DCT
1:24-cv-00395
Teva Pharma Intl GmbH v. Bendarx USA Corp
Key Events
Complaint
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Teva Pharmaceuticals International GmbH (Switzerland), Cephalon, LLC (Delaware), and Eagle Pharmaceuticals, Inc. (Delaware)
- Defendant: BendaRx USA Corp. (Virginia)
- Plaintiff’s Counsel: Hunton Andrews Kurth LLP; Nelson Mullins Riley & Scarborough LLP
- Case Identification: 1:24-cv-00395, E.D. Va., 06/16/2023
- Venue Allegations: Venue is alleged to be proper in the Eastern District of Virginia because Defendant BendaRx USA Corp. is incorporated in Virginia and therefore resides in the district.
- Core Dispute: Plaintiffs allege that Defendant’s submission of a New Drug Application to the FDA for a generic bendamustine hydrochloride product constitutes an act of infringement under the Hatch-Waxman Act, infringing eleven patents related to pharmaceutical compositions and solid forms of the drug.
- Technical Context: The technology concerns formulations of bendamustine, an alkylating drug used to treat chronic lymphocytic leukemia and non-Hodgkin lymphoma, focusing on creating stable lyophilized products and identifying specific crystalline forms of the active ingredient.
- Key Procedural History: The complaint states this is a "protective suit" filed after Plaintiffs learned that BendaRx USA Corp., not its Canadian affiliate BendaRx Canada, was the entity that submitted the New Drug Application. Plaintiffs had previously sued BendaRx Canada in the District of Delaware over the same NDA. The patents-in-suit have also been the subject of litigation against more than ten other groups of generic defendants, suggesting a history of enforcement.
Case Timeline
| Date | Event |
|---|---|
| 2005-01-14 | U.S. Patent No. 8,436,190 Priority Date |
| 2008-03-26 | U.S. Patent No. 8,445,524 Priority Date |
| 2009-01-15 | U.S. Patent No. 8,076,366 Priority Date |
| 2011-12-13 | U.S. Patent No. 8,076,366 Issued |
| 2013-05-07 | U.S. Patent No. 8,436,190 Issued |
| 2013-05-21 | U.S. Patent No. 8,445,524 Issued |
| 2013-06-11 | U.S. Patent No. 8,461,350 Issued |
| 2013-12-17 | U.S. Patent No. 8,609,863 Issued |
| 2014-03-11 | U.S. Patent No. 8,669,279 Issued |
| 2014-07-27 | U.S. Patent No. 8,791,270 Issued |
| 2014-11-11 | U.S. Patent No. 8,883,836 Issued |
| 2014-11-25 | U.S. Patent No. 8,895,756 Issued |
| 2015-02-13 | Cephalon executes exclusive license with Eagle Pharmaceuticals |
| 2015-10-14 | Cephalon assigns license rights to Teva Pharmaceuticals |
| 2017-01-03 | U.S. Patent No. 9,533,955 Issued |
| 2017-02-21 | U.S. Patent No. 9,572,887 Issued |
| 2023-03-23 | First Notice Letter sent by BendaRx Canada |
| 2023-05-04 | Plaintiffs sue BendaRx Canada in District of Delaware |
| 2023-05-05 | Second Notice Letter identifies BendaRx USA as NDA submitter |
| 2023-06-16 | Complaint Filed |
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's background describes that nitrogen mustard drugs like bendamustine are highly reactive and degrade in aqueous solutions, making them difficult to formulate (’190 Patent, col. 1:25-35). Existing lyophilized (freeze-dried) powders are difficult and slow to reconstitute, which is burdensome for healthcare professionals and increases the risk of drug degradation before administration ('190 Patent, col. 2:20-30).
- The Patented Solution: The invention is a stable, lyophilized pharmaceutical composition of bendamustine that is easier to reconstitute and has a better impurity profile. This is achieved by creating a pre-lyophilization solution that includes specific components, such as mannitol as a bulking agent and an organic solvent like tertiary-butyl alcohol, which stabilizes the bendamustine during the process and results in a superior final product ('190 Patent, Abstract; col. 3:1-12).
- Technical Importance: This technology creates a more stable and user-friendly version of an important chemotherapy drug, potentially improving safety and efficiency in a clinical setting.
Key Claims at a Glance
- The complaint’s allegations map to independent claim 1.
- Essential elements of Claim 1:
- A pharmaceutical composition comprising bendamustine or bendamustine hydrochloride
- mannitol
- tertiary-butyl alcohol
- and water
- The complaint does not explicitly reserve the right to assert dependent claims, but infringement allegations are made against "one or more claims" of the patent (Compl. ¶71).
U.S. Patent No. 8,445,524 - Solid Forms of Bendamustine Hydrochloride
The Invention Explained
- Problem Addressed: The patent explains that active pharmaceutical ingredients can exist in various solid forms (polymorphs) with different physical properties, such as solubility and stability. This variability can create challenges in manufacturing a consistent and effective drug product. The patent notes a need to identify and prepare novel, stable solid forms of bendamustine hydrochloride (’524 Patent, col. 1:24-41).
- The Patented Solution: The patent discloses the discovery and characterization of several novel crystalline polymorphic forms of bendamustine hydrochloride, designated Form 1, Form 2, Form 3, and Form 4. These forms are distinguished by their unique X-ray powder diffraction (XRPD) patterns, which arise from the specific arrangement of molecules in the crystal lattice, and processes for making them ('524 Patent, Abstract; FIG. 2).
- Technical Importance: By identifying and claiming distinct, reproducible crystalline forms, the invention allows for the manufacture of a drug substance with predictable and consistent physical properties, which is critical for drug formulation, stability, and regulatory approval.
Key Claims at a Glance
- The complaint’s allegations map to independent claims 1 and 11.
- Essential elements of Claim 1:
- A solid form of bendamustine hydrochloride, designated as 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 20
- Essential elements of Claim 11:
- A solid form of bendamustine hydrochloride, designated as 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 20
- The complaint does not explicitly reserve the right to assert dependent claims but alleges infringement of "one or more claims" of the patent (Compl. ¶93).
U.S. Patent No. 8,609,863 - Bendamustine Pharmaceutical Compositions
- Technology Synopsis: This patent relates to stable lyophilized pharmaceutical formulations of bendamustine. The invention aims to produce a product that is easier to reconstitute and has an improved impurity profile compared to prior art formulations, particularly by controlling the levels of degradation products like HP1.
- Asserted Claims: The complaint does not specify which claims are asserted.
- Accused Features: The complaint alleges that the BendaRx NDA Product is a stable lyophilized preparation with a specific weight ratio of bendamustine hydrochloride to mannitol and contains low levels of the HP1 degradant (Compl. ¶¶44, 48).
U.S. Patent No. 8,669,279 - Solid Forms of Bendamustine Hydrochloride
- Technology Synopsis: This patent describes and claims novel crystalline forms (polymorphs) of bendamustine hydrochloride. These distinct solid forms are characterized by unique physical properties, including specific X-ray powder diffraction patterns, which can provide advantages for pharmaceutical formulation.
- Asserted Claims: The complaint does not specify which claims are asserted.
- Accused Features: The complaint alleges that the BendaRx NDA Product comprises a crystalline form of bendamustine hydrochloride identified as Form 3 (Compl. ¶¶46, 51, 55).
U.S. Patent No. 8,791,270 - Bendamustine Pharmaceutical Compositions
- Technology Synopsis: This patent is directed to pharmaceutical compositions of bendamustine, particularly lyophilized formulations containing specific excipients and having certain concentrations. The technology aims to provide stable and readily usable forms of the drug for administration.
- Asserted Claims: The complaint does not specify which claims are asserted.
- Accused Features: The complaint alleges the BendaRx NDA Product's proposed labeling promotes using a vial containing a reconstituted solution of bendamustine hydrochloride and mannitol with a specific weight ratio and concentration (Compl. ¶53).
U.S. Patent No. 8,883,836 - Solid Forms of Bendamustine Hydrochloride
- Technology Synopsis: This patent discloses and claims specific solid crystalline forms of bendamustine hydrochloride. The invention is based on the discovery of novel polymorphs characterized by distinct X-ray powder diffraction patterns, which provides for a consistent and stable active pharmaceutical ingredient.
- Asserted Claims: The complaint does not specify which claims are asserted.
- Accused Features: The complaint alleges the BendaRx NDA Product comprises a crystalline form of bendamustine hydrochloride known as Form 3, which produces specific X-ray powder diffraction peaks (Compl. ¶55).
U.S. Patent No. 8,895,756 - Bendamustine Pharmaceutical Compositions
- Technology Synopsis: This patent relates to stable lyophilized pharmaceutical preparations of bendamustine. The invention seeks to solve problems of instability and difficult reconstitution by defining compositions with specific ratios of active ingredient to excipients.
- Asserted Claims: The complaint does not specify which claims are asserted.
- Accused Features: The complaint alleges the BendaRx NDA Product is a stable lyophilized preparation containing bendamustine hydrochloride and mannitol in a specific weight ratio (Compl. ¶44).
U.S. Patent No. 9,533,955 - Solid Forms of Bendamustine Hydrochloride
- Technology Synopsis: This patent is directed to novel solid forms of bendamustine hydrochloride, specifically crystalline polymorphs. These forms are characterized by unique physical data, such as X-ray powder diffraction patterns, and offer a way to produce a more stable and consistent drug substance.
- Asserted Claims: The complaint does not specify which claims are asserted.
- Accused Features: The complaint alleges the BendaRx NDA Product comprises bendamustine hydrochloride Form 3 (Compl. ¶46).
U.S. Patent No. 9,572,887 - Formulations of Bendamustine
- Technology Synopsis: This patent relates to stable, non-aqueous liquid formulations of bendamustine with low levels of impurities. The invention addresses the problem of bendamustine's instability in aqueous solutions by providing a formulation in a non-aqueous solvent system that is stable for long-term storage.
- Asserted Claims: The complaint does not specify which claims are asserted.
- Accused Features: The complaint alleges the proposed labeling for the BendaRx NDA Product promotes providing and administering a non-aqueous liquid composition with specific concentration ranges, impurity profiles, and administration instructions (Compl. ¶¶58-62).
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 desirability of using the free base form of a drug to avoid potential side effects from the salt counterion, and the prior instability of known free base forms.
- Asserted Claims: The complaint does not specify which claims are asserted.
- Accused Features: The complaint alleges the BendaRx NDA Product is a pharmaceutical composition comprising one or more specified forms of bendamustine free base (Compl. ¶64).
U.S. Patent No. 8,461,350 - Bendamustine Pharmaceutical Compositions
- Technology Synopsis: This patent pertains to pharmaceutical compositions of bendamustine, particularly lyophilized formulations that include specific solvents in their preparation. The technology aims to create stable and easily reconstituted bendamustine products.
- Asserted Claims: The complaint does not specify which claims are asserted.
- Accused Features: The complaint alleges the BendaRx NDA Product is a pharmaceutical composition comprising bendamustine, mannitol, water, and a solvent selected from a specific list (Compl. ¶65).
III. The Accused Instrumentality
Product Identification
- The accused instrumentality is "BendaRx's NDA Product," a generic drug product for which BendaRx USA Corp. has submitted New Drug Application No. 215291 to the FDA (Compl. ¶1).
Functionality and Market Context
- The BendaRx NDA Product is an alkylating drug intended for the treatment of chronic lymphocytic leukemia and non-Hodgkin lymphoma (Compl. ¶¶16, 18, 51). The complaint alleges, upon information and belief, that the product is a lyophilized pharmaceutical composition comprising bendamustine hydrochloride, mannitol, and tertiary-butyl alcohol (Compl. ¶40). It is further alleged to contain specific crystalline forms of bendamustine hydrochloride, namely Form 1 and Form 3 (Compl. ¶¶42, 46). The product is a generic version intended to compete with Plaintiffs' branded products, Treanda® and Bendeka®, and its submission to the FDA before the expiration of the patents-in-suit is the basis for this Hatch-Waxman Act lawsuit (Compl. ¶¶1, 67). No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
'190 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A pharmaceutical composition comprising bendamustine or bendamustine hydrochloride, | The BendaRx NDA Product is alleged to be a pharmaceutical composition comprising bendamustine hydrochloride. | ¶40 | col. 3:1-4 |
| mannitol, | The BendaRx NDA Product is alleged to comprise mannitol. | ¶40 | col. 3:1-4 |
| tertiary-butyl alcohol | The BendaRx NDA Product is alleged to comprise tertiary-butyl alcohol. | ¶40 | col. 3:1-4 |
| and water | The BendaRx NDA Product is alleged to comprise water. | ¶40 | col. 3:1-4 |
'524 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A solid form of bendamustine hydrochloride, designated as bendamustine hydrochloride Form 1, | The BendaRx NDA Product is alleged to comprise bendamustine hydrochloride designated as Form 1. | ¶42 | col. 6:40-42 |
| that produces an X-ray powder diffraction pattern comprising the following reflections: 8.3, 16.8, and 18.5±0.2 degrees 20 | The BendaRx NDA Product is alleged to produce an X-ray powder diffraction pattern with these characteristic reflections. | ¶42 | col. 6:42-45 |
Identified Points of Contention
- Evidentiary Questions: The primary point of contention appears to be factual. The complaint's allegations regarding the composition and crystalline form of the accused product are made "on information and belief" (Compl. ¶¶40, 42). The complaint simultaneously states that in its notice letters, BendaRx denied that its product contains mannitol and tertiary-butyl alcohol or that it produces the specific X-ray diffraction patterns for Form 1 or Form 3 (Compl. ¶¶41, 43). This raises the central evidentiary question of what the chemical composition and solid-state structure of the actual BendaRx NDA Product is, which will require discovery and expert analysis.
- Scope Questions: Should infringement be found, a potential question for the court may be the scope of what constitutes "bendamustine hydrochloride Form 1." The analysis may question whether matching the three characteristic peaks recited in the complaint is sufficient for infringement, or if substantial identity with the full XRPD pattern and other physical data disclosed in the patent is required.
V. Key Claim Terms for Construction
The Term: "pharmaceutical composition" ('190 Patent, Claim 1)
Context and Importance: The infringement allegation for the '190 Patent depends on whether the accused product, as a whole, meets the definition of the claimed "pharmaceutical composition." Practitioners may focus on this term because the defendant could argue that its product contains additional or different excipients that place it outside the scope of the composition as contemplated by the patent.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The claim uses the open-ended term "comprising," which generally means the composition can include other unrecited elements. The specification provides a non-exhaustive list of potential additional excipients, suggesting the invention is not limited to only the four recited components ('190 Patent, col. 11:1-12).
- Evidence for a Narrower Interpretation: A party could argue that the specific combination of bendamustine, mannitol, tertiary-butyl alcohol, and water creates a unique formulation whose properties are essential to the invention. The specification's focus on the stabilizing effect of tertiary-butyl alcohol and the role of mannitol as a bulking agent could be used to argue that the term "pharmaceutical composition" should be construed in light of this specific functional relationship ('190 Patent, col. 9:50-65).
The Term: "bendamustine hydrochloride Form 1" ('524 Patent, Claim 1)
Context and Importance: Infringement of the '524 Patent hinges on whether the accused product contains this specific, patented crystalline form of bendamustine HCl. The definition of "Form 1" will be dispositive, as the parties already appear to dispute its presence in the accused product.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: Claim 1 of the '524 Patent defines Form 1 by an XRPD pattern "comprising" a set of characteristic reflections. This language may support an interpretation where the presence of these key peaks is sufficient to establish the presence of Form 1, even if other peaks differ or are present.
- Evidence for a Narrower Interpretation: The specification provides a detailed characterization of Form 1, including a full XRPD pattern (FIG. 2) and extensive crystallographic data ('524 Patent, col. 5:44-6:45; Table 1). A defendant might argue that the term "bendamustine hydrochloride Form 1" requires substantial identity to the complete characterization data provided in the specification, not just a subset of identifying peaks.
VI. Other Allegations
- Indirect Infringement: The complaint alleges induced infringement for all asserted patents. The basis for inducement is the allegation that BendaRx's proposed product labeling will encourage, recommend, and instruct healthcare professionals to reconstitute and administer the NDA Product in a manner that directly infringes the claims (e.g., Compl. ¶¶74, 96, 118).
- Willful Infringement: The complaint alleges that the defendant acted with "full knowledge" of the patents-in-suit and "without a reasonable basis for believing that it would not be liable for infringing," which supports a claim for willfulness (e.g., Compl. ¶¶77, 99, 121). This knowledge is predicated on BendaRx's submission of a Paragraph IV Certification, an act which requires the generic applicant to certify its belief that the Orange Book-listed patents are invalid or not infringed.
VII. Analyst’s Conclusion: Key Questions for the Case
- A central issue will be one of evidentiary proof: given that the infringement allegations are based on "information and belief" and the defendant has allegedly denied them in its notice letters, the case will likely turn on discovery and expert testing to determine the actual chemical composition and solid-state crystal structure of the accused generic product.
- A key legal question will be one of claim construction and infringement: the dispute may center on the definition of specific crystalline forms, such as "bendamustine hydrochloride Form 1." The court may need to decide whether matching a subset of characteristic XRPD peaks is sufficient to prove the presence of the claimed polymorph, or if a more holistic comparison is required, potentially creating a significant hurdle for proving infringement.