.S. Patent No. 4,789,734 Issued
1988-12-20 U.S. Patent No. 4,792,525 Issued
1989-11-07 U.S. Patent No. 4,879,237 Issued
1991-01-29 U.S. Patent No. 4,988,621 Issued
1996-12-01 Integra acquires Telios Pharmaceuticals (approx.)
1997-12-09 U.S. Patent No. 5,695,997 Issued
1998-04-08 First Amended Complaint Filing Date

II. Technology and Patent(s)-in-Suit Analysis

U.S. Patent No. 4,792,525 - "Tetrapeptide"

The Invention Explained

  • Problem Addressed: The patent’s background describes scientific efforts to understand how cells attach to the extracellular matrix, a process mediated by the large glycoprotein fibronectin. The specific technical problem was to locate the precise, minimal molecular sequence within fibronectin responsible for its cell attachment function (Compl., Ex. A, '525 Patent, col. 1:21-41).
  • The Patented Solution: The invention claims to have isolated and identified a short tetrapeptide containing the amino acid sequence Arginine-Glycine-Aspartic acid (RGD) as the core active site for cell attachment. The specification describes a process of synthesizing progressively smaller fragments of the fibronectin molecule to pinpoint this minimal functional unit, which could then be synthesized independently ('525 Patent, Abstract; col. 3:9-20; Fig. 1).
  • Technical Importance: The identification of this short, transferrable peptide sequence provided a fundamental tool for studying cell adhesion and suggested the existence of a "universal attachment mechanism" that could be exploited for research and therapeutic purposes ('525 Patent, col. 5:46-49).

Key Claims at a Glance

  • The complaint does not identify specific asserted claims. A representative independent composition of matter claim is Claim 8:
    • A substantially pure peptide
    • including as the cell-attachment-promoting constituent the amino acid sequence Arg-Gly-Asp-R
    • wherein R is Ser, Cys, Thr or other amino acid
    • said peptide having cell-attachment-promoting activity
    • and said peptide not being a naturally occurring peptide
  • The complaint does not explicitly reserve the right to assert other claims.

U.S. Patent No. 4,988,621 - "Peptides in Cell Detachment and Aggregation"

The Invention Explained

  • Problem Addressed: The patent addresses the technical challenge of harvesting cells grown in culture. Conventional methods, such as using enzymes like trypsin, can damage or destroy the cells, complicating their use in further experiments or production processes ('621 Patent, col. 9:8-12).
  • The Patented Solution: The invention discloses a method for gently detaching cells from a substrate by introducing a solution containing soluble RGD peptides. These soluble peptides compete with the RGD sites on the substrate-bound proteins (like fibronectin), effectively blocking the cells' attachment points and causing them to release into the medium without enzymatic damage ('621 Patent, col. 3:36-44; col. 5:1-9).
  • Technical Importance: This method provided a non-toxic and reversible way to control cell adhesion, enabling the gentle harvesting of cultured cells for use in research, diagnostics, and industrial production of biological products ('621 Patent, col. 9:5-15, col. 10:31-34).

Key Claims at a Glance

  • The complaint does not identify specific asserted claims. A representative independent method claim is Claim 4:
    • A method of selectively detaching animals cells attached to fibronectin, vitronectin or a natural substrate not to type I collagen
    • comprising contacting the animal cells with a solution
    • containing a polypeptide consisting essentially of the amino acid sequence Arg-Gly-Asp
  • The complaint does not explicitly reserve the right to assert other claims.

U.S. Patent No. 4,789,734 - "Vitronectin Specific Cell Receptor Derived From Mammalian Mesenchymal Tissue"

Technology Synopsis

This patent addresses the need to isolate the cellular machinery that recognizes RGD sequences. It discloses a method for purifying a specific cell surface receptor that binds to the adhesion protein vitronectin (but not fibronectin) by using an affinity column functionalized with an RGD peptide. The patent claims the substantially purified receptor itself, characterized by two polypeptide subunits ('734 Patent, Abstract; col. 2:5-30).

Asserted Claims

The complaint does not specify claims. Independent claim 1 is asserted for infringement against Defendants Cheresh and Scripps (Compl., Third Claim for Relief, ¶¶ 24-27).

Accused Features

The complaint alleges that Defendants Cheresh and Scripps have infringed by making or using the claimed receptor in their research activities, but does not specify the exact nature of these activities (Compl. ¶25).

U.S. Patent No. 4,879,237 - "Use of Peptides in Control of Cell Attachment and Detachment"

Technology Synopsis

This patent is directed to methods of controlling cell adhesion using synthetic RGD-containing peptides. It describes how applying these peptides in soluble form can be used to either prevent cells from attaching to a substrate or to detach cells that are already attached, providing a versatile tool for managing cell cultures ('237 Patent, Abstract; col. 4:1-9).

Asserted Claims

The complaint does not specify claims. Independent method claims 1-9 are asserted against all Defendants (Compl., Fourth Claim for Relief, ¶¶ 28-35).

Accused Features

The complaint alleges infringement through the Defendants' "ongoing use of compounds and methods that infringe the '237 Patent," which suggests the use of soluble RGD peptides in laboratory research or experiments (Compl. ¶¶ 30, 33).

U.S. Patent No. 5,695,997 - "Tetrapeptide"

Technology Synopsis

A continuation of the family that includes the '525 patent, this patent claims methods of using RGD-containing peptides to modulate cell behavior. The invention covers methods of altering cell attachment activity by contacting cells with soluble peptides containing the "RGDX" sequence, where X is an amino acid ('997 Patent, Abstract; col. 7:17-25).

Asserted Claims

The complaint does not specify claims. Independent method claims 1, 4, 9, 14, 15, and 17 are asserted against all Defendants (Compl., Fifth Claim for Relief, ¶¶ 36-43).

Accused Features

The complaint alleges infringement based on the Defendants' "ongoing use of compounds and methods," pointing to the use of RGD peptides to influence cell attachment in research settings (Compl. ¶¶ 38, 41).

III. The Accused Instrumentality

Product Identification

  • The complaint does not identify any specific commercial products. Instead, it accuses "compounds and methods" used by Defendants (Compl. ¶¶ 10, 13).

Functionality and Market Context

  • The accused instrumentalities are described as research activities. The complaint alleges that Defendants Scripps and Cheresh use infringing compounds and methods in their laboratory work and that Defendant Merck provides "financial and other support" for this research and imports infringing compounds into the United States (Compl. ¶¶ 9-10, 12, 17-18). The complaint does not provide technical details of the accused compounds or methods, their specific functions in the defendants' research, or their market context beyond their use in preclinical scientific studies.

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

The complaint alleges infringement in general terms without providing a detailed mapping of accused activities to specific claim limitations. The central infringement theory appears to be that the defendants' basic scientific research—involving the synthesis, importation, and/or use of peptides containing the RGD sequence—constitutes direct infringement, inducement of infringement, and contributory infringement of the patents-in-suit (Compl. ¶¶ 9, 12, 13).

  • For the '525 Patent: The infringement allegation is that defendants make, use, or import "compounds" that are substantially pure, non-naturally occurring peptides containing the claimed Arg-Gly-Asp-R sequence and which possess cell-attachment activity (Compl. ¶¶ 12, 13).
  • For the '621 Patent: The infringement allegation is that defendants practice a method of detaching cells from substrates by contacting them with a solution containing a polypeptide with the claimed Arg-Gly-Asp sequence (Compl. ¶¶ 18, 21).

Identified Points of Contention

  • Evidentiary Question: A primary issue will be evidentiary: what specific compounds and methods were actually used by the defendants, and do they meet the limitations of the asserted claims? The complaint's allegations are made "upon information and belief" and lack specific factual support, suggesting that discovery will be necessary to define the scope of the accused activities.
  • Legal Scope Question: A central legal question may be whether the defendants' alleged research activities constitute infringing "use" under 35 U.S.C. § 271(a). The context—a research institute and a pharmaceutical company engaged in preclinical studies—raises the possibility that these activities could fall within the statutory safe harbor of 35 U.S.C. § 271(e)(1), which exempts activities "reasonably related to the development and submission of information under a Federal law which regulates the...use...of drugs."

V. Key Claim Terms for Construction

"cell-attachment-promoting activity" ('525 Patent, Claim 8)

  • Context and Importance: This functional language is a core limitation of the claimed peptide. The definition of this term is critical for determining whether a synthetically created RGD peptide performs the claimed function sufficiently to infringe. Practitioners may focus on whether this term requires a specific quantitative level of activity or merely any demonstrable promotion of cell attachment.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification describes the activity generally as promoting "the attachment of suspended cells" to various substrates, which may support a broad, qualitative definition ('525 Patent, col. 1:29-33).
    • Evidence for a Narrower Interpretation: The specification discloses specific assays using normal rat kidney (NRK) cells and quantifies activity by the concentration needed to achieve "half-maximal activity" ('525 Patent, col. 4:35-41; Fig. 1). This could support a narrower construction requiring the activity to be measurable and significant under similar experimental conditions.

"consisting essentially of" ('621 Patent, Claim 4)

  • Context and Importance: This transitional phrase defines the scope of the claimed polypeptide. It permits the inclusion of additional, unspecified amino acids beyond the core "Arg-Gly-Asp" sequence, but only if those additions do not materially affect the "basic and novel properties"—in this case, cell detachment—of the invention. The construction of this term will determine how long or complex the accused polypeptide can be while still falling within the claim's scope.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent's summary of the invention explicitly contemplates longer peptides, stating that additional amino acid sequences may extend "up to five to ten and even up to thirty amino acids on one or both ends of the ARG-GLY-ASP sequence" ('621 Patent, col. 3:50-53).
    • Evidence for a Narrower Interpretation: The detailed description and examples focus on specific, short peptides that work, such as the six-amino-acid peptide GRGDSP ('621 Patent, col. 5:1-3). This may support an argument that only short additions that do not introduce new functionalities are permissible.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that Defendant Merck induced infringement by providing "financial and other support" for the research activities of Defendants Scripps and Cheresh, with knowledge that such activities would infringe the patents (Compl. ¶¶ 9, 11, 17). It also alleges contributory infringement against Merck for importing infringing compounds (Compl. ¶12) and against all defendants (Compl. ¶13).
  • Willful Infringement: The complaint alleges that all defendants acted with "actual knowledge" of the patents-in-suit and with "willful and wanton disregard" of Plaintiffs' rights (Compl. ¶¶ 9, 13, 15). These allegations of pre-suit knowledge form the basis for a claim of willful infringement and a request for enhanced damages and attorneys' fees.

VII. Analyst’s Conclusion: Key Questions for the Case

  1. A foundational issue will be one of factual development: What specific preclinical research activities did the defendants perform, and what was the exact composition and use of the accused RGD-containing peptides? The complaint’s lack of detail makes discovery the immediate focal point for defining the technical and factual basis of the infringement claims.
  2. A core legal dispute will be one of statutory interpretation: Do the defendants' alleged preclinical research activities constitute an infringing "use" of the patented inventions under 35 U.S.C. § 271(a), or are they exempt from infringement under the safe harbor provision of 35 U.S.C. § 271(e)(1) for acts solely and reasonably related to developing information for submission to a federal regulatory agency?