DCT
1:23-cv-00633
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-00633, D. Del., 06/09/2023
- Venue Allegations: Venue is alleged to be proper because BendaRx is a foreign corporation subject to personal jurisdiction in the district. The complaint alleges BendaRx has purposefully availed itself of Delaware's laws by seeking FDA approval to market its product throughout the United States, including Delaware, and intends to derive substantial revenue from sales within the state.
- Core Dispute: Plaintiffs allege that Defendant’s New Drug Application to market a generic version of the cancer drug bendamustine hydrochloride infringes eleven patents related to bendamustine compositions, formulations, and solid forms.
- Technical Context: The technology concerns pharmaceutical formulations of bendamustine, an alkylating drug used to treat certain leukemias and lymphomas, focusing on improving its stability and methods of administration.
- Key Procedural History: This action was filed under the Hatch-Waxman Act following Defendant’s Paragraph IV certification notice letter dated March 23, 2023. Plaintiffs allege that Cephalon executed an exclusive license to Eagle Pharmaceuticals on February 13, 2015, for patents including the ’887 Patent, which covers the rapid infusion product Bendeka®. This license was subsequently assigned to Teva Pharmaceuticals on October 14, 2015.
Case Timeline
| Date | Event |
|---|---|
| 2005-01-14 | Earliest Priority Date for ’190, ’863, ’270, ’756, ’350 Patents |
| 2008-03-26 | Earliest Priority Date for ’524, ’279, ’836, ’955 Patents |
| 2009-01-15 | Earliest Priority Date for ’366 Patent |
| 2011-12-13 | U.S. Patent No. 8,076,366 Issues |
| 2012-03-20 | Earliest Priority Date for ’887 Patent |
| 2013-05-07 | U.S. Patent No. 8,436,190 Issues |
| 2013-05-21 | U.S. Patent No. 8,445,524 Issues |
| 2013-06-11 | U.S. Patent No. 8,461,350 Issues |
| 2013-12-17 | U.S. Patent No. 8,609,863 Issues |
| 2014-03-11 | U.S. Patent No. 8,669,279 Issues |
| 2014-07-27 | U.S. Patent No. 8,791,270 Issues |
| 2014-11-11 | U.S. Patent No. 8,883,836 Issues |
| 2014-11-25 | U.S. Patent No. 8,895,756 Issues |
| 2015-02-13 | Cephalon executes exclusive license to Eagle Pharmaceuticals |
| 2015-10-14 | Cephalon assigns its license rights to Teva Pharmaceuticals |
| 2017-01-03 | U.S. Patent No. 9,533,955 Issues |
| 2017-02-21 | U.S. Patent No. 9,572,887 Issues |
| 2017-03-14 | BendaRx Corp. is incorporated in Canada |
| 2023-03-23 | BendaRx sends "First Notice Letter" of its NDA filing |
| 2023-05-05 | BendaRx sends "Second Notice Letter" |
| 2023-06-09 | Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 8,436,190 - “Bendamustine Pharmaceutical Compositions,” Issued May 7, 2013
The Invention Explained
- Problem Addressed: The patent describes that bendamustine is highly reactive and unstable in aqueous solutions, leading to degradation and impurity formation during reconstitution of lyophilized (freeze-dried) powders (Compl. ¶1; ’190 Patent, col. 1:25-31). This instability and the difficulty of reconstitution can require lengthy preparation times by healthcare professionals, increasing the risk of potency loss (Compl. ¶1; ’190 Patent, col. 2:1-27).
- The Patented Solution: The invention is a stable, lyophilized pharmaceutical formulation that includes bendamustine hydrochloride, a bulking agent (mannitol), and a non-aqueous, stabilizing organic solvent such as tertiary-butyl alcohol (TBA) (’190 Patent, col. 10:56-62). This combination is designed to create a more stable lyophilized cake that is easier to reconstitute and has a better impurity profile than previous formulations (’190 Patent, col. 2:28-32, Abstract).
- Technical Importance: This formulation aimed to provide a commercially viable bendamustine product with improved shelf-life and faster, more reliable reconstitution, enhancing convenience and safety for clinical use (’190 Patent, col. 2:28-32).
Key Claims at a Glance
- The complaint alleges infringement of "one or more claims" without specifying which ones (Compl. ¶87). Independent claim 1 is representative of the invention.
- Independent Claim 1 elements:
- 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.
U.S. Patent No. 8,445,524 - “Solid Forms of Bendamustine Hydrochloride,” Issued May 21, 2013
The Invention Explained
- Problem Addressed: The patent background explains that active pharmaceutical ingredients (APIs) can exist in different solid forms (polymorphs), which can affect physical properties like solubility, stability, and bioavailability. The patent notes a need to identify and prepare novel, stable solid forms of bendamustine hydrochloride (’524 Patent, col. 1:19-44).
- The Patented Solution: The invention describes the discovery and characterization of several novel crystalline forms (polymorphs) of bendamustine hydrochloride, designated as Forms 1, 2, 3, and 4, as well as an amorphous form (’524 Patent, col. 2:40-45). Each crystalline form is defined by a unique pattern of peaks in an X-ray powder diffraction (XRPD) analysis, providing distinct and reproducible solid-state structures (’524 Patent, col. 3:9-15).
- Technical Importance: Identifying distinct, stable polymorphs is critical for pharmaceutical manufacturing to ensure batch-to-batch consistency, predictable dissolution rates, and regulatory compliance (’524 Patent, col. 1:31-44).
Key Claims at a Glance
- The complaint alleges infringement of "one or more claims" (Compl. ¶109). Independent claim 1 is representative.
- Independent Claim 1 elements:
- 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.
U.S. Patent No. 8,609,863 - “Bendamustine Pharmaceutical Compositions,” Issued Dec. 17, 2013
- Technology Synopsis: This patent relates to stable lyophilized preparations of bendamustine hydrochloride containing mannitol and a trace amount of tertiary-butyl alcohol. It is directed at specific weight ratios of bendamustine to mannitol, aiming to improve stability and ease of reconstitution (Compl. ¶1; ’863 Patent, Abstract).
- Asserted Claims: The complaint asserts infringement of "one or more claims" (Compl. ¶131). Independent claim 1 is representative.
- Accused Features: The accused product is alleged to be a stable lyophilized preparation containing bendamustine hydrochloride, mannitol, and a trace amount of tertiary-butyl alcohol at the claimed ratio (Compl. ¶60).
U.S. Patent No. 8,669,279 - “Solid Forms of Bendamustine Hydrochloride,” Issued Mar. 11, 2014
- Technology Synopsis: This patent claims specific crystalline forms (polymorphs) of bendamustine hydrochloride, characterized by their unique X-ray powder diffraction (XRPD) patterns. The invention addresses the need for stable, well-defined solid forms of the drug for consistent manufacturing and performance (Compl. ¶1; ’279 Patent, Abstract).
- Asserted Claims: The complaint asserts infringement of "one or more claims" (Compl. ¶153). Independent claim 1 is representative.
- Accused Features: The accused product is alleged to comprise bendamustine hydrochloride Form 3, which is characterized by specific XRPD peaks claimed in the patent (Compl. ¶62).
U.S. Patent No. 8,791,270 - “Bendamustine Pharmaceutical Compositions,” Issued Jul. 29, 2014
- Technology Synopsis: This patent covers lyophilized pharmaceutical compositions of bendamustine that contain specific impurities below a certain threshold, indicating a stable formulation. It is directed at compositions containing not more than about 0.5% to 0.9% of the impurity HP1 at the time of release (’270 Patent, Abstract; Compl. ¶1).
- Asserted Claims: The complaint asserts infringement of "one or more claims" (Compl. ¶175). Independent claim 1 is representative.
- Accused Features: The proposed labeling for the accused product is alleged to promote a composition containing not more than about 0.9% of HP1 (Compl. ¶64).
U.S. Patent No. 8,883,836 - “Solid Forms of Bendamustine Hydrochloride,” Issued Nov. 11, 2014
- Technology Synopsis: This patent describes and claims specific crystalline forms of bendamustine hydrochloride, including Form 1. These forms are identified by characteristic X-ray powder diffraction (XRPD) peaks, providing a solution to the need for stable and reproducible solid forms of the drug (’836 Patent, Abstract; Compl. ¶1).
- Asserted Claims: The complaint asserts infringement of "one or more claims" (Compl. ¶197). Independent claim 1 is representative.
- Accused Features: The accused product is alleged to comprise bendamustine hydrochloride Form 1, identified by its characteristic XRPD peaks (Compl. ¶58).
U.S. Patent No. 8,895,756 - “Bendamustine Pharmaceutical Compositions,” Issued Nov. 25, 2014
- Technology Synopsis: This patent is directed to stable, lyophilized pharmaceutical preparations of bendamustine comprising mannitol and a trace amount of tertiary-butyl alcohol. The claims focus on a specific ratio by weight of bendamustine hydrochloride to mannitol of 15:25.5 (’756 Patent, Abstract; Compl. ¶1).
- Asserted Claims: The complaint asserts infringement of "one or more claims" (Compl. ¶219). Independent claim 1 is representative.
- Accused Features: The accused product is alleged to be a stable lyophilized preparation containing bendamustine hydrochloride, mannitol, and tertiary-butyl alcohol, with the specific weight ratio of 15:25.5 (Compl. ¶60, ¶69).
U.S. Patent No. 9,533,955 - “Solid Forms of Bendamustine Hydrochloride,” Issued Jan. 3, 2017
- Technology Synopsis: This patent claims specific crystalline forms of bendamustine hydrochloride, including Form 3, which are defined by X-ray powder diffraction patterns. The invention provides distinct and reproducible solid forms of the active pharmaceutical ingredient (’955 Patent, Abstract; Compl. ¶1).
- Asserted Claims: The complaint asserts infringement of "one or more claims" (Compl. ¶241). Independent claim 1 is representative.
- Accused Features: The accused product is alleged to comprise bendamustine hydrochloride Form 3, which is defined by specific XRPD peaks claimed in the patent (Compl. ¶62, ¶71).
U.S. Patent No. 9,572,887 - “Formulations of Bendamustine,” Issued Feb. 21, 2017
- Technology Synopsis: This patent covers non-aqueous liquid compositions of bendamustine with low levels of impurities after extended storage. It is directed to methods of treatment involving administering a diluted composition in a small volume over a short period, such as 15 minutes or less (’887 Patent, Abstract; Compl. ¶1).
- Asserted Claims: The complaint asserts infringement of "one or more claims" (Compl. ¶263). Independent claim 1 is representative.
- Accused Features: The proposed labeling for the accused product is alleged to promote a method of administering a diluted, non-aqueous liquid composition in a volume of about 100 mL or less over a time period of 15 minutes or less (Compl. ¶74-78).
U.S. Patent No. 8,076,366 - “Forms of Bendamustine Free Base,” Issued Dec. 13, 2011
- Technology Synopsis: This patent describes novel polymorphic forms of bendamustine free base, as distinct from its hydrochloride salt. The invention provides stable forms of the free base for potential use in pharmaceutical compositions (’366 Patent, Abstract; Compl. ¶1).
- Asserted Claims: The complaint asserts infringement of "one or more claims" (Compl. ¶285). Independent claim 1 is representative.
- Accused Features: The accused product is alleged to be a pharmaceutical composition comprising bendamustine free base in one of the claimed polymorphic forms (Compl. ¶80).
U.S. Patent No. 8,461,350 - “Bendamustine Pharmaceutical Compositions,” Issued Jun. 11, 2013
- Technology Synopsis: This patent relates to stable lyophilized preparations of bendamustine hydrochloride containing mannitol and a trace amount of tertiary-butyl alcohol. It claims a specific ratio of bendamustine hydrochloride to mannitol of 15:25.5 (’350 Patent, Abstract; Compl. ¶1).
- Asserted Claims: The complaint asserts infringement of "one or more claims" (Compl. ¶307). Independent claim 1 is representative.
- Accused Features: The accused product is alleged, on information and belief, to be a lyophilized preparation containing bendamustine hydrochloride and mannitol in the claimed ratio (Compl. ¶60, ¶81).
III. The Accused Instrumentality
- Product Identification: Defendant’s proposed generic bendamustine hydrochloride product, submitted to the FDA under New Drug Application (“NDA”) No. 215291 ("BendaRx's NDA Product") (Compl. ¶1).
- Functionality and Market Context:
- The BendaRx NDA Product is a generic version of Plaintiffs' branded drugs, Treanda® and/or Bendeka®, which are alkylating drugs used to treat chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma (Compl. ¶21, ¶23, ¶83).
- Based on "information and belief," the complaint alleges the product is a stable lyophilized preparation comprising bendamustine hydrochloride, mannitol, and a trace amount of tertiary-butyl alcohol, with a specific weight ratio of bendamustine to mannitol of 15:25.5 (Compl. ¶60). The product is also alleged to comprise specific crystalline forms of bendamustine hydrochloride, including Form 1 and Form 3 (Compl. ¶58, ¶62).
- The complaint alleges BendaRx seeks approval to market this generic product before the expiration of the patents-in-suit (Compl. ¶1, ¶52).
- Visual Evidence: No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
’190 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A stable lyophilized preparation comprising bendamustine hydrochloride, mannitol, and a trace amount of tertiary-butyl alcohol (TBA), | BendaRx’s NDA Product is alleged to be a stable lyophilized preparation comprising bendamustine hydrochloride, mannitol, and a trace amount of tertiary-butyl alcohol (TBA). | ¶60 | col. 10:56-59 |
| wherein the ratio by weight of bendamustine hydrochloride to mannitol is 15:25.5. | The ratio by weight of bendamustine hydrochloride to mannitol in the accused product is alleged to be 15:25.5. | ¶60 | col. 10:59-62 |
- Identified Points of Contention:
- Factual Question: A central issue will be factual: does BendaRx's NDA Product actually contain the combination of bendamustine hydrochloride, mannitol, and tertiary-butyl alcohol at the specific 15:25.5 ratio as alleged by Plaintiffs? The complaint repeatedly notes that BendaRx denied its product contains mannitol and TBA in its notice letters (Compl. ¶61, ¶70).
- Scope Question: A potential point of contention may be the interpretation of "a trace amount" of tertiary-butyl alcohol. The parties may dispute what quantity qualifies as a "trace amount" and whether the amount present in the accused product, if any, falls within the scope of the claim.
’524 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A crystalline form of bendamustine hydrochloride that is bendamustine hydrochloride Form 3, | The BendaRx NDA Product is alleged to comprise a crystalline form of bendamustine hydrochloride that is Form 3. | ¶62 | col. 4:51-53 |
| that produces an X-ray powder diffraction pattern comprising the following reflections: 7.9, 15.5, and 26.1±0.2 degrees 2θ. | The accused product is alleged to produce an X-ray powder diffraction pattern with reflections at 7.9, 15.5, and 26.1±0.2 degrees 2θ. | ¶62 | col. 5:10-18 |
- Identified Points of Contention:
- Factual Question: The primary dispute will be factual, centering on whether the accused product comprises the specific crystalline Form 3 of bendamustine hydrochloride. This will likely be resolved through expert analysis of the accused product's XRPD data. The complaint notes that BendaRx's notice letters denied that its product produces the claimed diffraction pattern (Compl. ¶63).
- Technical Question: What evidence will be presented to establish that any peaks observed in the accused product's XRPD pattern are attributable to the claimed Form 3, and not to other components of the formulation or other polymorphic forms?
V. Key Claim Terms for Construction
The Term: "a stable lyophilized preparation" (from Claim 1 of the ’190 Patent)
- Context and Importance: The definition of this term is critical because the infringement allegation hinges on the accused product being a specific type of formulation. Practitioners may focus on this term because its scope could determine whether any lyophilized bendamustine product containing the recited ingredients infringes, or only those meeting a specific, heightened standard of stability.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification describes the problems of the prior art, Ribomustin®, as relating to difficult and lengthy reconstitution (’190 Patent, col. 2:1-27). This may support an argument that any lyophilized preparation that solves these problems meets the "stable" requirement.
- Evidence for a Narrower Interpretation: The detailed description provides specific impurity profiles, such as containing "not more than about 0.5% to about 0.9% (area percent of bendamustine) HP1" (’190 Patent, col. 3:5-7). This could support a narrower construction where "stable" requires meeting these specific, low-level impurity metrics.
The Term: "a crystalline form...that produces an X-ray powder diffraction pattern comprising the following reflections: 7.9, 15.5, and 26.1±0.2 degrees 2θ" (from Claim 1 of the ’524 Patent)
- Context and Importance: This term defines the patented invention by its specific physical structure, as measured by XRPD. The infringement case for this patent turns entirely on whether the accused product meets this structural definition. Practitioners will focus on the precision of the peak locations and the significance of the "±0.2 degrees" range, as minor variations in measurement could place the accused product inside or outside the claim scope.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent states that XRPD patterns can have slight variations depending on instrumentation and sample preparation (’524 Patent, col. 4:26-34). This language may be used to argue that the claimed peak values should be interpreted with some flexibility beyond the explicit "±0.2" range.
- Evidence for a Narrower Interpretation: The patent explicitly defines Form 3 with a list of characteristic peaks in Table 3, providing a precise, multi-peak fingerprint (’524 Patent, col. 5:10-29). This detailed definition could support a narrow construction requiring the presence of not just the three peaks from claim 1, but a pattern substantially matching the one disclosed for Form 3 in the specification.
VI. Other Allegations
- Indirect Infringement: For each patent, the complaint alleges active inducement on the belief that BendaRx's proposed product labeling will encourage, recommend, instruct, and/or promote infringing uses by others, such as administering the drug to treat claimed indications (e.g., Compl. ¶90, ¶112). It also alleges contributory infringement on the belief that the product is especially made or adapted for an infringing use and is not suitable for a substantial non-infringing use (e.g., Compl. ¶91, ¶113).
- Willful Infringement: Willfulness is alleged for each patent based on BendaRx's alleged full knowledge of the patents-in-suit and proceeding with its NDA submission without a reasonable basis for believing it would not be liable for infringement (e.g., Compl. ¶93, ¶115).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central issue will be one of compositional fact: what is the actual chemical and polymorphic composition of BendaRx's NDA product? The dispute will likely depend heavily on discovery and expert analysis to determine if the product contains mannitol, tertiary-butyl alcohol, and the specific crystalline forms of bendamustine hydrochloride as alleged by Plaintiffs, particularly in light of Defendant’s apparent denials in pre-suit correspondence.
- A key evidentiary question will be one of technical proof: can Plaintiffs demonstrate that the proposed generic product, as described in its confidential NDA, will necessarily meet the quantitative limitations of the asserted claims? This includes not only the specific 15:25.5 weight ratio for the formulation patents but also the precise impurity thresholds and X-ray diffraction peak locations for the composition and polymorph patents.
- A core issue will be one of corporate identity and conduct: does the evidence support Plaintiffs' detailed allegations that BendaRx Corp. (Canada) is the true actor behind the NDA filing, despite the later identification of BendaRx USA Corp.? The resolution of this question may impact jurisdiction, liability, and the assessment of intent for indirect and willful infringement.