DCT
1:23-cv-00490
Teva Pharma Intl GmbH v. Bendarx
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Teva Pharmaceuticals International GmbH (Switzerland), Cephalon, LLC (Delaware), and Eagle Pharmaceuticals, Inc. (Delaware)
- Defendant: BendaRx Corp. (Canada)
- Plaintiff’s Counsel: Shaw Keller LLP; McCarter & English, LLP
- Case Identification: 1:23-cv-00490, D. Del., 05/05/2023
- Venue Allegations: Venue is alleged to be proper in the District of Delaware because BendaRx is a foreign corporation subject to personal jurisdiction in the district. The complaint asserts that BendaRx purposefully directed activities at Delaware, including filing a New Drug Application (NDA) with the intent to market its product throughout the U.S., including Delaware.
- Core Dispute: Plaintiffs allege that Defendant's submission of a New Drug Application to the U.S. Food and Drug Administration for a generic bendamustine hydrochloride product constitutes an act of infringement against eleven patents covering pharmaceutical compositions, solid forms, and formulations of the drug.
- Technical Context: Bendamustine hydrochloride is an alkylating drug used to treat chronic lymphocytic leukemia and non-Hodgkin lymphoma, marketed by Plaintiffs under the brand names Treanda® and Bendeka®.
- Key Procedural History: This action was initiated under the Hatch-Waxman Act following Defendant’s notice letter, dated March 23, 2023, which provided a Paragraph IV Certification asserting that its proposed generic product would not infringe the asserted patents or that the patents are invalid.
Case Timeline
| Date | Event |
|---|---|
| 2005-01-14 | Patent Priority Date (’190, ’863, ’270, ’756, ’350 Patents) |
| 2008-03-26 | Patent Priority Date (’524, ’279, ’836, ’955 Patents) |
| 2009-01-15 | Patent Priority Date (’366 Patent) |
| 2011-12-13 | Issue Date (U.S. Patent No. 8,076,366) |
| 2013-05-07 | Issue Date (U.S. Patent No. 8,436,190) |
| 2013-05-21 | Issue Date (U.S. Patent No. 8,445,524) |
| 2013-06-11 | Issue Date (U.S. Patent No. 8,461,350) |
| 2013-12-17 | Issue Date (U.S. Patent No. 8,609,863) |
| 2014-03-11 | Issue Date (U.S. Patent No. 8,669,279) |
| 2014-07-27 | Issue Date (U.S. Patent No. 8,791,270) |
| 2014-11-11 | Issue Date (U.S. Patent No. 8,883,836) |
| 2014-11-25 | Issue Date (U.S. Patent No. 8,895,756) |
| 2015-02-13 | Cephalon executes exclusive license to Eagle Pharmaceuticals (the "Eagle License") (Compl. ¶36) |
| 2015-10-14 | Cephalon assigns its rights in the Eagle License to Teva Pharmaceuticals (Compl. ¶37) |
| 2016-02-23 | Patent Priority Date (’887 Patent) |
| 2017-01-03 | Issue Date (U.S. Patent No. 9,533,955) |
| 2017-02-21 | Issue Date (U.S. Patent No. 9,572,887) |
| 2023-03-23 | BendaRx issues Notice Letter with Paragraph IV Certification (Compl. ¶38) |
| 2023-05-05 | First Amended Complaint Filed (Compl. Header) |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 8,436,190 - "Bendamustine Pharmaceutical Compositions"
The Invention Explained
- Problem Addressed: The patent describes that bendamustine degrades in aqueous solutions, making it difficult to formulate as a pharmaceutical (U.S. Patent No. 8,436,190, col. 1:25-32). Existing lyophilized (freeze-dried) powders were reportedly difficult and slow to reconstitute, which could increase the potential for degradation and impurity formation prior to administration to a patient (’190 Patent, col. 2:1-24).
- The Patented Solution: The invention is a stable, lyophilized pharmaceutical composition of bendamustine created using a specific combination of excipients, including a bulking agent (mannitol) and a non-aqueous solvent (tertiary-butyl alcohol, or TBA). This composition is designed to create a lyophilized product that reconstitutes more easily and has a better impurity profile than prior formulations (’190 Patent, col. 2:29-37; col. 3:1-12).
- Technical Importance: Developing a stable, easily reconstituted lyophilized formulation of a hydrolytically unstable drug like bendamustine was important for ensuring accurate dosing, minimizing impurities, and improving ease of use for healthcare professionals in a clinical setting (’190 Patent, col. 2:1-9).
Key Claims at a Glance
- The complaint asserts infringement of one or more claims of the ’190 patent (Compl. ¶88). Independent claim 1 is excerpted below.
- Independent Claim 1 requires:
- A stable lyophilized preparation
- comprising bendamustine hydrochloride,
- mannitol, and
- a trace amount of tertiary-butyl alcohol (TBA),
- wherein the ratio by weight of bendamustine hydrochloride to mannitol is 15:25.5.
- The complaint does not explicitly reserve the right to assert dependent claims but makes a general allegation against "one or more claims" (Compl. ¶88).
U.S. Patent No. 8,445,524 - "Solid Forms of Bendamustine Hydrochloride"
The Invention Explained
- Problem Addressed: The patent background explains that active pharmaceutical ingredients (APIs) can exist in different solid forms, such as various crystalline polymorphs, which can affect physical properties like solubility, stability, and bioavailability (U.S. Patent No. 8,445,524, col. 1:23-40). The patent implies a need to identify and characterize specific, stable solid forms of bendamustine hydrochloride suitable for pharmaceutical use.
- The Patented Solution: The invention identifies and characterizes novel solid forms of bendamustine hydrochloride, including multiple crystalline forms (polymorphs). These forms are defined by their unique X-ray powder diffraction (XRPD) patterns, which provide a fingerprint for the specific crystal structure (’524 Patent, col. 2:36-40; col. 2:50-54). By isolating and claiming these specific forms, the patent provides a basis for creating a consistent and stable drug product.
- Technical Importance: Identifying and controlling the polymorphic form of a drug substance is critical in pharmaceutical development to ensure batch-to-batch consistency, predictable dissolution rates, and overall product stability (’524 Patent, col. 1:33-40).
Key Claims at a Glance
- The complaint asserts infringement of one or more claims of the ’524 patent (Compl. ¶110). Independent claims 1 and 3 are representative.
- Independent Claim 1 requires:
- A crystalline form of bendamustine hydrochloride
- that is bendamustine hydrochloride Form 1,
- that produces an X-ray powder diffraction pattern comprising the following reflections: 8.3, 16.8, and 18.5±0.2 degrees 2θ.
- Independent Claim 3 requires:
- A crystalline form of bendamustine hydrochloride
- that is bendamustine hydrochloride Form 3,
- that produces an X-ray powder diffraction pattern comprising the following reflections: 7.9, 15.5, and 26.1±0.2 degrees 2θ.
- The complaint does not explicitly reserve the right to assert dependent claims but makes a general allegation against "one or more claims" (Compl. ¶110).
U.S. Patent No. 8,609,863 - "Bendamustine Pharmaceutical Compositions"
- Technology Synopsis: This patent relates to lyophilized pharmaceutical compositions of bendamustine hydrochloride. It addresses the problem of bendamustine's instability in aqueous solutions by creating a stable, easily reconstituted freeze-dried formulation containing mannitol and a trace amount of tertiary-butyl alcohol, similar to the '190 Patent.
- Asserted Claims: One or more claims are asserted (Compl. ¶132). Claim 1 is independent.
- Accused Features: The accused features are the alleged composition of BendaRx's NDA Product, which is alleged to be a stable lyophilized preparation containing bendamustine HCl and mannitol in a specific ratio, along with trace amounts of tertiary-butyl alcohol (Compl. ¶47).
U.S. Patent No. 8,669,279 - "Solid Forms of Bendamustine Hydrochloride"
- Technology Synopsis: This patent, similar to the '524 Patent, relates to specific solid crystalline forms (polymorphs) of bendamustine hydrochloride. The invention addresses the need for consistent and stable pharmaceutical products by identifying and claiming distinct crystalline forms characterized by unique X-ray powder diffraction (XRPD) patterns.
- Asserted Claims: One or more claims are asserted (Compl. ¶154). Claims 1 and 4 are independent.
- Accused Features: The accused feature is the alleged crystalline form of the bendamustine hydrochloride in BendaRx's NDA Product, specifically Form 3, identified by its characteristic XRPD reflections (Compl. ¶49, ¶54).
U.S. Patent No. 8,791,270 - "Bendamustine Pharmaceutical Compositions"
- Technology Synopsis: This patent relates to stable lyophilized pharmaceutical compositions of bendamustine hydrochloride containing mannitol. The invention aims to improve upon prior formulations that were difficult to reconstitute and subject to degradation by creating a more stable and easily reconstituted formulation.
- Asserted Claims: One or more claims are asserted (Compl. ¶176). Claim 1 is independent.
- Accused Features: The accused features are the alleged formulation of BendaRx's NDA product, which is alleged to contain specific ratios of bendamustine hydrochloride to mannitol in a reconstituted solution for injection (Compl. ¶56).
U.S. Patent No. 8,883,836 - "Solid Forms of Bendamustine Hydrochloride"
- Technology Synopsis: This patent relates to specific solid forms of bendamustine hydrochloride, including crystalline Form 1. The invention provides a way to ensure the consistency and stability of the bendamustine drug product by claiming specific polymorphs defined by their X-ray powder diffraction patterns.
- Asserted Claims: One or more claims are asserted (Compl. ¶198). Claim 1 is independent.
- Accused Features: The accused feature is the alleged crystalline structure of the bendamustine hydrochloride in BendaRx's NDA Product, specifically Form 1, which produces a characteristic set of XRPD reflections (Compl. ¶45).
U.S. Patent No. 8,895,756 - "Bendamustine Pharmaceutical Compositions"
- Technology Synopsis: This patent covers a reconstituted solution of bendamustine hydrochloride and mannitol in sterile water for injection. The invention addresses the clinical need for a properly formulated bendamustine solution by claiming specific concentrations and ratios of the active drug and excipient in a vial.
- Asserted Claims: One or more claims are asserted (Compl. ¶220). Claim 1 is independent.
- Accused Features: The accused features are the alleged concentration and composition of BendaRx's product when reconstituted for administration, including a specific ratio of bendamustine HCl to mannitol and a specific drug concentration (Compl. ¶56).
U.S. Patent No. 9,533,955 - "Solid Forms of Bendamustine Hydrochloride"
- Technology Synopsis: This patent relates to solid forms of bendamustine hydrochloride, specifically crystalline Form 3. The invention provides a means to control the physical properties and ensure stability of the final drug product by claiming a specific polymorph defined by its unique XRPD pattern.
- Asserted Claims: One or more claims are asserted (Compl. ¶242). Claim 1 is independent.
- Accused Features: The accused feature is the alleged crystalline form of the bendamustine hydrochloride in BendaRx's NDA Product, which is alleged to be Form 3 and produce a characteristic set of XRPD reflections (Compl. ¶49, ¶58).
U.S. Patent No. 9,572,887 - "Formulations of Bendamustine"
- Technology Synopsis: This patent addresses the problem of bendamustine degradation by disclosing non-aqueous liquid compositions that exhibit long-term storage stability. The invention provides a formulation with low total impurities after extended storage at room or refrigerated temperatures, intended for dilution before parenteral administration.
- Asserted Claims: One or more claims are asserted (Compl. ¶264). Claims 1 and 18 are independent.
- Accused Features: The accused features relate to the proposed labeling for BendaRx's product, which allegedly promotes providing a non-aqueous liquid composition with specific bendamustine concentrations and low impurity levels after long-term storage (Compl. ¶61, ¶62).
U.S. Patent No. 8,076,366 - "Forms of Bendamustine Free Base"
- Technology Synopsis: This patent describes novel polymorphic forms of bendamustine free base, as opposed to the hydrochloride salt. The invention addresses the need for stable forms of the free base API, which are desirable to minimize potential side effects from the salt counterion.
- Asserted Claims: One or more claims are asserted (Compl. ¶286). Claims 1, 2, and 33 are independent.
- Accused Features: The accused feature is the alleged composition of BendaRx's NDA Product, which is alleged "on information and belief" to comprise a crystalline form of bendamustine free base (Compl. ¶67).
U.S. Patent No. 8,461,350 - "Bendamustine Pharmaceutical Compositions"
- Technology Synopsis: This patent covers a stable, lyophilized preparation of bendamustine hydrochloride formulated with mannitol. The invention is directed at overcoming the instability and reconstitution difficulties of prior bendamustine formulations by claiming a composition with very low levels of specific degradation impurities (HP1 and bendamustine dimer).
- Asserted Claims: One or more claims are asserted (Compl. ¶308). Claims 1 and 9 are independent.
- Accused Features: The accused features are the alleged low impurity levels in BendaRx's NDA Product, specifically containing not more than about 0.9% of the degradant HP1 and containing less than or equal to 4.0% total bendamustine degradants (Compl. ¶51, ¶52).
III. The Accused Instrumentality
Product Identification
The accused instrumentality is BendaRx Corp.’s proposed generic bendamustine product, which is the subject of New Drug Application (NDA) No. 215291 submitted to the FDA (Compl. ¶1).
Functionality and Market Context
- The BendaRx NDA Product is an injectable drug intended for treating chronic lymphocytic leukemia and non-Hodgkin's lymphoma (Compl. ¶54). The complaint alleges, "on information and belief," that the product is a "stable lyophilized preparation comprising bendamustine hydrochloride, mannitol, and a trace amount of tertiary-butyl alcohol" in a specific weight ratio of 15:25.5 (bendamustine HCl to mannitol) (Compl. ¶47). It further alleges that the product comprises specific crystalline forms of bendamustine hydrochloride, namely Form 1 and Form 3, which are characterized by specific X-ray powder diffraction patterns (Compl. ¶45, ¶49).
- The complaint notes that in its Paragraph IV notice letter, BendaRx denied that its product contained mannitol and tertiary-butyl alcohol, and denied that it produces the specific X-ray diffraction patterns claimed in the patents (Compl. ¶44, ¶46, ¶48, ¶50). Plaintiffs allege that BendaRx did not provide sufficient data to independently confirm its product's composition (Compl. ¶41). The product is a generic version intended to compete with Plaintiffs' branded Treanda® and Bendeka® products (Compl. ¶1, ¶69).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint.
'190 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A stable lyophilized preparation | BendaRx's NDA Product is alleged to be a "stable lyophilized preparation." | ¶47 | col. 11:7-10 |
| comprising bendamustine hydrochloride, | The product is alleged to comprise bendamustine hydrochloride. | ¶47 | col. 11:7-8 |
| mannitol, | The product is alleged to comprise mannitol. | ¶47 | col. 11:8 |
| and a trace amount of tertiary-butyl alcohol (TBA), | The product is alleged to contain a "trace amount of tertiary-butyl alcohol (TBA)." | ¶47 | col. 11:8-9 |
| wherein the ratio by weight of bendamustine hydrochloride to mannitol is 15:25.5. | The product is alleged to have a ratio by weight of bendamustine hydrochloride to mannitol of 15:25.5. | ¶47 | col. 11:9-10 |
Identified Points of Contention
- Factual Questions: The primary point of contention appears to be factual: what is the actual composition of BendaRx's product? The complaint alleges infringement based on "information and belief" while simultaneously noting that BendaRx's notice letter denies the presence of key claimed ingredients like mannitol and TBA (Compl. ¶48). This raises the question of what evidence Plaintiffs will be able to produce to prove the product's composition.
- Scope Questions: The court may need to determine the scope of the term "trace amount," as its specific quantitative limits are not defined in the claim itself.
'524 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A crystalline form of bendamustine hydrochloride | BendaRx's NDA Product is alleged to comprise a crystalline form of bendamustine hydrochloride. | ¶45 | col. 1:41-43 |
| that is bendamustine hydrochloride Form 1, | The product is alleged to be designated as bendamustine hydrochloride Form 1. | ¶45 | col. 4:10-12 |
| that produces an X-ray powder diffraction pattern comprising the following reflections: 8.3, 16.8, and 18.5±0.2 degrees 2θ. | The product is alleged to produce an X-ray powder diffraction pattern with reflections at the specified degrees 2θ. | ¶45 | col. 20:39-44 |
Identified Points of Contention
- Factual Questions: As with the '190 Patent, the central issue is factual. The complaint alleges the product comprises Form 1, but also states that BendaRx's notice letter denies that its product produces the claimed X-ray powder diffraction pattern (Compl. ¶46). The case will depend on experimental evidence (e.g., XRPD analysis) of BendaRx's product.
- Technical Questions: A technical question is whether any observed XRPD peaks from the accused product fall within the "±0.2 degrees 2θ" range required by the claim, and whether experimental variability could be a defense.
V. Key Claim Terms for Construction
"stable lyophilized preparation" ('190 Patent, Claim 1)
- Context and Importance: The definition of "stable" is central to infringement, as it is a required property of the claimed preparation. Practitioners may focus on this term because the specification provides potential quantitative metrics for stability, such as the amount of degradation products formed over time under specific storage conditions, which could be imported into the claim.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The parties may argue that "stable" should be given its plain and ordinary meaning in the context of a pharmaceutical product suitable for commercial use, without being limited to a specific numerical impurity profile unless specified in the claim itself.
- Evidence for a Narrower Interpretation: The specification describes stability in terms of specific impurity levels, such as keeping degradants below about 4.0% at release and below 7.0% over the product's shelf-life (U.S. Patent No. 8,436,190, col. 5:20-33). A defendant may argue that these descriptions define the scope of what the inventor considered "stable."
"produces an X-ray powder diffraction pattern comprising the following reflections: ... ±0.2 degrees 2θ" ('524 Patent, Claim 1)
- Context and Importance: Infringement of the polymorph claims depends entirely on whether the accused product's XRPD pattern matches the claimed peaks within the specified tolerance. The construction of the "±0.2 degrees 2θ" language determines how much variation is permitted for a finding of literal infringement.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: A patentee might argue that "±0.2 degrees 2θ" is a standard convention in the field of XRPD analysis to account for minor instrumental variations and should not be interpreted hyper-technically to allow for escape from infringement based on trivial differences. The specification states that XRPD measurements of 2θ values are "typically accurate to within ±0.2 degrees" (U.S. Patent No. 8,445,524, col. 15:5-7), which may support this as a standard instrument tolerance.
- Evidence for a Narrower Interpretation: A defendant might argue that the "±0.2" range is a precise boundary and that any peak falling outside this range, no matter how close, avoids literal infringement. The patent consistently uses this specific tolerance when defining its claimed forms, suggesting it is an intentional and definite limitation.
VI. Other Allegations
Indirect Infringement
- The complaint alleges that BendaRx will actively induce infringement upon FDA approval. This allegation is based on the proposed product labeling, which will allegedly encourage, recommend, and instruct healthcare professionals and patients to use the product in a manner that directly infringes the asserted composition and method claims (Compl. ¶¶ 54, 56, 91, 113).
Willful Infringement
- The complaint alleges that BendaRx "has acted with full knowledge" of the Patents-in-Suit and "without a reasonable basis for believing that it would not be liable for infringing" them (Compl. ¶¶ 94, 116). This allegation of willful infringement is based on BendaRx’s pre-suit knowledge of the patents, evidenced by its March 23, 2023 notice letter that provided a Paragraph IV Certification against them (Compl. ¶38).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central issue will be one of factual proof: Can Plaintiffs produce sufficient evidence to demonstrate that BendaRx's NDA Product, despite BendaRx's denials, in fact contains the specific combination of ingredients (e.g., mannitol, TBA) and possesses the specific crystalline structures (e.g., Form 1, Form 3) required by the asserted claims?
- A key question of claim interpretation will be whether the definition of a "stable lyophilized preparation" is limited by the specific impurity profiles described in the specification of the '190 patent family, or if it carries a broader meaning.
- The case may also present an issue of technical equivalence: If BendaRx's product does not literally infringe—for instance, if its XRPD peaks fall just outside the claimed "±0.2 degrees 2θ" range—a key evidentiary question will be whether any differences between the claimed polymorphs and the accused product's form are insubstantial under the doctrine of equivalents.