DCT

5:24-cv-04089

Wuhan Healthgen Biotechnology Corp v. Expresstec LLC

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 5:24-cv-04089, D. Del., 03/11/2024
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware because all named Defendants are Delaware corporations. The complaint further alleges that Defendants have committed acts of infringement and purposefully transacted business in the district.
  • Core Dispute: Plaintiff alleges that Defendant’s methods for manufacturing plant-derived recombinant human serum albumin (rHSA) products, including Optibumin, infringe three U.S. patents covering specific methods for extracting and purifying rHSA from transgenic rice.
  • Technical Context: The technology involves producing high-purity recombinant proteins for therapeutic and clinical use, offering an alternative to sourcing human serum albumin from donated blood plasma, which carries risks of contamination and supply limitations.
  • Key Procedural History: The complaint alleges that Plaintiff provided Defendant with notice of the patents-in-suit on or about March 1, 2024, approximately ten days before filing the lawsuit. No other prior litigation or administrative proceedings involving the patents are mentioned.

Case Timeline

Date Event
2010-12-20 Priority Date for U.S. Patent No. 10,183,984
2010-12-24 Priority Date for U.S. Patent No. 9,951,100
2012-12-21 Priority Date for U.S. Patent No. 10,730,926
2018-04-24 U.S. Patent No. 9951100 Issued
2019-01-22 U.S. Patent No. 10183984 Issued
2020-08-04 U.S. Patent No. 10730926 Issued
2023-02-03 Date of Defendant's Certificate of Analysis for Optibumin
2023-08-01 ExpressTec acquisition of Ventria Bioscience alleged (approx.)
2024-03-01 Plaintiff alleges providing notice of patents to Defendant
2024-03-11 Complaint Filed

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

U.S. Patent No. 9,951,100

  • Patent Identification: U.S. Patent No. 9,951,100, "Method for isolating and purifying recombinant human serum albumin from transgenic rice grain", issued April 24, 2018 (Compl. ¶23).

The Invention Explained

  • Problem Addressed: The patent's background describes the difficulty in purifying rHSA derived from sources like rice grain, which can contain impurities such as pigments and polysaccharides, as well as protein aggregates that form during purification. These impurities pose risks to patients and complicate large-scale manufacturing (Compl. ¶¶ 18, 25; ’100 Patent, col. 1:15-24, col. 2:15-24).
  • The Patented Solution: The invention is a specific, sequential three-step chromatography process designed to achieve very high purity. It requires first subjecting a crude extract to cation exchange chromatography, then anion exchange chromatography, and finally hydrophobic chromatography. A critical feature of the final step is that it is performed under a condition where the desired rHSA does not bind to the chromatography resin and is instead collected in the flow-through fractions (Compl. ¶26; ’100 Patent, Abstract).
  • Technical Importance: This specific sequence and method, particularly the flow-through hydrophobic step, is presented as a cost-effective and reliable process for achieving over 99% purity, a key hurdle for the commercial viability of plant-based rHSA for clinical applications (Compl. ¶25; ’100 Patent, col. 2:20-24).

Key Claims at a Glance

  • The complaint asserts independent claim 1 (Compl. ¶26).
  • The essential elements of Claim 1 are:
    • A method for isolating and purifying rHSA from transgenic rice grain, sequentially comprising the steps of:
      1. subjecting a crude extract from the transgenic rice grain containing the rHSA to cation exchange chromatography to obtain primary product I;
      1. subjecting the primary product I to anion exchange chromatography to obtain secondary product II, which contains the rHSA and a specified concentration of ammonium sulfate;
      1. subjecting the secondary product II to hydrophobic chromatography, under a condition that the rHSA does not adsorb to the resins of the hydrophobic chromatography; and
      1. recovering non-adsorbed flow-through fractions to obtain purified rHSA with a purity of more than about 99%.
  • The complaint alleges infringement of "one or more claims" of the patent, reserving the right to assert others (Compl. ¶43).

U.S. Patent No. 10,183,984

  • Patent Identification: U.S. Patent No. 10,183,984, "Method for extracting recombinant human serum albumin from transgenic rice grain", issued January 22, 2019 (Compl. ¶27).

The Invention Explained

  • Problem Addressed: The patent identifies a lack of a "mature production process for extracting rHSA from transgenic rice grain" (’984 Patent, col. 2:16-18). The initial extraction step is critical; inefficient methods can lead to low yields of the target protein and high levels of contaminating non-target proteins and endotoxins, which complicates subsequent purification (Compl. ¶29).
  • The Patented Solution: The invention provides a specific method for the initial extraction. The process involves grinding dehusked rice and mixing it with an extraction buffer having a specific chemical composition, including defined ranges for pH, phosphate, sodium acetate, ammonium sulfate, and sodium caprylate. This is followed by a specific pH adjustment step to precipitate and remove non-target proteins before filtration (Compl. ¶30; ’984 Patent, Abstract, col. 2:35-44).
  • Technical Importance: This tailored extraction method is claimed to significantly increase the concentration of the desired rHSA in the extracted solution while simultaneously reducing impurities, thereby improving the efficiency and quality of the entire manufacturing process (Compl. ¶29; ’984 Patent, col. 4:5-27).

Key Claims at a Glance

  • The complaint asserts independent claim 1 (Compl. ¶30).
  • The essential elements of Claim 1 are:
    • A method for extracting rHSA from transgenic rice grain, comprising:
      1. removing the hull of transgenic paddy rice and grinding the dehusked rice grain;
      1. mixing the milled rice grain with a specific extraction buffer (defined by pH and concentration ranges for phosphate, sodium acetate, ammonium sulfate, and sodium caprylate);
      1. adjusting the pH of the resulting mixture to between about 4.0 and 4.5 to precipitate non-target proteins; and
      1. filtering the mixture to collect the filtrate containing a high concentration of rHSA.
  • The complaint alleges infringement of "one or more claims" of the '984 Patent (Compl. ¶52).

Multi-Patent Capsule: U.S. Patent No. 10,730,926

  • Patent Identification: U.S. Patent No. 10,730,926, "Chromatographic method for isolating and purifying high-purity recombined human serum albumin", issued August 4, 2020 (Compl. ¶31).
  • Technology Synopsis: This patent discloses a purification method intended to achieve an exceptionally high purity of more than 99.9999% and an endotoxin content of less than 0.08 EU/mg, levels critical for therapeutic applications (Compl. ¶¶33-34). The method comprises a specific sequence of chromatographic steps, beginning with a cation/hydrophobic composite resin equilibrated with an alcohol-comprising buffer, followed by anion exchange chromatography and hydrophobic chromatography (Compl. ¶34).
  • Asserted Claims: The complaint asserts independent claim 1 (Compl. ¶34).
  • Accused Features: The complaint alleges on information and belief that Defendant's methods used to prepare its high-purity, low-endotoxin rHSA products, including Optibumin, practice the steps claimed in the ’926 patent (Compl. ¶¶40, 61).

III. The Accused Instrumentality

Product Identification

The accused instrumentalities are the methods used by Defendant to manufacture its line of rHSA products derived from rice grain, with the product "Optibumin" being specifically identified (Compl. ¶¶36, 40).

Functionality and Market Context

  • The complaint alleges that Defendant's rHSA is derived from rice grain, where the protein is concentrated in the rice-seed endosperm (Compl. ¶36).
  • Defendant markets its Optibumin product as the "highest purity albumin on the market" with the "lowest product-related high molecular weight impurity" (Compl. ¶37).
  • A Certificate of Analysis for Optibumin, provided as Exhibit 8, is a tabular document specifying the product's purity as "100.0%" and endotoxin level as "0.22 EU/mL" (Compl. ¶38, Ex. 8).
  • The complaint also cites a publication by an executive at Defendant's subsidiary, which states that Optibumin has "100% monomer purity" (Compl. ¶39). These marketing claims and quality certificates are used to suggest that Defendant's manufacturing process achieves the high-purity results claimed by the patents-in-suit.

IV. Analysis of Infringement Allegations

'100 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
1) subjecting a crude extract from the transgenic rice grain containing the recombinant human serum albumin to cation exchange chromatography to obtain primary product I; The complaint alleges on information and belief that Defendant manufactures Optibumin using the claimed technologies of the '100 Patent, which would include this initial step. ¶45 col. 2:53-55
2) subjecting the primary product I to anion exchange chromatography to obtain secondary product II... wherein the secondary product II further comprises ammonium sulfate... The complaint alleges on information and belief that Defendant's process includes this sequential anion exchange chromatography step. ¶45 col. 2:55-58
3) subjecting the secondary product II to hydrophobic chromatography, under a condition that the rHSA does not adsorb to the resins of the hydrophobic chromatography; The complaint alleges on information and belief that Defendant's process includes this specific flow-through hydrophobic chromatography step. ¶45 col. 2:58-62
4) recovering non-adsorbed flow-through fractions... to obtain the purified recombinant human serum albumin having a purity of more than about 99%... Defendant's product, Optibumin, is alleged to meet this purity limitation, as evidenced by a Certificate of Analysis claiming "100.0%" purity and marketing materials claiming the "highest purity." ¶¶37-39 col. 2:62-65

Identified Points of Contention

  • Evidentiary Question: The complaint alleges the use of the specific three-step chromatographic sequence largely "on information and belief" (Compl. ¶45), noting that the process cannot be reverse engineered (Compl. ¶41). A central question will be whether discovery produces evidence to substantiate that Defendant's proprietary process actually performs these specific steps in the claimed sequence.
  • Technical Question: What evidence will be used to prove that Defendant’s hydrophobic chromatography step operates in the claimed "flow-through" mode, where rHSA "does not adsorb to the resins," as opposed to a more conventional "bind-and-elute" mode?

'984 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
1) removing the hull of transgenic paddy rice containing recombinant human serum albumin, and grinding the dehusked rice grain; Defendant is alleged to derive its rHSA from rice grain, which implies de-hulling and grinding as part of the extraction process. ¶36 col. 2:37-40
2) mixing the transgenic milled rice grain with an extraction buffer... wherein the extraction buffer has a pH of between about 6.5 and about 8, and comprises [specific salt components and concentrations]; The complaint alleges on information and belief that Defendant uses the claimed technologies of the '984 patent, but provides no specific facts about the composition of Defendant's extraction buffer. ¶54 col. 2:53-65
3) adjusting pH of the mixture I of step 2) to between about 4.0 and about 4.5 and precipitating non-target proteins...; The complaint makes only a general allegation of infringement and provides no specific facts regarding a pH adjustment or precipitation step in Defendant's process. ¶54 col. 2:40-42
4) filtrating the mixture II of step 3) and collecting the filtrate to obtain a solution containing high concentration of recombinant human serum albumin. Defendant's process is alleged to yield a high-purity, high-concentration rHSA product, implying an effective filtration and collection step. ¶¶37-40 col. 2:42-45

Identified Points of Contention

  • Evidentiary Question: The complaint provides no factual detail regarding the chemical composition of Defendant's extraction buffer or its use of a specific pH-based precipitation step. The infringement case for the '984 patent will depend almost entirely on evidence obtained in discovery regarding the precise chemical and physical steps of Defendant's proprietary extraction process.

V. Key Claim Terms for Construction

For the '100 Patent

  • The Term: "a condition that the rHSA does not adsorb to the resins of the hydrophobic chromatography"
  • Context and Importance: This negative limitation is a central feature of the claimed invention, distinguishing it from conventional bind-and-elute chromatography. Infringement will hinge on whether Defendant's process, if it uses hydrophobic chromatography, operates in this specific "flow-through" mode. Practitioners may focus on this term because its construction will define whether any flow-through method infringes, or only those using conditions similar to the patent's examples.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The claim language is functional ("a condition that..."). Plaintiff may argue this covers any combination of parameters (e.g., pH, salt type, salt concentration) that achieves the stated result of non-adsorption, as described generally in the specification ('100 Patent, col. 16:21-30).
    • Evidence for a Narrower Interpretation: Defendant may argue the term should be limited by the specific embodiments, where the condition is achieved using particular concentrations of ammonium sulfate in the sample prior to loading ('100 Patent, col. 13:2-7, col. 16:35-40).

For the '984 Patent

  • The Term: "extraction buffer" (in conjunction with its claimed components and concentrations, e.g., "between about 10 mM and about 30 mM phosphate")
  • Context and Importance: The specific "recipe" for the buffer is the core of the '984 patent's claimed invention. The interpretation of "about" will be critical for determining the scope of infringement, especially under the doctrine of equivalents.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The repeated use of "about" for the concentration ranges suggests the patentee did not intend to be strictly limited to the recited endpoints. The specification also provides different ranges in its summary and detailed description, which may support a more flexible interpretation ('984 Patent, col. 2:53-65).
    • Evidence for a Narrower Interpretation: Defendant may argue that the term "about" must be interpreted in light of the patent's examples and the invention's stated goal, and cannot be so broad as to cover buffer systems that are chemically or functionally distinct from the preferred embodiment (e.g., '984 Patent, col. 3:1-4).

VI. Other Allegations

  • Indirect Infringement: The complaint pleads inducement and contributory infringement for all patents, alleging Defendant encourages its customers to use the infringing products (e.g., rHSA made by the patented methods) and that the products themselves are non-staple articles specially adapted for infringement (Compl. ¶¶47-48, 56-57, 64-65). The allegations are framed generally and may be difficult to apply to a method claim where the primary direct infringer is the manufacturer.
  • Willful Infringement: Willfulness is alleged for all patents based on knowledge acquired "at least as of March 1, 2024," the date of Plaintiff's alleged notice letter. This supports a theory of post-notice willfulness (Compl. ¶¶49, 58, 66). The complaint also asserts that Defendant "was also generally aware of Healthgen's technologies," a more general allegation that may be used to argue pre-notice knowledge (Compl. ¶49).

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

The resolution of this case appears to hinge on three central questions:

  1. Evidentiary Substantiation: A primary issue will be one of evidentiary proof. Can Plaintiff, through discovery, obtain direct evidence that Defendant's confidential manufacturing process employs the specific sequence of chromatographic techniques of the '100 and '926 patents and the specific extraction buffer formulation of the '984 patent, given the complaint's reliance on "information and belief" for these core technical allegations?
  2. Scope of Negative Limitations: The infringement analysis for the '100 patent will likely involve a key question of definitional scope: how broadly will the court construe the negative limitation "a condition that the rHSA does not adsorb"? Will it cover any "flow-through" hydrophobic process, or will it be narrowed to the specific chemical conditions disclosed in the patent's examples?
  3. Chemical and Process Equivalence: A core dispute may be one of technical equivalence. Assuming Defendant’s process is not literally identical to the claims, does its extraction buffer and purification sequence perform substantially the same function, in substantially the same way, to achieve the same high-purity result, thereby infringing under the doctrine of equivalents?