DCT

3:18-cv-03244

Boehringer Ingelheim Pharma Inc v. Fresenius Kabi USA LLC

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 3:18-cv-03244, D.N.J., 03/07/2018
  • Venue Allegations: Venue is alleged in the District of New Jersey based on Defendant Fresenius Kabi USA, LLC being registered to do business and having customers in the state, and on Defendant Fresenius Kabi Oncology Limited being a foreign entity not resident in the United States.
  • Core Dispute: Plaintiff alleges that Defendant’s Abbreviated New Drug Application (ANDA) seeking approval to market a generic version of the cancer drug GILOTRIF® (afatinib) constitutes an act of infringement of two patents covering the afatinib compound and a process for its manufacture.
  • Technical Context: The technology relates to small-molecule kinase inhibitors used in targeted cancer therapy, specifically for treating non-small cell lung cancer (NSCLC) in patients with certain mutations in the epidermal growth factor receptor (EGFR).
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiff's receipt of a Notice Letter from Defendant, which stated that Defendant had filed an ANDA with a Paragraph IV certification alleging that the patents-in-suit are invalid, unenforceable, or will not be infringed by the proposed generic product.

Case Timeline

Date Event
2000-12-20 ’431 Patent Priority Date
2003-10-17 ’586 Patent Priority Date
2012-05-29 ’431 Patent Issue Date
2013-04-23 ’586 Patent Issue Date
2013-07-XX GILOTRIF® (afatinib) NDA Approval
2018-01-24 Date of Defendant's Notice Letter to Plaintiff
2018-03-07 Complaint Filing Date

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

U.S. Reissue Patent No. RE43,431 - "Quinazoline Derivatives and Pharmaceutical Compositions Containing Them," issued May 29, 2012

The Invention Explained

  • Problem Addressed: The patent addresses the need for therapeutic compounds with an "inhibitory effect on signal transduction mediated by tyrosine kinases," which are implicated in various diseases. (’431 Patent, Abstract).
  • The Patented Solution: The invention provides a class of chemical compounds based on a quinazoline structure, defined by a general Formula I, which are designed to inhibit tyrosine kinases. (’431 Patent, Abstract; col. 54:25-41). The claims define the permissible chemical groups (substituents) that can be attached at various positions on the core structure to achieve the desired therapeutic effect. (’431 Patent, col. 54:29-41).
  • Technical Importance: This chemical class provides a basis for developing targeted therapies for "tumoral diseases and diseases of the lungs and airways." (’431 Patent, Abstract).

Key Claims at a Glance

  • The complaint asserts one or more claims of the ’431 Patent (Compl. ¶36). Independent Claim 1 is representative of the broadest compound genus.
  • Essential elements of Independent Claim 1 include:
    • A compound of a core chemical structure (Formula I) based on a quinazoline ring
    • A "3-chloro-4-fluorophenyl" group at position Rₐ
    • A "dimethylamino" group at position Rₑ
    • A "tetrahydrofuran-3-yloxy" group at position Rₑ
  • The complaint does not explicitly reserve the right to assert dependent claims, but alleges infringement of "one or more claims." (Compl. ¶36).

U.S. Patent No. 8,426,586 - "Process for Preparing Amino Crotonyl Compounds," issued April 23, 2013

The Invention Explained

  • Problem Addressed: The patent’s background section describes prior art methods for synthesizing the subject compounds as having low yields (at most 50%), requiring purification by column chromatography, and relying on starting materials not commercially available in high purity, rendering the process unsuitable for industrial-scale production. (’586 Patent, col. 1:19-39).
  • The Patented Solution: The patent discloses an improved, multi-step process for preparing the target compounds that allegedly achieves high yields and high chemical purity (low cis content of less than 0.1%), making it commercially viable. (’586 Patent, col. 1:40-56). The process involves reacting an aminoaryl starting material with a phosphonoacetic acid in an activation step, followed by a Wittig-Horner-Emmons reaction with an aldehyde. (’586 Patent, col. 3:1-4, col. 4:1-9). The patent provides X-ray powder diffraction data for the resulting dimaleate salt, characterizing its specific crystalline form. (’586 Patent, Fig. 1).
  • Technical Importance: The invention provides a method for the industrial-scale synthesis of afatinib, the active ingredient in GILOTRIF®, and characterizes a specific salt form suitable for pharmaceutical use.

Key Claims at a Glance

  • The complaint asserts one or more claims of the ’586 Patent (Compl. ¶53). Independent Claim 1 is representative of the broadest process claim.
  • Essential elements of Independent Claim 1 include:
    • A process for preparing a compound of formula (VII)
    • Step (a): reacting a compound of formula (V) in suitable solvents after corresponding activation with di-(C₁-₄alkyl)-phosphonoacetic acid
    • Step (b): reacting the resulting compound of formula (VI) with a specific aldehyde
  • The complaint does not explicitly reserve the right to assert dependent claims.

III. The Accused Instrumentality

Product Identification

  • The accused instrumentality is the generic drug product described in Fresenius Kabi’s ANDA No. 209985, identified as "afatinib dimaleate tablets." (Compl. ¶¶1, 24).

Functionality and Market Context

  • The complaint alleges that the ANDA Product is a generic version of Plaintiff's GILOTRIF® drug. (Compl. ¶24). The active pharmaceutical ingredient in GILOTRIF® is afatinib, a kinase inhibitor. (Compl. ¶19). The GILOTRIF® prescribing label, attached to the complaint, provides the full chemical name and structure for afatinib dimaleate. (Compl. Ex. A, p. 29). The Kaplan-Meier curve presented in the product label illustrates the drug's efficacy in improving progression-free survival in clinical trials for NSCLC. (Compl. Ex. A, Fig. 1, p. 33).
  • The ANDA Product is intended for the same therapeutic uses as GILOTRIF®, which includes the first-line treatment of patients with metastatic NSCLC whose tumors have specific EGFR mutations. (Compl. ¶19). The complaint alleges that Defendant intends to commercially manufacture and sell the ANDA Product in the United States upon receiving FDA approval. (Compl. ¶10).

IV. Analysis of Infringement Allegations

RE43,431 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A compound of formula I The ANDA product's active ingredient, afatinib, is alleged to be a quinazoline derivative compound. ¶19; Ex. A, p. 29 col. 54:25-28
wherein Rₐ is a ... 3-chloro-4-fluorophenyl group The afatinib molecule contains a 3-chloro-4-fluorophenyl group attached to the amino group at position 4 of the quinazoline core. ¶19; Ex. A, p. 29 col. 54:29-31
Rₑ is a dimethylamino ... group The afatinib molecule contains a crotonylamino side chain that terminates in a dimethylamino group. ¶19; Ex. A, p. 29 col. 54:32-35
and Rₑ is a ... tetrahydrofuran-3-yloxy ... group The afatinib molecule contains a tetrahydrofuran-3-yloxy group at position 7 of the quinazoline core. ¶19; Ex. A, p. 29 col. 54:35-41

'586 Patent Infringement Allegations

The complaint alleges that Fresenius Kabi's "commercial manufacture, use, offer for sale, sale, or importation" of the ANDA Product would infringe one or more claims of the ’586 patent (Compl. ¶53). However, the complaint does not provide sufficient detail for analysis of the accused manufacturing process against the limitations of the asserted process claims. The infringement theory for a process patent in this context may rely on 35 U.S.C. § 271(g), which makes it an act of infringement to import, sell, offer to sell, or use within the United States a product which is made by a process patented in the United States.

  • Identified Points of Contention:
    • Scope Questions: For the ’431 Patent, a potential point of contention may be whether the specific afatinib molecule, which is the (S) stereoisomer, falls within the scope of independent claim 1, which does not explicitly recite the stereochemistry of the tetrahydrofuran-3-yloxy group.
    • Evidentiary Questions: For the ’586 Patent, the central question will be factual and evidentiary: what specific chemical synthesis process will Defendant use to manufacture its afatinib dimaleate active ingredient, and does that process meet all the steps recited in any asserted claim of the patent?

V. Key Claim Terms for Construction

  • For the ’431 Patent:

    • The Term: "tetrahydrofuran-3-yloxy group" (from the definition of Rₑ in Claim 1)
    • Context and Importance: This term defines a key substituent on the quinazoline core. The approved drug, afatinib, contains a specific stereoisomer, (S)-tetrahydrofuran-3-yloxy. Practitioners may focus on this term because its construction—specifically whether it is limited to a particular stereoisomer or covers a racemic mixture—could be dispositive of infringement.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The plain language of the term in independent claim 1 does not specify any stereochemistry. (’431 Patent, col. 54:35-41). This may support a construction covering the (S)-enantiomer, the (R)-enantiomer, and mixtures thereof.
      • Evidence for a Narrower Interpretation: Dependent claim 8 of the original patent (U.S. 7,019,012, of which the '431 patent is a reissue) specifically recites the (S) configuration. A party could argue that this specificity in a dependent claim implies the independent claim should be read broadly, but an opposing argument might be constructed around enablement or written description for other isomers.

  • For the ’586 Patent:

    • The Term: "activating" (from Claim 1, step a)
    • Context and Importance: This term describes the chemical preparation of the starting material (formula V) for its reaction with phosphonoacetic acid. The specific chemical transformations that fall within the scope of "activating" will be critical to determining whether a given manufacturing process infringes this claim limitation.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The term could be interpreted functionally to mean any process step that renders the amino group of formula (V) reactive to form the desired amide bond.
      • Evidence for a Narrower Interpretation: The specification discloses specific activating agents, including 1,1-carbonyldiimidazole, which could be used to argue for a narrower construction limited to the disclosed methods or their direct chemical equivalents. (’586 Patent, col. 3:5-13).

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that if the ANDA is approved, Defendant will contribute to and actively induce infringement by third parties (e.g., healthcare professionals and patients) (Compl. ¶¶36, 53). The basis for this allegation is that Defendant's product labeling will instruct users to administer the afatinib dimaleate tablets for the patented therapeutic indications, which Plaintiff alleges is a direct infringement. (Compl. ¶¶44, 61).
  • Willful Infringement: The complaint alleges that Defendant had "actual and constructive notice" of both patents prior to filing its ANDA. (Compl. ¶¶37, 54). The complaint further alleges that Defendant's conduct in certifying non-infringement or invalidity lacks adequate justification, rendering the case "exceptional" under 35 U.S.C. § 285. (Compl. ¶¶39, 56).

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

  • A core issue will be one of validity: Can the asserted claims of the ’431 and ’586 patents, which are listed in the FDA’s Orange Book for GILOTRIF®, withstand Defendant's challenges that they are invalid under U.S. patent law, as asserted in the Paragraph IV certification?
  • A second issue will be one of claim scope: For the ’431 patent, will the court construe the claims to be broad enough to encompass the specific afatinib dimaleate compound contained in the Defendant's ANDA product, particularly concerning the stereochemistry of the active molecule?
  • A final key question will be evidentiary for the ’586 patent: Assuming the asserted process claims are found valid, what manufacturing process does the Defendant actually intend to use, and does the evidence produced during discovery demonstrate that this process performs all the steps required by the asserted claims?