DCT

1:17-cv-01316

Baxalta Inc v. Bayer Healthcare LLC

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Key Events
Amended Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:17-cv-01316, D. Del., 09/04/2019
  • Venue Allegations: Venue is alleged as proper in the District of Delaware on the basis that Defendant is a Delaware corporation that resides in, does business in, and has continuous and systematic contacts with the district.
  • Core Dispute: Plaintiffs allege that Defendant’s hemophilia A treatment, Jivi®, infringes a family of eight U.S. patents related to the conjugation of the Factor VIII protein with water-soluble polymers, such as polyethylene glycol (PEG), to extend the drug's therapeutic effect.
  • Technical Context: The technology involves chemically modifying Factor VIII, a critical blood-clotting protein deficient in hemophilia A patients, to increase its circulating half-life, thereby reducing the required frequency of intravenous infusions.
  • Key Procedural History: This action is a Second Amended Complaint filed within a consolidated case that is related to prior litigation between the parties in both the U.S. and Germany. The complaint references a 2003 Research Agreement between Nektar and Bayer, alleging that Bayer's technology was developed in violation of that agreement. The Court has already issued a claim construction (Markman) ruling on July 22, 2019, construing several key terms and rejecting a narrow construction proposed by the Defendant.

Case Timeline

Date Event
2003-02-26 Priority Date for all Patents-in-Suit
2003-12-11 Nektar and Bayer enter into Research Agreement
2007-04-03 U.S. Patent No. 7,199,223 Issued
2011-01-04 U.S. Patent No. 7,863,421 Issued
2012-03-27 U.S. Patent No. 8,143,378 Issued
2012-08-21 U.S. Patent No. 8,247,536 Issued
2013-08-27 U.S. Patent No. 8,519,102 Issued
2013-12-31 U.S. Patent No. 8,618,259 Issued
2014-11-18 U.S. Patent No. 8,889,831 Issued
2017-08-30 Bayer submits Biologics License Application for Jivi®
2018-06-19 U.S. Patent No. 9,999,657 Issued
2018-08-29 Bayer receives marketing approval for Jivi®
2018-09-01 Bayer launches Jivi® (approx. date from complaint)
2019-09-04 Second Amended Complaint Filed

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

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

  • Patent Identification: U.S. Patent No. 7,199,223, "Polymer-Factor VIII Moiety Conjugates," issued April 3, 2007 (Compl. ¶39).

The Invention Explained

  • Problem Addressed: The patent's background section describes that standard Factor VIII treatments for hemophilia A have a short in vivo half-life, requiring patients to undergo frequent and painful injections to manage their condition (’223 Patent, col. 2:50-55, col. 4:38-42). Prior attempts to attach polymers like PEG to extend this half-life often resulted in a significant loss of the protein's therapeutic activity ('223 Patent, col. 3:20-33).
  • The Patented Solution: The invention claims to solve this problem by creating a conjugate of a Factor VIII moiety and one, two, or three water-soluble polymers where each polymer has a nominal average molecular weight greater than 5,000 Daltons (Compl. ¶111; ’223 Patent, col. 4:1-6). This specific, larger polymer size is described as providing an extended half-life while retaining sufficient biological activity, thereby reducing the required dosing frequency ('223 Patent, Abstract; col. 4:38-42).
  • Technical Importance: This approach represented an effort to create a longer-acting Factor VIII therapy that could significantly improve quality of life for hemophilia patients by reducing the burden of frequent intravenous infusions (Compl. ¶¶12, 63).

Key Claims at a Glance

  • The complaint asserts at least dependent Claim 6, which relies on independent Claim 1 (Compl. ¶106).
  • The essential elements of independent Claim 1 are:
    • 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 reserves the right to assert fifty-five claims collectively from the asserted patents (Compl. ¶36).

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

  • Patent Identification: U.S. Patent No. 7,863,421, "Polymer-Factor VIII Moiety Conjugates," issued January 4, 2011 (Compl. ¶42).

The Invention Explained

  • Problem Addressed: Similar to the '223 Patent, this patent addresses the need for a Factor VIII therapeutic with a longer half-life that does not suffer from a significant loss of activity, a problem with previous PEGylation efforts (’421 Patent, col. 3:25-39).
  • The Patented Solution: This invention describes a more precise method of conjugation. The solution involves attaching a water-soluble polymer to the Factor VIII polypeptide specifically "via a thiol group of a cysteine residue" that has been engineered into the protein sequence ('421 Patent, col. 4:55-66). This site-specific attachment is designed to avoid disrupting the protein's active sites, thereby better preserving its therapeutic function while still extending its half-life ('421 Patent, Abstract).
  • Technical Importance: Site-specific conjugation allows for more controlled and predictable modification of a protein, which may avoid the loss of activity associated with random conjugation to naturally occurring amino acids like lysines (Compl. ¶69).

Key Claims at a Glance

  • The complaint asserts at least dependent Claim 4, which relies on independent Claim 1 (Compl. ¶126).
  • The essential elements of independent Claim 1 are:
    • 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 a group including Factor VIII and B-domain deleted Factor VIII,
    • and wherein the water-soluble polymer is selected from a group including poly(alkylene glycol).
  • The complaint reserves the right to assert additional claims (Compl. ¶36).

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

  • Patent Identification: "Polymer Factor VIII Moiety Conjugates," issued March 27, 2012 (Compl. ¶45).
  • Technology Synopsis: This patent claims a composition comprising a plurality of conjugates where a polymer is attached to a Factor VIII moiety via a "hydrolytically stable linkage." A key feature is that the resulting composition retains a specified level of bioactivity, comprising an in-vitro activity of at least 15% compared to the unconjugated form (’378 Patent, col. 73:1-26).
  • Asserted Claims: At least Claim 1 is asserted (Compl. ¶143).
  • Accused Features: BAY 94 is alleged to be a composition of Factor VIII conjugates with a hydrolytically stable "thioether linkage" that is bioactive and retains at least 15% of its in-vitro activity (Compl. ¶¶146, 149).

U.S. Patent No. 8,247,536 - "Factor VIII Compositions"

  • Patent Identification: "Factor VIII Compositions," issued August 21, 2012 (Compl. ¶48).
  • Technology Synopsis: This patent is directed to a pharmaceutical composition that is "free from albumin" and comprises a conjugate of Factor VIII and one to three water-soluble polymers (’536 Patent, col. 73:13-29).
  • Asserted Claims: At least Claim 3 is asserted (Compl. ¶157).
  • Accused Features: BAY 94 is alleged to be produced "without the addition of any exogenous human or animal derived protein," such as albumin, in its manufacturing process (Compl. ¶¶70, 194).

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

  • Patent Identification: "Polymer Factor VIII Moiety Conjugates," issued August 27, 2013 (Compl. ¶51).
  • Technology Synopsis: This patent claims a conjugate where a polymer is attached via a thiol group of a cysteine residue that has been "added to or substituted in" the Factor VIII polypeptide. The invention requires the final conjugate to retain a significant level of bioactivity, specifically at least 15% (Claim 1) or at least 40% (Claim 3) of the unconjugated form's in-vitro activity (’102 Patent, col. 73:1-26).
  • Asserted Claims: At least Claim 3 is asserted (Compl. ¶173).
  • Accused Features: BAY 94 is alleged to be a conjugate wherein a PEG is attached to an introduced cysteine and to retain at least 40% of its in-vitro activity after PEGylation (Compl. ¶¶177, 180).

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

  • Patent Identification: "Polymer-Factor VIII Conjugate Compositions," issued December 31, 2013 (Compl. ¶54).
  • Technology Synopsis: This patent claims a composition comprising a cysteine-modified Factor VIII conjugate that is substantially free from albumin. The claims specify purity levels of at least 85% free from albumin (Claim 1) and at least 99% free from albumin (Claim 3) (’259 Patent, col. 73:1-21).
  • Asserted Claims: At least Claim 3 is asserted (Compl. ¶188).
  • Accused Features: BAY 94 is alleged to be produced without adding exogenous proteins like albumin, resulting in a composition that is at least 99% free from albumin (Compl. ¶¶194-195).

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

  • Patent Identification: "Unit Dosage Forms of Pharmaceutical Compositions Comprising a Polymer-Factor VIII Polypeptide Conjugate," issued November 18, 2014 (Compl. ¶57).
  • Technology Synopsis: This patent covers a "unit dose" of a pharmaceutical composition containing a cysteine-modified Factor VIII conjugate and an excipient. The claims specify a particular dosage range for the Factor VIII polypeptide, such as from 0.01 mg to 75 mg (Claim 2) (’831 Patent, col. 75:1-26).
  • Asserted Claims: At least Claim 2 is asserted (Compl. ¶203).
  • Accused Features: BAY 94 is alleged to be available in lyophilized powder form containing 250, 500, 1000, 2000, or 3000 International Units, which allegedly corresponds to a Factor VIII polypeptide amount within the claimed range of 0.01 mg to 75 mg (Compl. ¶¶70, 210).

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

  • Patent Identification: "Polymer-Factor VIII Moiety Conjugates," issued June 19, 2018 (Compl. ¶60).
  • Technology Synopsis: This patent claims a monoPEGylated conjugate of a B-domain deleted Factor VIII where a "single poly(ethylene glycol) polymer" is attached to a cysteine residue. The claims further require the polymer to be "branched" and have a specific nominal average molecular weight, such as between 20,000 and 85,000 daltons (’657 Patent, col. 77:1-12).
  • Asserted Claims: At least Claim 2 is asserted (Compl. ¶218).
  • Accused Features: BAY 94 is alleged to be a monoPEGylated conjugate using a single, large (60 kDa), branched PEG molecule, which falls within the claimed molecular weight range (Compl. ¶¶69, 221-222).

III. The Accused Instrumentality

Product Identification

The accused product is Bayer's BAY 94-9027, marketed as Jivi® (Compl. ¶66). This includes the PEGylated Factor VIII conjugates, active ingredient, bulk drug substance, and final drug product composition (Compl. ¶66).

Functionality and Market Context

  • Jivi® is a therapy for hemophilia A, designed to have a longer-acting effect (Compl. ¶¶68, 77). Its active ingredient is a recombinant B-domain deleted (BDD) form of Factor VIII that is conjugated ("pegylated") with a 60 kDa polyethylene glycol (PEG) molecule (Compl. ¶69).
  • The complaint alleges the manufacturing process involves site-specific modification, entailing the "introduction of a cysteine" into the BDD Factor VIII protein, to which the 60 kDa PEG molecule is then attached via a "thioether linkage" (Compl. ¶69). The final product is a lyophilized powder for intravenous administration and is produced without exogenous human or animal-derived protein (Compl. ¶70).
  • Jivi® is alleged to compete directly with Plaintiffs' ADYNOVATE® product for an overlapping patient population (Compl. ¶77). The complaint states that Bayer launched Jivi® "at-risk" in September 2018, while this and related litigation were pending (Compl. ¶99).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

U.S. Patent No. 7,199,223 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 BAY 94 is comprised of a Factor VIII polypeptide conjugated with PEG, which is a water-soluble polymer ¶112 col. 3:56-58
covalently attached to a Factor VIII moiety, The PEG polymer is covalently attached to the Factor VIII moiety in the BAY 94 product ¶112 col. 4:1-3
wherein each water-soluble polymer has a nominal average molecular weight in the range of from 6,000 Daltons to 150,000 Daltons BAY 94 is comprised of a conjugate that is pegylated with a 60 kDa water-soluble polymer, which is within the claimed range ¶113 col. 4:1-6
and further wherein the cojugate [sic] is a 1-mer, 2-mer or 3-mer. BAY 94 comprises a conjugate that is pegylated at an amino acid position with a water-soluble polymer, satisfying the 1-mer element ¶114 col. 37:15-25

U.S. Patent No. 7,863,421 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 BAY 94 is comprised of a Factor VIII polypeptide conjugated with PEG, a water-soluble polymer ¶130 col. 4:55-58
via a thiol group of a cysteine residue contained within the Factor VIII polypeptide, In BAY 94, the PEG is bound via a thiol group at a cysteine residue, with the complaint citing a "thioether linkage" ¶131 col. 29:30-49
wherein the Factor VIII polypeptide is selected from the group consisting of...B-domain deleted Factor VIII, The active ingredient in BAY 94 is a recombinant B-domain deleted form of Factor VIII ¶132 col. 10:25-35
and wherein the water-soluble polymer is selected from the group consisting of poly(alkylene glycol), poly(vinyl pyrrolidone), poly(vinyl alcohol)... The polymer used in BAY 94 is PEG, which is a poly(alkylene glycol) ¶133 col. 11:66-12:5

Identified Points of Contention

  • Scope Questions: A central question may be how the term "Factor VIII moiety" or "Factor VIII polypeptide" is construed across the patent family. Although the court rejected a narrow construction limited to native Factor VIII (Compl. ¶102), disputes may arise over whether Bayer's specific B-domain deleted, recombinantly produced protein meets the full scope of the term as understood in the context of each patent.
  • Technical Questions: The infringement analysis for the '378 and '102 patents will raise factual questions about the bioactivity of Jivi®. What evidence will show that Jivi® retains "at least 15%" or "at least 40%" of the in-vitro activity of its unconjugated form, as required by the respective claims? (Compl. ¶¶149, 180). Similarly, for the '259 patent, what is the precise, factual basis for the allegation that Jivi® is "at least 99% free from albumin"? (Compl. ¶195). These questions suggest that the case will involve competing laboratory data and expert testimony.

V. Key Claim Terms for Construction

The Term: "modified to add a cysteine residue" (from '421 Patent, Claim 2)

Context and Importance

This term is foundational to the patents claiming site-specific conjugation ('421, '102, '259, '831 patents). The infringement case hinges on whether Bayer's manufacturing process, which allegedly "entails, inter alia, introduction of a cysteine" (Compl. ¶69), falls within this scope. Practitioners may focus on this term because the distinction between modifying an existing protein sequence versus other methods of "introduction" could be a central point of non-infringement or invalidity arguments.

Intrinsic Evidence for Interpretation

  • Evidence for a Broader Interpretation: The specification states that the Factor VIII moiety "can advantageously be modified to include one or more amino acid residues such as, for example, lysine, cysteine and/or arginine, in order to provide facile attachment of the polymer" ('421 Patent, col. 10:35-39). This language suggests a broad, functional purpose that could cover any method of engineering a new cysteine into the protein for conjugation.
  • Evidence for a Narrower Interpretation: The patent's detailed description provides a list of specific, preferred thiol groups for attaching a polymer, corresponding to specific cysteine residues in the sequence (e.g., Cys329, Cys630) ('421 Patent, col. 37:58-64). A party could argue that "modified to add" should be construed in light of these specific embodiments, limiting the claim to substitutions at or near these disclosed locations rather than any possible introduction of a cysteine anywhere on the polypeptide.

The Term: "hydrolytically stable linkage" (from '378 Patent, Claim 1)

Context and Importance

The '378 patent requires this specific type of linkage, and Plaintiffs allege that Jivi®'s "thioether linkage" meets the limitation (Compl. ¶146). This term's definition is critical because other patents in the same family (e.g., the '749 patent, which is not asserted here but is part of the family history mentioned in Exhibit K) claim conjugates with degradable linkages. The stability of the bond is therefore a key technical distinction.

Intrinsic Evidence for Interpretation

  • Evidence for a Broader Interpretation: The '223 patent specification, which is substantially similar, defines a "hydrolytically stable" linkage as one that "is substantially stable in water, that is to say, does not undergo hydrolysis under physiological conditions to any appreciable extent over an extended period of time." It lists examples including "carbon-carbon bonds..., ethers, amides, urethanes, and the like" ('223 Patent, col. 8:1-10). A thioether linkage is chemically similar in stability to an ether and could be argued to fall within the scope of "and the like."
  • Evidence for a Narrower Interpretation: The same section distinguishes these stable linkages from "hydrolysable or degradable" linkages like esters and acetals ('223 Patent, col. 7:64-8:4). A defendant could argue that since "thioether" is not explicitly listed among the stable examples, its specific rate of hydrolysis under all relevant physiological conditions must be proven to be as slow as the enumerated examples, raising a question of degree rather than kind.

VI. Other Allegations

Indirect Infringement

The complaint does not contain separate counts for indirect infringement and provides minimal specific facts to support such a theory. It makes broad reference to infringement under 35 U.S.C. §§ 271(a), (b), (c), (f), and/or (g) in each count, but the factual allegations focus on Bayer's own acts of making, using, and selling Jivi® (Compl. ¶¶106, 126, 143).

Willful Infringement

The complaint alleges willful infringement based on both pre- and post-suit knowledge. It alleges Bayer had knowledge of the patent applications as early as 2004 and of the issued patents since at least 2017 (Compl. ¶¶80, 86-93). The complaint further alleges that Bayer approached Nektar in 2012 to discuss a license to "avoid patent litigation" (Compl. ¶84). Post-suit willfulness is alleged based on Bayer's "at-risk" launch of Jivi® in September 2018, after litigation had commenced, and its continued infringement after the Court issued a claim construction ruling that was unfavorable to Bayer's non-infringement position (Compl. ¶¶99, 102).

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

  • A core issue will be one of inventorship and derivation: did Bayer independently develop its site-specific PEGylation technology for Factor VIII, or was its invention, as Plaintiffs allege, improperly derived from confidential technology and know-how disclosed by Nektar under a 2003 Research Agreement? The extensive history of related US and German litigation suggests this foundational dispute over the technology's origin may be dispositive.
  • A key evidentiary question will be one of technical compliance: assuming the patents are valid and owned by Plaintiffs, does Bayer's Jivi® product meet the specific quantitative limitations recited across the eight asserted patents? This will require a detailed factual inquiry into Jivi®'s precise level of bioactivity, purity from albumin, polymer molecular weight, and dosage amounts, likely turning on a battle of competing expert analyses and laboratory testing.
  • A final central question will be one of subjective intent: given the allegations of a long litigation history, pre-suit knowledge, licensing discussions, and an "at-risk" launch following an adverse Markman ruling, did Bayer act with willful blindness or objective recklessness regarding its potential infringement? The answer will determine its exposure to enhanced damages.