DCT

1:19-cv-00360

Beloteca Inc v. Apicore US LLC

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:19-cv-00360, N.D. Ill., 01/17/2019
  • Venue Allegations: Venue is based on Defendant Mylan having a principal place of business in the district, and on Defendant Apicore’s business activities and its licensing of the patents-in-suit to Mylan.
  • Core Dispute: Plaintiff seeks a declaratory judgment that its generic isosulfan blue for injection product does not infringe, and that Defendants’ patents related to manufacturing processes for isosulfan blue and the resulting high-purity compound are invalid.
  • Technical Context: The technology concerns chemical synthesis processes for producing isosulfan blue, a triarylmethane dye used as a contrast agent for delineating the lymphatic system in medical imaging procedures.
  • Key Procedural History: Plaintiff Beloteca filed this action one day after receiving FDA approval for its Abbreviated New Drug Application (ANDA) to market a generic isosulfan blue product. The complaint notes that Defendants previously sued another generic manufacturer, Aurobindo Pharma, in 2016 over the same patents, suggesting a credible threat of litigation. Additionally, the complaint states that the ’050 patent is the subject of a pending Inter Partes Review (IPR) proceeding (IPR2018-01640) before the Patent Trial and Appeal Board, which introduces a parallel validity challenge that could impact this case.

Case Timeline

Date Event
2007-05-11 Priority Date for ’992, ’616, and ’050 Patents
2010-02-16 U.S. Patent No. 7,662,992 Issues
2010-07-20 Mylan's ANDA No. 90,874 Approved
2011-01-XX Mylan Acquires Synerx
2015-03-03 U.S. Patent No. 8,969,616 Issues
2016-05-31 U.S. Patent No. 9,353,050 Issues
2016-XX-XX Defendants Sue Aurobindo Pharma Over Patents-in-Suit
2017-07-26 Beloteca Submits ANDA No. 210714
2019-01-16 FDA Approves Beloteca's ANDA No. 210714
2019-01-17 Complaint for Declaratory Judgment Filed

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

U.S. Patent No. 7,662,992 - "Process for Preparation of Isosulfan Blue"

  • Patent Identification: U.S. Patent No. 7,662,992, titled "Process for Preparation of Isosulfan Blue," issued on February 16, 2010.

The Invention Explained

  • Problem Addressed: The patent's background describes prior art methods for synthesizing triarylmethane dyes like isosulfan blue as being unsuitable for producing pharmaceutical-grade material. These older methods allegedly involved hazardous oxidizing agents (e.g., lead oxide), strong acids for condensation, and "tedious neutralization/basification" steps for purification, resulting in crude, impure dyes (’992 Patent, col. 2:1-12).
  • The Patented Solution: The invention provides a multi-step chemical process designed to produce isosulfan blue in a "substantially pure form" suitable for pharmaceutical use (’992 Patent, col. 2:25-31). A key feature of the process is the oxidation of an "isoleuco acid" intermediate using a mild oxidizing agent, specifically silver oxide, followed by purification and isolation procedures such as crystallization to achieve a high-purity final product (’992 Patent, col. 2:56-62, col. 7:22-30). The overall chemical transformation is depicted in the reaction scheme presented in the specification (’992 Patent, col. 3-4).
  • Technical Importance: The described process claims to enable "large scale cGMP production" of isosulfan blue pure enough for use in injectable pharmaceutical formulations (’992 Patent, col. 2:20-24).

Key Claims at a Glance

  • The complaint seeks a declaratory judgment of non-infringement of any valid claim (’992 Patent, ¶34). Based on a prior suit filed by the patent holders involving these patents, Independent Claim 1 is a representative claim (Compl., Ex. D, ¶70).
  • Independent Claim 1 of the ’992 Patent recites:
    • A process of preparing N-[4-[[4-(diethyl amino) phenyl] (2, 5-disulfophenyl) methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium, sodium salt
    • comprising combining a suspension of isoleuco acid of the formula (4) in a polar solvent with 2.0 to 3.0 equivalents of silver oxide,
    • recovering isosulfan blue acid, and
    • treating the isosulfan blue acid with a sodium solution.
  • The complaint seeks a declaration of non-infringement as to all claims, which would include any asserted dependent claims.

U.S. Patent No. 8,969,616 - "Process for Preparation of Isosulfan Blue"

  • Patent Identification: U.S. Patent No. 8,969,616, titled "Process for Preparation of Isosulfan Blue," issued on March 3, 2015.

The Invention Explained

  • Problem Addressed: As a continuation in the same patent family, the ’616 Patent addresses the same technical problem as the ’992 Patent: the inadequacy of prior art processes for creating high-purity isosulfan blue for pharmaceutical applications due to harsh reagents and difficult purification (’616 Patent, col. 2:1-12).
  • The Patented Solution: The ’616 Patent discloses a virtually identical process to the ’992 Patent. The core of the patented solution remains the use of specific intermediates and a mild oxidation step with silver oxide to convert an isoleuco acid precursor into the final isosulfan blue product, followed by specific isolation and purification steps to achieve high purity (’616 Patent, Abstract; col. 2:57-62). The process is detailed in the specification’s reaction scheme (’616 Patent, col. 3-4).
  • Technical Importance: The invention provides a described pathway for reliable, large-scale cGMP manufacturing of high-purity isosulfan blue suitable for injection (’616 Patent, col. 2:21-25).

Key Claims at a Glance

  • The complaint seeks a declaratory judgment of non-infringement of any valid claim of the ’616 Patent (’616 Patent, ¶38). Independent Claim 1 is representative (Compl., Ex. D, ¶81).
  • Independent Claim 1 of the ’616 Patent recites:
    • A process of preparing N-4-[[4-(diethyl amino) phenylmethylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium, sodium salt
    • comprising combining a suspension of isoleuco acid of the formula (4) in a polar solvent with silver oxide,
    • recovering isosulfan blue acid, and
    • treating the isosulfan blue acid with a sodium solution.
  • The complaint’s request for relief covers all claims, implicitly including any dependent claims that might be asserted.

U.S. Patent No. 9,353,050 - "Process for Preparation of Isosulfan Blue"

  • Patent Identification: U.S. Patent No. 9,353,050, "Process for Preparation of Isosulfan Blue," issued on May 31, 2016.

Technology Synopsis

Unlike the ’992 and ’616 patents that claim a process, the ’050 patent claims the compound isosulfan blue itself, defined by specific purity characteristics. The patent addresses the need for a pharmaceutically acceptable form of the dye by claiming the compound when it has a purity of at least 99.0% as measured by High Performance Liquid Chromatography (HPLC) and, in some claims, a silver content of less than 20 ppm (’050 Patent, Abstract; Claim 1; Claim 3).

Asserted Claims

Independent Claim 1 is representative (Compl., ¶20; Compl., Ex. D, ¶55).

Accused Features

The dispute centers on whether Beloteca’s isosulfan blue for injection product, manufactured pursuant to ANDA No. 210714, meets the purity and/or composition limitations of the ’050 patent's claims (Compl., ¶¶ 28, 42).

III. The Accused Instrumentality

  • Product Identification: The subject of the declaratory judgment action is Beloteca’s isosulfan blue for injection product, a 1% strength formulation approved under ANDA No. 210714 (Compl. ¶26).
  • Functionality and Market Context: The product is a generic version of the isosulfan blue dye commercialized by Defendant Mylan (Compl. ¶22, ¶25). It is used as a contrast agent in lymphography, a medical imaging procedure that stains lymph nodes and vessels to visualize the lymphatic system (Compl. ¶2). With its ANDA now approved, Beloteca states its intent to manufacture and sell the product in the U.S. as a direct competitor to Defendants' product (Compl. ¶28). The complaint does not provide any technical details regarding the specific manufacturing process used by Beloteca or the final purity of its product.

IV. Analysis of Infringement Allegations

The complaint, being an action for declaratory judgment of non-infringement, does not contain infringement allegations or a claim chart. Instead, it makes conclusory statements that Beloteca's product and process do not infringe the patents-in-suit (Compl. ¶¶ 36, 40, 45). The complaint does not provide a technical basis or specific facts to support these assertions, such as identifying the specific steps of its manufacturing process or the measured purity of its final product. Therefore, the complaint does not provide sufficient detail for a claim-chart analysis.

  • Identified Points of Contention:
    • Process vs. Process (’992 and ’616 Patents): The central question for the process patents will be factual. Does the manufacturing process used by Beloteca for its ANDA product meet every limitation of the asserted claims? The reaction scheme included in the patents visually represents the claimed synthesis, including the key oxidation of the isoleuco acid intermediate (formula 4) with silver oxide (’992 Patent, col. 3-4, Scheme). A primary point of dispute will be whether Beloteca's process uses "silver oxide" as the oxidizing agent or an alternative, which would raise questions under the doctrine of equivalents.
    • Product vs. Product (’050 Patent): The dispute over the ’050 patent will likely focus on a quantitative analysis of Beloteca's final product. The key question is whether Beloteca's isosulfan blue for injection has "a purity of at least 99.0% by HPLC" as required by claim 1. This raises a factual question that will depend on analytical testing of Beloteca's product.

V. Key Claim Terms for Construction

’992 and ’616 Patents

  • The Term: "silver oxide" (from Claim 1 of both patents)
  • Context and Importance: This term recites the specific oxidizing agent required by the core process claims. Infringement will likely depend on whether Beloteca uses this exact chemical. If Beloteca uses a different oxidant, the case will turn on whether that alternative is equivalent to "silver oxide," making the construction of this term critical.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patents do not appear to provide explicit language suggesting that "silver oxide" is merely an example of a broader class of "mild oxidizing agents." The claims themselves are specific to this one reagent.
    • Evidence for a Narrower Interpretation: The specification consistently refers to "silver oxide" as the agent for the key oxidation step (’992 Patent, col. 7:22-24, col. 9:1-3). The claims explicitly recite "silver oxide," not a broader functional class of reagents. This consistency may support an interpretation that limits the claim scope to the use of that specific compound.

’050 Patent

  • The Term: "a purity of at least 99.0% by HPLC" (from Claim 1)
  • Context and Importance: This limitation defines the patented compound. The infringement analysis for the product patent will hinge on whether Beloteca's product meets this quantitative threshold. Practitioners may focus on this term because while the percentage is precise, the underlying measurement methodology (HPLC) can be subject to variation.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: A party might argue that the term should be read to encompass any standard HPLC method recognized in the art at the time of the invention, giving some flexibility in test parameters.
    • Evidence for a Narrower Interpretation: The specification provides examples that report purity results from HPLC testing (e.g., ’050 Patent, col. 7:35-38, "purity NLT 99.5% performed by High Performance Liquid Chromatography"). A party could argue that the term should be construed in light of the specific, albeit incompletely described, methods used to generate the data in the patent's examples, potentially narrowing the range of acceptable testing protocols.

VI. Other Allegations

  • Indirect Infringement: This declaratory judgment complaint does not contain allegations of indirect infringement against the plaintiff, Beloteca. However, the complaint attaches a prior lawsuit filed by Defendants against Aurobindo Pharma as evidence of a credible threat of suit (Compl., Ex. D). That prior complaint includes allegations that Aurobindo induced infringement by providing its product to wholesalers and customers with knowledge of the patent and with the intent that they would directly infringe by using it (Compl., Ex. D, ¶52). This suggests that any future infringement suit against Beloteca may also include such allegations.
  • Willful Infringement: The complaint does not allege willfulness. However, it does request that the court declare the case "exceptional" in favor of Beloteca to award attorneys' fees, which is the statutory counterpart to a plaintiff's willfulness claim (Compl., p. 9, ¶(c)). The attached Aurobindo complaint alleges that Aurobindo's infringement was willful (Compl., Ex. D, ¶61), further establishing the nature of the anticipated suit against Beloteca.

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

This declaratory judgment action frames the dispute for the court, which will likely center on three key questions:

  • A primary evidentiary question for the ’992 and ’616 process patents will be one of process identity: Does Beloteca's undisclosed manufacturing process use "silver oxide" as the claimed oxidizing agent? If not, the dispute will shift to whether its alternative process step is legally equivalent.
  • For the ’050 product patent, the core issue is a quantitative threshold: Does Beloteca’s final drug product, when analyzed, possess the "purity of at least 99.0% by HPLC" required by the claims, and does it meet the other composition limitations?
  • A significant procedural issue will be the impact of the parallel administrative challenge: How will the pending Inter Partes Review of the ’050 patent at the USPTO, which challenges that patent's validity, affect the district court litigation, potentially leading to a stay or simplification of the case?