DCT

1:17-cv-01316

Baxalta Inc v. Bayer Healthcare LLC

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:17-cv-01316, D. Del., 07/02/2018
  • Venue Allegations: Venue is alleged to be proper as Defendant is a Delaware corporation that resides in the district and has previously submitted to the court's jurisdiction in other litigation.
  • Core Dispute: Plaintiffs allege that Defendant’s hemophilia A treatment, Jivi (BAY 94-9027), infringes eight patents related to the conjugation of the Factor VIII protein with water-soluble polymers such as polyethylene glycol (PEG) to extend its therapeutic effect.
  • Technical Context: The patents relate to methods of modifying Factor VIII, a critical blood-clotting protein deficient in patients with hemophilia A, to increase its in-vivo half-life, thereby reducing the frequency of required intravenous injections for patients.
  • Key Procedural History: The complaint alleges a complex history between Plaintiff Nektar and Defendant Bayer, including a 2003 Research Agreement under which Nektar allegedly shared proprietary technology with Bayer. The complaint notes parallel patent ownership proceedings in Germany and prior patent litigation in the U.S. between the parties involving related technology, framing the current suit as part of a long-running dispute over the inventorship and ownership of PEGylated Factor VIII technology.

Case Timeline

Date Event
2003-02-26 Earliest Patent Priority Date (Nektar provisional application)
2003-12-01 Nektar and Bayer enter Research Agreement
2004-11-01 Bayer allegedly proceeds to prosecute patent applications using Nektar technology
2007-04-03 U.S. Patent No. 7,199,223 Issues
2011-01-04 U.S. Patent No. 7,863,421 Issues
2012-03-27 U.S. Patent No. 8,143,378 Issues
2012-08-21 U.S. Patent No. 8,247,536 Issues
2013-08-27 U.S. Patent No. 8,519,102 Issues
2013-12-31 U.S. Patent No. 8,618,259 Issues
2014-11-18 U.S. Patent No. 8,889,831 Issues
2017-08-30 Defendant files Biologics License Application for BAY 94
2018-06-19 U.S. Patent No. 9,999,657 Issues
2018-07-02 Amended Complaint Filing Date
2018-10-01 Expected Launch of BAY 94 (Q4 2018)

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

U.S. Patent No. 7,199,223 - "Polymer-Factor VIII Moiety Conjugates," issued April 3, 2007

The Invention Explained

  • Problem Addressed: The patent's background describes the challenge of treating hemophilia A, a bleeding disorder caused by a deficiency of Factor VIII protein (Compl. ¶60). Existing treatments require frequent and painful injections because Factor VIII has a short half-life in the body (’223 Patent, col. 3:4-12). Prior attempts to attach polymers like PEG to extend this half-life had proven to be of "little predictive value" (’223 Patent, col. 3:15-18).
  • The Patented Solution: The invention is a Factor VIII conjugate comprising a limited number of relatively large water-soluble polymers (one, two, or three polymers, each over 6,000 Daltons) (’223 Patent, Abstract). By attaching a small number of larger polymer chains, the invention seeks to prolong the protein's circulation time and reduce immunogenicity without substantially compromising its therapeutic activity, which can be diminished by excessive polymer attachment (’223 Patent, col. 4:26-44).
  • Technical Importance: This approach represented a strategy to balance the competing goals of extending a biologic's half-life via polymer conjugation while preserving its essential function, a central problem in the field of protein therapeutics (’223 Patent, col. 4:26-30).

Key Claims at a Glance

  • The complaint asserts infringement of at least independent claim 1 (Compl. ¶80).
  • Claim 1 Elements:
    • A conjugate comprising one, two or three water-soluble polymers covalently attached to a Factor VIII moiety,
    • wherein each water-soluble polymer has a nominal average molecular weight in the range of from 6,000 Daltons to 150,000 Daltons
    • and further wherein the conjugate is a 1-mer, 2-mer or 3-mer.
  • The complaint alleges infringement of at least claim 1, reserving the right to assert other claims (Compl. ¶80).

U.S. Patent No. 7,863,421 - "Polymer-Factor VIII Moiety Conjugates," issued January 4, 2011

The Invention Explained

  • Problem Addressed: As with related patents, the invention addresses the need for improved Factor VIII therapeutics with longer in-vivo half-lives (’421 Patent, col. 3:23-28). This patent focuses on achieving this by controlling the specific site of polymer attachment.
  • The Patented Solution: The invention claims a Factor VIII conjugate where a water-soluble polymer is covalently attached "via a thiol group of a cysteine residue contained within the Factor VIII polypeptide" (’421 Patent, Abstract). This "thiol-specific" chemistry allows for more precise, site-directed conjugation compared to methods that target more numerous and less specific amino acid residues like lysines (’421 Patent, col. 29:30-49).
  • Technical Importance: Site-specific conjugation can preserve the bioactivity of a complex protein like Factor VIII by directing the polymer away from regions critical to its function, a significant refinement over random conjugation methods (’421 Patent, col. 15:23-31).

Key Claims at a Glance

  • The complaint asserts infringement of at least independent claim 1 (Compl. ¶91).
  • Claim 1 Elements:
    • A conjugate comprising a water-soluble polymer covalently attached to a Factor VIII polypeptide via a thiol group of a cysteine residue contained within the Factor VIII polypeptide,
    • wherein the Factor VIII polypeptide is selected from the group consisting of Factor VIII, Factor VIIIa, Factor VIII:C, Factor VIII:vWF and B-domain deleted Factor VIII,
    • and wherein the water-soluble polymer is selected from the group consisting of poly(alkylene glycol), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline, and poly(N-acryloylmorpholine).
  • The complaint alleges infringement of at least claim 1, reserving the right to assert other claims (Compl. ¶91).

U.S. Patent No. 8,143,378 - "Polymer Factor VIII Moiety Conjugates," issued March 27, 2012

  • Technology Synopsis: This patent claims a composition comprising a plurality of Factor VIII conjugates. The claims require the polymer to be attached via a "hydrolytically stable linkage" and for the final composition to be "bioactive," retaining at least 15% of the in-vitro activity compared to the unconjugated protein (Compl. ¶104).
  • Asserted Claims: Independent claim 1 (Compl. ¶103).
  • Accused Features: The complaint alleges that the BAY 94 product is a composition comprising Factor VIII conjugates attached via a thioether linkage, which is characterized as hydrolytically stable, and that the product retains its bioactivity (Compl. ¶¶105-109).

U.S. Patent No. 8,247,536 - "Factor VIII Compositions," issued August 21, 2012

  • Technology Synopsis: This patent claims a Factor VIII conjugate composition that is specifically "free from albumin" (Compl. ¶117). This addresses a potential issue with earlier biologic formulations that required albumin as a stabilizer, which could cause allergic reactions.
  • Asserted Claims: Independent claim 1 (Compl. ¶116).
  • Accused Features: The complaint alleges that the BAY 94 product is produced "without the addition of any exogenous human or animal derived protein" and is therefore free from albumin (Compl. ¶¶67, 117 referencing Ex. K ¶70).

U.S. Patent No. 8,519,102 - "Polymer Factor VIII Moiety Conjugates," issued August 27, 2013

  • Technology Synopsis: This patent is directed to a Factor VIII conjugate attached via a thiol group of a cysteine residue that "has been added to or substituted in the Factor VIII polypeptide" (Compl. ¶128). This explicitly claims site-specific conjugation at an engineered, non-native cysteine residue.
  • Asserted Claims: Independent claim 1 (Compl. ¶127).
  • Accused Features: The complaint alleges that the manufacturing process for BAY 94 "entails, inter alia, introduction of a cysteine and pegylation of a BDD Factor VIII protein" (Compl. ¶¶66, 130).

U.S. Patent No. 8,618,259 - "Polymer-Factor VIII Conjugate Compositions," issued December 31, 2013

  • Technology Synopsis: This patent combines concepts from prior patents, claiming a composition that is "at least 85% free from albumin" and comprises a conjugate where the polymer is attached via an "added to or substituted" cysteine residue (Compl. ¶140).
  • Asserted Claims: Independent claim 1 (Compl. ¶139).
  • Accused Features: The complaint alleges the BAY 94 product is at least 85% free from albumin and is manufactured using an introduced cysteine for PEG attachment (Compl. ¶¶142, 144).

U.S. Patent No. 8,889,831 - "Unit Dosage Forms of Pharmaceutical Compositions Comprising a Polymer-Factor VIII Polypeptide Conjugate," issued November 18, 2014

  • Technology Synopsis: This patent claims a "unit dose" of a pharmaceutical composition comprising the conjugate technology. It specifically claims a unit dose containing the conjugate (attached via an added or substituted cysteine) and a pharmaceutically acceptable excipient, with the Factor VIII polypeptide present in an amount from 0.001 mg to 100 mg (Compl. ¶152).
  • Asserted Claims: Independent claim 1 (Compl. ¶151).
  • Accused Features: The complaint alleges that BAY 94 will be available as a lyophilized powder in unit doses containing 250 to 3000 International Units, which falls within the claimed mass range (Compl. ¶¶67, 155).

U.S. Patent No. 9,999,657 - "Polymer-Factor VIII Moiety Conjugates," issued June 19, 2018

  • Technology Synopsis: This patent claims a "monoPEGylated" Factor VIII conjugate with specific chemical characteristics. It requires a "single poly(ethylene glycol) polymer" that is "branched" and has a molecular weight between 20,000 and 85,000 daltons (Compl. ¶164).
  • Asserted Claims: Independent claim 1 (Compl. ¶163).
  • Accused Features: The complaint alleges BAY 94 is a monoPEGylated conjugate using a single, large (60 kDa) PEG molecule that is branched (Compl. ¶¶165-166).

III. The Accused Instrumentality

Product Identification

  • BAY 94-9027, also known by the trade name Jivi (Compl. ¶63).

Functionality and Market Context

  • Jivi is a therapeutic product for the treatment of hemophilia A (Compl. ¶65). The complaint alleges, based on Defendant's representations in other litigation, that its active ingredient is a recombinant B-domain deleted (BDD) form of Factor VIII. This protein is allegedly pegylated with a 60 kDa polyethylene glycol (PEG) molecule (Compl. ¶66).
  • The complaint further alleges that the manufacturing process for Jivi involves the "introduction of a cysteine" into the BDD Factor VIII protein, with the 60 kDa PEG molecule being attached to this introduced cysteine via a thioether linkage (Compl. ¶66). The product is intended for intravenous administration and will be supplied as a lyophilized powder (Compl. ¶67).
  • The complaint alleges that Bayer has filed a Biologics License Application (BLA) with the FDA for Jivi and is preparing for a commercial launch, positioning the product to compete directly with Plaintiffs' ADYNOVATE® product for an overlapping patient population (Compl. ¶¶65, 74).

IV. Analysis of Infringement Allegations

’223 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A conjugate comprising one, two or three water-soluble polymers covalently attached to a Factor VIII moiety, BAY 94 is comprised of a Factor VIII polypeptide conjugated with PEG, a water-soluble polymer, which is covalently attached. The complaint alleges a visual in an exhibit shows a PEG conjugated to the Factor VIII moiety at amino acid position 1804. ¶82 col. 3:48-51
wherein each water-soluble polymer has a nominal average molecular weight in the range of from 6,000 Daltons to 150,000 Daltons The PEG molecule in BAY 94 is alleged to be a 60 kDa water-soluble polymer. ¶83 col. 4:5-9
and further wherein the cojugate [sic] is a 1-mer, 2-mer or 3-mer. BAY 94 is alleged to comprise a conjugate that is pegylated at an amino acid position, which the complaint alleges satisfies this limitation. ¶84 col. 5:1-5

’421 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A conjugate comprising a water-soluble polymer covalently attached to a Factor VIII polypeptide via a thiol group of a cysteine residue contained within the Factor VIII polypeptide, BAY 94 is alleged to be a conjugate wherein the PEG molecule is bound via a thiol group of a cysteine residue through a thioether linkage. ¶¶93, 94 col. 29:30-34
wherein the Factor VIII polypeptide is selected from the group consisting of...B-domain deleted Factor VIII, The active ingredient in BAY 94 is alleged to be a B-domain deleted Factor VIII polypeptide. ¶95 col. 15:47-53
and wherein the water-soluble polymer is selected from the group consisting of poly(alkylene glycol), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline, and poly(N-acryloylmorpholine). The water-soluble polymer used in BAY 94 is alleged to be PEG, which is a poly(alkylene glycol). ¶96 col. 11:62-12:5

Identified Points of Contention

  • Scope Questions: A central question for infringement of the ’421 Patent may be whether the claim term "cysteine residue contained within the Factor VIII polypeptide" can be construed to read on a cysteine residue that was allegedly introduced into the polypeptide sequence for the purpose of conjugation (Compl. ¶66). The existence of other patents in the asserted family that explicitly recite an "added or substituted" cysteine (e.g., the ’102 Patent) may suggest a narrower scope for the term "contained within."
  • Technical Questions: For the ’223 Patent, a potential point of dispute is what technical evidence supports the allegation that BAY 94, described as a "conjugate that is pegylated at an amino acid position," meets the specific claim limitation of being a "1-mer, 2-mer or 3-mer" (Compl. ¶84). The complaint does not detail how the structure of the accused product corresponds to this specific terminology, which the patent specification often uses in the context of analyzing and separating mixtures of conjugates with different numbers of attached polymers.

V. Key Claim Terms for Construction

The Term: "cysteine residue contained within the Factor VIII polypeptide" (’421 Patent, Claim 1)

  • Context and Importance: The construction of this term may be dispositive for the infringement analysis of the ’421 Patent. The complaint alleges that BAY 94 is created by "introduction of a cysteine" for PEG attachment (Compl. ¶66). Practitioners may focus on this term because if "contained within" is construed to mean only native, naturally-occurring cysteine residues, the infringement allegation may fail. Conversely, if it is construed to also include non-native, engineered residues, the allegation may be supported.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: A party could argue that the plain meaning of "contained within" simply requires the cysteine to be part of the final polypeptide chain, irrespective of its origin, and that the patent does not explicitly exclude engineered cysteines.
    • Evidence for a Narrower Interpretation: The specification discusses available sites for conjugation, including thiol groups from cysteine residues, in the context of the protein's existing structure (’421 Patent, col. 29:30-49). Furthermore, a related patent in the family, U.S. Patent No. 8,519,102, explicitly claims a conjugate attached to a cysteine that has been "added to or substituted" (Compl. ¶128). A party may argue this demonstrates that the patentees viewed "contained within" and "added or substituted" as distinct concepts, implying a narrower meaning for the former term.

The Term: "1-mer, 2-mer or 3-mer" (’223 Patent, Claim 1)

  • Context and Importance: This term defines the number of polymer chains per Factor VIII moiety in the claimed conjugate. The complaint alleges that BAY 94 satisfies this limitation by being "pegylated at an amino acid position" (Compl. ¶84). The construction of this term will determine whether a product described as mono-pegylated necessarily meets this limitation.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification describes the terms as corresponding to the number of attached polymers, stating that "mono-PEGylated protein (1-mer)" has one PEG moiety attached (’223 Patent, Ex. A, p. 68, col. 46:3-7). This could support a simple structural interpretation where a "1-mer" is any conjugate with one polymer.
    • Evidence for a Narrower Interpretation: The patent frequently uses the terms "1-mer," "2-mer," and "3-mer" in the context of describing the results of a purification process, such as size exclusion chromatography, which separates a mixture of reaction products into distinct fractions based on the number of attached polymers (’223 Patent, col. 38:43-50). A party might argue that the term, as used in the claims, is not just a structural descriptor but implies a conjugate that is the result of such a separation process.

VI. Other Allegations

  • Indirect Infringement: The complaint includes boilerplate references to infringement under 35 U.S.C. §§ 271(b) and (c) in the introductory paragraphs to the infringement counts (Compl. ¶¶80, 91). However, the complaint does not provide sufficient detail for analysis of indirect infringement, as it pleads no specific facts regarding, for example, Defendant's intent to induce infringement by others or the sale of a component for an infringing use.

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

This case presents a multifaceted dispute over advanced biologic drug technology, layered upon a contentious history between the parties. The resolution will likely depend on the court’s determination of a several key technical and legal questions:

  • A core issue will be one of claim scope differentiation: can the term "cysteine residue contained within the Factor VIII polypeptide" from the ’421 Patent be construed to cover a cysteine that was allegedly "introduced" into the polypeptide, particularly when a later asserted patent in the same family, the ’102 Patent, explicitly claims an "added or substituted" cysteine?
  • A key question of claim construction will be whether the term "1-mer, 2-mer or 3-mer" in the ’223 Patent refers simply to the number of polymers on a conjugate, as Plaintiffs' allegations suggest, or if it carries a more specific technical meaning derived from the patent's description of manufacturing and purification processes that might narrow its scope.
  • An underlying evidentiary question will be one of structural proof: what evidence will be presented to establish that the accused Jivi product, as manufactured and sold, possesses the specific structural and compositional features required by each of the eight asserted patents, which claim distinct attributes ranging from polymer number and size to albumin content and specific chemical linkages?