DCT

3:18-cv-11350

Boehringer Ingelheim Pharma Inc v. Apotex Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 3:18-cv-11350, D.N.J., 07/03/2018
  • Venue Allegations: Plaintiff alleges venue is proper in the District of New Jersey because Defendant Apotex Corp. is registered with the New Jersey Department of Health, transacts business in the state, derives substantial revenue from pharmaceutical sales in the state, and has previously been sued in the district without objecting to jurisdiction.
  • Core Dispute: Plaintiff alleges that Defendant’s filing of an Abbreviated New Drug Application (ANDA) for a generic version of the cancer drug GILOTRIF® (afatinib) constitutes an act of infringement of a patent directed to a process for manufacturing the drug's active ingredient.
  • Technical Context: The technology involves a multi-step chemical synthesis process for producing afatinib, a kinase inhibitor used to treat specific types of non-small cell lung cancer.
  • Key Procedural History: This action was filed under the Hatch-Waxman Act following Plaintiff’s receipt of a Paragraph IV certification notice from Apotex, in which Apotex stated its belief that the patent-in-suit is invalid, unenforceable, or will not be infringed by its proposed generic product. The complaint notes that the patent-in-suit is also the subject of related litigation against another generic manufacturer.

Case Timeline

Date Event
2003-10-17 ’586 Patent Priority Date
2013-04-23 ’586 Patent Issue Date
2013-07-01 FDA Approval of GILOTRIF® NDA (approx. date)
2018-05-25 Apotex Sends Paragraph IV Notice Letter (approx. date)
2018-07-03 Complaint Filing Date

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

U.S. Patent No. 8,426,586 - "Process for Preparing Amino Crotonyl Compounds"

The Invention Explained

  • Problem Addressed: The patent’s background section describes a prior art process for synthesizing the active pharmaceutical ingredient afatinib that was unsuitable for industrial-scale manufacturing due to low yields (at most 50%), the need for chromatographic purification, and the use of starting materials that were not commercially available in high purity or large quantities (’586 Patent, col. 2:21-39).
  • The Patented Solution: The patent discloses an improved, two-step synthesis method claimed to be more efficient for commercial production. The process first involves reacting a specific aminoaryl compound with an activated phosphonoacetic acid to create a phosphonate intermediate (as shown in Diagram 2). This intermediate is then reacted with a protected amino-aldehyde in a Wittig-Horner-Emmons reaction to form the final aminocrotonyl compound, the base form of afatinib (’586 Patent, col. 3:1-4:2).
  • Technical Importance: The patented process provides a method for manufacturing the target compound that is described as "industrially practicable with high yields," achieving "very good chemical purities," and using readily available starting materials, which are critical improvements for commercial-scale pharmaceutical production (’586 Patent, col. 2:40-56).

Key Claims at a Glance

  • The complaint alleges infringement of "one or more claims" without specifying which ones (Compl. ¶34). The patent contains several independent claims, including process claim 1 and composition claim 9.
  • Independent Claim 1 (Process):
    • A process for preparing a specific aminocrotonyl compound of formula (VII),
    • comprising the synthesis steps of:
    • a) reacting an aminoaryl compound of formula (V) with an "activated" di-(C1-4-alkyl)-phosphonoacetic acid to create an intermediate of formula (VI); and
    • b) reacting that intermediate (VI) with a specific aldehyde or an "aldehyde equivalent" using a suitable base.
  • Independent Claim 9 (Composition):
    • A crystalline form of the dimaleate salt of the aminocrotonyl compound,
    • characterized by specific 2θ values obtained by X-ray powder diffraction, including characteristic peaks at 4.91, 19.91, and 25.56 degrees.

III. The Accused Instrumentality

Product Identification

The accused instrumentality is Apotex's generic "Afatinib Tablets," as described in its Abbreviated New Drug Application (ANDA) No. 210725 (the "ANDA Product") (Compl. ¶¶ 9, 21).

Functionality and Market Context

The ANDA Product contains the active ingredient afatinib and is intended as a generic version of Plaintiff's branded drug, GILOTRIF® (Compl. ¶¶ 17, 21). GILOTRIF® is a kinase inhibitor prescribed for the treatment of patients with certain forms of metastatic non-small cell lung cancer (Compl. ¶17). Apotex seeks to manufacture and sell its generic version in the United States prior to the expiration of the ’586 Patent (Compl. ¶22). The GILOTRIF® prescribing label, attached to the complaint, shows the chemical structure of afatinib dimaleate. (Compl. Ex. A, p. 24).

IV. Analysis of Infringement Allegations

The complaint does not provide a detailed claim chart or specific factual allegations mapping elements of Apotex's manufacturing process to the patent claims. The infringement allegation is a statutory one arising from the act of filing an ANDA with a Paragraph IV certification, which is deemed an act of infringement under 35 U.S.C. § 271(e)(2)(A) (Compl. ¶31). The complaint alleges that the commercial manufacture of the ANDA Product, if approved, would infringe one or more claims of the ’586 Patent (Compl. ¶32). The patent, attached as Exhibit B, includes an X-ray powder diffractogram for the crystalline dimaleate salt, which is foundational to the patent's composition claims. (Compl. Ex. B, Fig. 1).

Identified Points of Contention

  • Factual Questions (Process Claims): The central dispute will be factual: does the confidential manufacturing process described in Apotex's ANDA fall within the scope of the patent’s process claims? The analysis will require comparing Apotex's synthesis pathway, including its specific reagents, solvents, and reaction conditions, against the steps recited in claims like independent claim 1.
  • Factual Questions (Composition Claims): For composition claims like claim 9, the key question is whether Apotex's final drug substance is the specific crystalline form defined by the X-ray powder diffraction peaks listed in the claim. A related question may be whether that specific crystalline form can only be produced by an infringing process.
  • Scope Questions: Should the processes differ, the case may turn on claim construction. For example, a dispute could arise over the meaning of "activation" in claim 1(a)—whether it is limited to the specific activating agents listed in the specification or covers a broader class of chemical activations.

V. Key Claim Terms for Construction

The Term: "activation" (Claim 1)

Context and Importance

This term defines a key chemical step in creating the phosphonate intermediate. The scope of this term is critical, as Apotex may avoid infringement if its process uses a reagent or method that is not considered an "activation" as required by the claim. Practitioners may focus on this term because it is a functional, rather than purely structural, limitation whose boundaries are defined by examples.

Intrinsic Evidence for Interpretation

  • Evidence for a Broader Interpretation: The specification provides a non-exhaustive list of suitable methods, stating the activation "may be carried out by any possible method of amide linking, i.e. for example with 1,1-carbonyldiimidazole, ... DCC, ... EDC, ... TBTU, ... or by conversion into the corresponding acid chloride" (’586 Patent, col. 3:11-18). The phrase "for example" may support a construction that is not limited to the enumerated examples.
  • Evidence for a Narrower Interpretation: The specification also identifies a "particularly preferably" method using 1,1-carbonyldiimidazole (’586 Patent, col. 3:7-9). A party might argue that the term should be construed more narrowly in light of this stated preference.

The Term: "aldehyde equivalent" (Claim 1)

Context and Importance

This term provides an alternative to using the aldehyde reactant directly in the Wittig-Horner-Emmons reaction step. Whether a chemical used by Apotex constitutes an "equivalent" will be a central question for infringement.

Intrinsic Evidence for Interpretation

  • Evidence for a Broader Interpretation: The specification explains that "Instead of the aldehyde a corresponding equivalent, e.g. a hydrate or acetal, may be used, from which the aldehyde is released (beforehand or in situ)" (’586 Patent, col. 3:67-4:2). This language suggests that any precursor compound that generates the required aldehyde under the reaction conditions could be considered an "equivalent."
  • Evidence for a Narrower Interpretation: A party could argue that the term should be limited to the specific classes of equivalents disclosed—hydrates and acetals—and not other potential aldehyde precursors (’586 Patent, col. 4:35-45).

VI. Other Allegations

Indirect Infringement

The complaint alleges that Apotex will induce and contribute to infringement upon FDA approval of its ANDA (Compl. ¶33). The primary basis for this is the future "commercial manufacture, use, offer for sale, sale, or importation" of the ANDA product, which would infringe the process patent (Compl. ¶33).

Willful Infringement

The complaint does not explicitly allege "willful" infringement. However, it alleges that Apotex had "actual and constructive notice" of the ’586 Patent before filing its ANDA and that its Paragraph IV certification lacked an adequate basis, rendering the case "exceptional" under 35 U.S.C. § 285 (Compl. ¶¶ 34, 36). These allegations lay the foundation for a potential future request for enhanced damages or attorneys' fees.

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

  • A core factual question will be one of process identity: Does the confidential manufacturing process detailed in Apotex's ANDA employ the same chemical reagents and reaction sequence described in the asserted process claims of the ’586 Patent, or does it utilize a distinct and non-infringing synthetic pathway?
  • A key question of claim construction and scope will likely arise if the processes are similar but not identical: Can functional terms like "activation" and "aldehyde equivalent" be interpreted broadly enough to read on the specific chemicals and methods used by Apotex, or are they limited to the embodiments expressly disclosed in the patent's specification?
  • A central evidentiary question regarding the composition claims will be one of structural identity: Does the final crystalline form of afatinib dimaleate in Apotex's product exhibit the specific X-ray powder diffraction pattern recited in claims like Claim 9, thereby infringing the patent's composition claims regardless of the process used?