DCT

1:18-cv-01533

Acrotech Biopharma LLC v. Fresenius Kabi USA LLC

Log In

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:18-cv-01533, D. Del., 10/03/2018
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendants Fresenius LLC and Fresenius Inc. are Delaware corporations, and Defendant Fresenius Oncology is an Indian corporation that may be sued in any judicial district.
  • Core Dispute: Plaintiffs allege that Defendants’ Abbreviated New Drug Application (ANDA) seeking approval for a generic version of the cancer drug BELEODAQ® constitutes an act of infringement of two patents covering the active compound (belinostat) and its pharmaceutical formulation.
  • Technical Context: The technology involves histone deacetylase (HDAC) inhibitors, a class of compounds used in oncology to disrupt cancer cell growth and survival by modifying gene expression.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiffs' receipt of a Paragraph IV certification letter from Defendant Fresenius LLC on August 21, 2018, which asserted that the patents-in-suit were invalid, unenforceable, or would not be infringed by the proposed generic product.

Case Timeline

Date Event
2001-06-14 ’027 Patent Priority Date
2005-05-03 ’027 Patent Issue Date
2005-05-13 ’501 Patent Priority Date
2014-07-03 FDA Approval for BELEODAQ® (belinostat) NDA
2014-09-16 ’501 Patent Issue Date
2018-08-21 Defendant Fresenius LLC sends Paragraph IV Notice Letter
2018-10-03 Complaint Filing Date

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

U.S. Patent No. 6,888,027, "Carbamic Acid Compounds Comprising a Sulfonamide Linkage as HDAC Inhibitors," issued May 3, 2005 (’027 Patent)

The Invention Explained

  • Problem Addressed: The patent describes a need for new therapeutic agents that can inhibit histone deacetylases (HDACs), enzymes whose aberrant activity is linked to the uncontrolled cell proliferation characteristic of cancer and other diseases (e.g., psoriasis) (’027 Patent, col. 4:1-18, col. 5:58-63).
  • The Patented Solution: The invention provides a class of carbamic acid compounds that feature a specific sulfonamide linkage. These molecules are designed to inhibit HDAC activity, thereby arresting cell cycle progression and treating proliferative conditions like cancer (’027 Patent, Abstract; col. 7:30-49).
  • Technical Importance: This patent claims a specific chemical entity, belinostat, which targets epigenetic regulatory mechanisms, representing a key therapeutic strategy in modern oncology (’027 Patent, col. 200:56-62; Compl. ¶24).

Key Claims at a Glance

  • The complaint asserts infringement of "one or more claims," and the analysis below focuses on the independent claim covering the specific compound at issue (Compl. ¶46).
  • Independent Claim 37:
    • A compound of the formula for N-hydroxy-3-(3-phenylsulfamoyl-phenyl)-acrylamide (belinostat), or a pharmaceutically acceptable salt thereof.
  • The complaint reserves the right to assert additional claims (Compl. ¶46).

U.S. Patent No. 8,835,501, "Pharmaceutical Formulations of HDAC Inhibitors," issued September 16, 2014 (’501 Patent)

The Invention Explained

  • Problem Addressed: The patent addresses significant formulation challenges associated with HDAC inhibitors like belinostat (referred to as PXD-101), including low aqueous solubility and chemical instability, which can hinder the development of a practical drug product for intravenous administration (’501 Patent, col. 4:22-31).
  • The Patented Solution: The invention describes pharmaceutical compositions that overcome these problems by combining the HDAC inhibitor with specific solubilizing and stabilizing agents, namely arginine or meglumine. This combination enables the creation of stable, concentrated liquid formulations suitable for administration or for lyophilization (freeze-drying) into a powder for later reconstitution (’501 Patent, Abstract; col. 4:32-54).
  • Technical Importance: Developing stable, highly soluble formulations is critical for the clinical viability of intravenously delivered drugs, transforming a promising chemical compound into a usable therapeutic product.

Key Claims at a Glance

  • The complaint asserts infringement of "one or more claims," and the analysis below focuses on a representative independent claim (Compl. ¶66).
  • Independent Claim 1:
    • A pharmaceutical composition consisting essentially of:
    • (a) a histone deacetylase (HDAC) inhibitor (which includes belinostat);
    • (b) at least one basic in situ salt former, selected from free arginine or meglumine; and
    • (c) a pharmaceutically acceptable excipient or carrier.
  • The complaint reserves the right to assert additional claims (Compl. ¶66).

III. The Accused Instrumentality

Product Identification

  • Defendants' proposed generic version of BELEODAQ®, identified as ANDA No. 211485, for a 500 mg vial of belinostat for intravenous injection (Compl. ¶1).

Functionality and Market Context

  • The accused product is a generic drug intended to be a therapeutic equivalent to Plaintiffs' BELEODAQ®, an HDAC inhibitor approved to treat relapsed or refractory peripheral T-cell lymphoma (PTCL) (Compl. ¶¶ 22, 24). The complaint alleges the product is a "lyophilized belinostat (an HDAC inhibitor) and L-arginine" formulation intended for intravenous use after reconstitution and dilution (Compl. ¶63). By filing an ANDA, Defendants seek to enter the market and compete with BELEODAQ® before the expiration of the patents-in-suit (Compl. ¶¶ 41, 61).

IV. Analysis of Infringement Allegations

The complaint provides the chemical structure of belinostat, which is the active pharmaceutical ingredient in the accused generic product. (Compl. ¶25).

’027 Patent Infringement Allegations

Claim Element (from Independent Claim 37) Alleged Infringing Functionality Complaint Citation Patent Citation
A compound of the following formula... [structure of belinostat] "Fresenius LLC's August 21, 2018 letter states that the active ingredient in Defendants' ANDA product for which it seeks approval is belinostat." ¶43 col. 100:11-40
and pharmaceutically acceptable salts thereof. The accused ANDA product is a generic version of BELEODAQ® (belinostat). ¶41 col. 198:34-42

’501 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A pharmaceutical composition consisting essentially of: Defendants' ANDA product is a pharmaceutical composition intended for intravenous administration. ¶63 col. 42:35-46
(a) a histone deacetylase (HDAC) inhibitor... "Defendants' ANDA product contains lyophilized belinostat (an HDAC inhibitor)..." ¶63 col. 43:1-27
(b) at least one basic in situ salt former, wherein the salt former is free arginine... "Defendants' ANDA product contains... L-arginine..." ¶63 col. 22:37-43
and, (c) a pharmaceutically acceptable excipient or carrier; The product is "intended for intravenous administration after reconstitution with sterile water for injection, and further dilution with sterile 0.9% sodium chloride for injection." ¶63 col. 23:36-52

Identified Points of Contention

  • Scope Questions: For the ’501 Patent, a central issue may be the claim term "consisting essentially of." This raises the question of whether any unlisted excipients in Defendants' ANDA product materially alter the basic and novel characteristics of the claimed formulation, potentially placing it outside the scope of the claims. The complaint does not detail all excipients in the ANDA product.
  • Technical Questions: While the infringement allegation for the ’027 Patent appears direct, the primary dispute will likely concern validity, as is common in ANDA litigation (Compl. ¶36). For the ’501 Patent, a key technical question is whether the L-arginine in the accused product functions as a "basic in situ salt former" to enhance solubility and stability, as required by the claim, a point that will require factual evidence.

V. Key Claim Terms for Construction

  • The Term: "consisting essentially of" (’501 Patent, Claim 1)
    • Context and Importance: This transitional phrase is critical for defining the scope of the formulation claim. Practitioners may focus on this term because its interpretation determines whether additional, unlisted ingredients in the accused generic product can serve as a basis for a non-infringement defense. The dispute will center on whether any such ingredients materially affect the claimed invention's "basic and novel properties"—namely, the enhanced solubility and stability provided by the salt former.
    • Evidence for a Broader Interpretation: The patent's detailed description of various other acceptable pharmaceutical carriers, diluents, and excipients could be used to argue that the invention contemplates the presence of other standard formulation agents without departing from the invention's core characteristics (’501 Patent, col. 23:36-52).
    • Evidence for a Narrower Interpretation: Defendants may argue that the invention is narrowly focused on the specific combination of the HDAC inhibitor and the salt former. The Abstract and Summary of the Invention emphasize the roles of cyclodextrin, arginine, and meglumine, suggesting that compositions with other components that affect these properties fall outside the claim (’501 Patent, Abstract; col. 4:32-65).

VI. Other Allegations

  • Indirect Infringement: The complaint alleges induced infringement, stating that Defendants know their product will be used by healthcare professionals according to the product's label, which will instruct the infringing acts of reconstituting and administering the claimed composition (Compl. ¶¶ 54, 74).
  • Willful Infringement: Willfulness is alleged based on Defendants' actual knowledge of the patents, evidenced by the Paragraph IV notification letter sent to Plaintiffs prior to the lawsuit (Compl. ¶¶ 47, 67). The complaint further alleges this is an "exceptional case" warranting an award of attorneys' fees (Compl. ¶¶ 49, 69).

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

  • A central issue will be one of validity: will the asserted claims of the ’027 Patent (covering the belinostat compound) and the ’501 Patent (covering the L-arginine formulation) withstand Defendants' challenges, which the complaint indicates are based on obviousness?
  • A key question for the ’501 Patent will be one of claim scope and function: will the term "consisting essentially of" be construed to read on a generic formulation that may contain other unlisted excipients, and will Plaintiffs be able to prove that the L-arginine in the accused product functions as the claimed "basic in situ salt former"?