DCT

1:19-cv-01251

Teva Pharma Intl GmbH v. Lupin Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:19-cv-01251, D. Del., 07/02/2019
  • Venue Allegations: Venue is alleged to be proper as to Lupin Ltd., a foreign corporation, and as to Lupin Pharmaceuticals, Inc., a Delaware corporation subject to personal jurisdiction in the district.
  • Core Dispute: Plaintiffs allege that Defendants’ submission of an Abbreviated New Drug Application (ANDA) to the FDA for a generic version of BENDEKA® constitutes an act of infringement of fourteen U.S. patents covering formulations of bendamustine hydrochloride.
  • Technical Context: The patents relate to stable, liquid pharmaceutical formulations of bendamustine, an alkylating agent used in chemotherapy, designed to overcome the drug's rapid degradation in aqueous solutions and improve its long-term storage stability.
  • Key Procedural History: The litigation was triggered by Lupin Ltd.'s submission of ANDA No. 212412, which seeks FDA approval to market a generic bendamustine product before the expiration of Plaintiffs' patents. The complaint states that Lupin filed a Paragraph IV Certification asserting that the patents-in-suit are invalid or will not be infringed by the proposed generic product.

Case Timeline

Date Event
2010-01-28 Priority Date for '707, '831, '796, '797, '887, and '533 Patents
2012-03-20 Priority Date for '908, '568, '021, '384, and '385 Patents
2013-12-17 U.S. Patent No. 8,609,707 Issues
2015-02-13 Cephalon executes an exclusive license from Eagle Pharmaceuticals
2015-04-07 U.S. Patent No. 9,000,021 Issues
2015-05-19 U.S. Patent No. 9,034,908 Issues
2015-09-29 U.S. Patent No. 9,144,568 Issues
2015-10-14 Cephalon assigns its license rights to Teva Pharmaceuticals
2016-02-23 U.S. Patent No. 9,265,831 Issues
2017-02-21 U.S. Patent Nos. 9,572,796, 9,572,797, and 9,572,887 Issue
2017-02-28 U.S. Patent No. 9,579,384 Issues
2017-03-21 U.S. Patent Nos. 9,597,397, 9,597,398, and 9,597,399 Issue
2018-07-03 U.S. Patent No. 10,010,533 Issues
2018-08-21 U.S. Patent No. 10,052,385 Issues
2019-05-21 Lupin sends Paragraph IV Notice Letter to Eagle Pharmaceuticals
2019-07-02 Complaint Filed

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

U.S. Patent No. 8,609,707 - Formulations of Bendamustine

The Invention Explained

  • Problem Addressed: The patent's background describes that bendamustine, the active ingredient in the commercial cancer drug Treanda®, exhibits rapid degradation when its lyophilized (powder) form is reconstituted into a liquid for administration, making it unsuitable for long-term storage in liquid form (Compl., Ex. A, ’707 Patent, col. 1:44-53). Reconstituting the powder is also described as clinically inconvenient (Compl., Ex. A, ’707 Patent, col. 1:55-58).
  • The Patented Solution: The invention provides long-term, storage-stable, non-aqueous liquid compositions of bendamustine by combining the active ingredient with a specific pharmaceutically acceptable fluid and an antioxidant (Compl., Ex. A, ’707 Patent, col. 2:50-57). This approach avoids the need for on-site reconstitution of a powder and is intended to yield a ready-to-use formulation with substantially fewer impurities after extended storage periods (Compl., Ex. A, ’707 Patent, col. 1:58-61, col. 2:11-18).
  • Technical Importance: The development of a stable, ready-to-use liquid formulation of a known but unstable chemotherapy drug offered potential improvements in clinical convenience, safety, and chemical stability over the existing lyophilized powder product (Compl., Ex. A, ’707 Patent, col. 1:55-61).

Key Claims at a Glance

  • The complaint asserts claims of the '707 patent, including independent claim 1 (Compl. ¶51).
  • Essential elements of independent claim 1 (as corrected) include:
    • A long term storage stable non-aqueous liquid bendamustine-containing composition, comprising:
    • bendamustine or a pharmaceutically acceptable salt thereof; and
    • a pharmaceutically acceptable fluid comprising i) about 90% polyethylene glycol and about 10% propylene glycol; and ii) a stabilizing amount of an antioxidant.
  • The complaint does not explicitly reserve the right to assert dependent claims.

U.S. Patent No. 9,265,831 - Formulations of Bendamustine

The Invention Explained

  • Problem Addressed: Similar to the '707 patent, the '831 patent addresses the problem of bendamustine's rapid degradation in aqueous solutions, which makes lyophilized powder formulations that require reconstitution clinically inconvenient and introduces chemical instability (Compl., Ex. B, ’831 Patent, col. 1:47-61).
  • The Patented Solution: The patent discloses a non-aqueous liquid composition designed for long-term storage stability (Compl., Ex. B, ’831 Patent, col. 2:53-60). The solution comprises bendamustine, a fluid containing a specific range of propylene glycol mixed with polyethylene glycol, and a stabilizing antioxidant, which together are intended to limit the formation of degradation impurities over time (Compl., Ex. B, ’831 Patent, col. 2:11-18; Abstract).
  • Technical Importance: This technology provides an alternative stable, liquid formulation for bendamustine, potentially expanding the options for ready-to-use chemotherapy products that avoid the drawbacks of lyophilized powders (Compl., Ex. B, ’831 Patent, col. 1:58-61).

Key Claims at a Glance

  • The complaint asserts claims of the '831 patent, including independent claim 1 (Compl. ¶62).
  • Essential elements of independent claim 1 include:
    • A non-aqueous liquid bendamustine-containing composition, comprising:
    • bendamustine or a pharmaceutically acceptable salt thereof; and
    • a pharmaceutically acceptable fluid comprising: i) about 5% to about 10% by volume propylene glycol, ii) polyethylene glycol, and iii) a stabilizing amount of an antioxidant selected from a specific group.
  • The complaint does not explicitly reserve the right to assert dependent claims.

U.S. Patent No. 9,572,796 - Formulations of Bendamustine

  • Technology Synopsis: This patent, from the same family as the '707 and '831 patents, also addresses the instability of bendamustine in liquid form. It claims a stable, non-aqueous liquid composition containing bendamustine, a fluid with specific ratios of polyethylene glycol (PEG) and propylene glycol (PG), and a stabilizing amount of an antioxidant.
  • Asserted Claims: The complaint asserts claims including independent claim 1 (Compl. ¶73).
  • Accused Features: The complaint alleges that Lupin's ANDA Product, which is a liquid formulation containing bendamustine, PEG, PG, and an antioxidant, infringes the patent (Compl. ¶43, ¶74).

U.S. Patent No. 9,572,797 - Formulations of Bendamustine

  • Technology Synopsis: This patent is directed to methods of treatment using specific bendamustine formulations. It claims methods of treating conditions like leukemia or lymphoma by administering a composition containing bendamustine, a fluid with PEG and PG, and an antioxidant, with specific limitations on the amount of impurities present after storage.
  • Asserted Claims: The complaint asserts claims including independent claim 1 (Compl. ¶84).
  • Accused Features: The complaint alleges that the use of Lupin's ANDA Product as directed by its proposed labeling for treating certain cancers will infringe the method claims (Compl. ¶44, ¶45, ¶87).

U.S. Patent No. 9,034,908 - Formulations of Bendamustine

  • Technology Synopsis: This patent relates to methods of treating bendamustine-responsive conditions by administering a low-volume bendamustine formulation over a short duration. The claimed methods involve administering about 100 ml or less of a composition containing bendamustine, a solubilizer with PEG and PG, and a diluent, over a period of 10 minutes or less.
  • Asserted Claims: The complaint asserts claims including independent claim 1 (Compl. ¶95).
  • Accused Features: The complaint alleges that Lupin's proposed product labeling, which instructs administration in a volume of about 50 mL or less over 10 minutes or less, will induce infringement of these method claims (Compl. ¶46, ¶98).

U.S. Patent No. 9,144,568 - Formulations of Bendamustine

  • Technology Synopsis: This patent is directed to methods of treating bendamustine-responsive conditions with low-volume infusions. It claims methods involving the administration of about 120 ml or less of a liquid composition containing bendamustine, a PEG/PG solubilizer, and a diluent over a short time period to patients with fluid or sodium intake restrictions.
  • Asserted Claims: The complaint asserts claims including independent claim 1 (Compl. ¶106).
  • Accused Features: The complaint alleges that the use of Lupin's proposed low-volume product will infringe, particularly as directed by its labeling (Compl. ¶46, ¶109).

U.S. Patent No. 9,572,887 - Formulations of Bendamustine

  • Technology Synopsis: This patent claims specific liquid compositions of bendamustine with low levels of impurities. The composition comprises bendamustine, a fluid of PEG and PG in certain ratios, and an antioxidant, where the composition has less than a specified percentage of total impurities after storage.
  • Asserted Claims: The complaint asserts claims including independent claim 1 (Compl. ¶117).
  • Accused Features: The complaint alleges Lupin's ANDA Product is a composition that infringes these claims (Compl. ¶43, ¶118).

U.S. Patent Nos. 9,597,397, 9,597,398, and 9,597,399 - Formulations of Bendamustine

  • Technology Synopsis: These three related patents claim methods of treating bendamustine-responsive conditions using low-volume, rapid infusions. The claims cover administering about 100 ml or less of a bendamustine composition containing a PEG/PG solubilizer over a period of about 15 minutes or less.
  • Asserted Claims: The complaint asserts claims including independent claim 1 of each patent (Compl. ¶128, ¶139, ¶150).
  • Accused Features: The complaint alleges Lupin's proposed labeling, instructing administration in about 50 mL over 10 minutes, will induce infringement of these method claims (Compl. ¶46, ¶131, ¶142, ¶153).

U.S. Patent No. 9,000,021 - Method of Treating Bendamustine-Responsive Conditions in Patients Requiring Reduced Volumes for Administration

  • Technology Synopsis: This patent claims methods for treating bendamustine-responsive conditions in patients with fluid and/or sodium intake restrictions. It involves administering a low volume (about 120 ml or less) of a bendamustine composition containing a PEG/PG solubilizer.
  • Asserted Claims: The complaint asserts claims including independent claim 1 (Compl. ¶161).
  • Accused Features: The use of Lupin's proposed low-volume product, as directed by its labeling, is alleged to infringe these method claims (Compl. ¶46, ¶164).

U.S. Patent No. 9,579,384 - Method of Treating Bendamustine-Responsive Conditions in Patients Requiring Reduced Volumes for Administration

  • Technology Synopsis: This patent claims methods of treating bendamustine-responsive conditions by administering a composition comprising specific concentrations of bendamustine, PEG, PG, and an antioxidant in a low volume (about 120 ml or less) over a short period.
  • Asserted Claims: The complaint asserts claims including independent claim 1 (Compl. ¶172).
  • Accused Features: The complaint alleges that use of Lupin's proposed low-volume product as directed by its labeling infringes the claimed methods (Compl. ¶46, ¶175).

U.S. Patent No. 10,010,533 - Formulations of Bendamustine

  • Technology Synopsis: This patent claims liquid bendamustine compositions with specific impurity profiles. The composition includes bendamustine, a fluid with about 5% to 10% PG and PEG, and an antioxidant, characterized by having less than a certain percentage of propylene glycol esters after storage.
  • Asserted Claims: The complaint asserts claims including independent claim 1 (Compl. ¶183).
  • Accused Features: The complaint alleges Lupin's ANDA Product is a composition that infringes these claims (Compl. ¶43, ¶184).

U.S. Patent No. 10,052,385 - Formulations of Bendamustine

  • Technology Synopsis: This patent claims methods of treatment using small-volume bendamustine infusions. The claims cover administering about 100 ml or less of a liquid composition comprising specified concentrations of bendamustine, a nonaqueous component, and a diluent, over a short time period.
  • Asserted Claims: The complaint asserts claims including independent claim 1 (Compl. ¶194).
  • Accused Features: The complaint alleges that use of Lupin's proposed low-volume product as directed by its labeling infringes these method claims (Compl. ¶46, ¶197).

III. The Accused Instrumentality

Product Identification

  • Lupin's Abbreviated New Drug Application ("ANDA") Product, which is a generic version of BENDEKA® (bendamustine hydrochloride) Injection, 100 mg/4 mL, with a proposed dosage strength of 25 mg/mL (Compl. ¶1, ¶42).

Functionality and Market Context

  • The accused product is a liquid pharmaceutical formulation intended for intravenous administration to treat chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma (Compl. ¶44-45). The complaint alleges, on information and belief, that the formulation contains bendamustine hydrochloride, propylene glycol, polyethylene glycol, and the antioxidant monothioglycerol (Compl. ¶41, ¶43). The proposed labeling for the product allegedly recommends, instructs, and/or promotes administration in a small volume of about 50 mL or less over a time period of 10 minutes or less (Compl. ¶46). The product is the subject of an ANDA, indicating Lupin seeks to market it as a generic equivalent to the branded BENDEKA® drug prior to the expiration of the patents-in-suit (Compl. ¶39-40).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

8,609,707 Patent Infringement Allegations

Claim Element (from Independent Claim 1, as corrected) Alleged Infringing Functionality Complaint Citation Patent Citation
A long term storage stable non-aqueous liquid bendamustine-containing composition... The accused ANDA Product is a non-aqueous liquid formulation of bendamustine hydrochloride. ¶41, ¶43 col. 2:50-51
...comprising: a) bendamustine or a pharmaceutically acceptable salt thereof... The active ingredient of the accused ANDA Product is bendamustine hydrochloride. ¶41 col. 2:52-53
...and b) a pharmaceutically acceptable fluid comprising i) about 90% polyethylene glycol and about 10% propylene glycol... The accused ANDA Product contains polyethylene glycol and propylene glycol. ¶43 col. 3:30-45
...and ii) a stabilizing amount of an antioxidant. The accused ANDA Product contains monothioglycerol, which is an antioxidant. ¶43 col. 3:57-60
  • Identified Points of Contention:
    • Scope Questions: A central question may be whether the term "about," as used in "about 90% polyethylene glycol and about 10% propylene glycol," encompasses the specific concentrations of these components in Lupin's ANDA product. The definition of "stabilizing amount of an antioxidant" may also be disputed, raising the question of whether the amount of monothioglycerol in the accused product performs the claimed stabilizing function.
    • Technical Questions: The complaint alleges the components are present in the "same or equivalent amounts" as BENDEKA® (Compl. ¶43). A key factual question will be what those amounts are in Lupin's actual formulation and whether they meet the claim limitations literally or under the doctrine of equivalents.

9,265,831 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A non-aqueous liquid bendamustine-containing composition, comprising: The accused ANDA Product is a non-aqueous liquid formulation. ¶43 col. 4:60-61
a) bendamustine or a pharmaceutically acceptable salt thereof; and The active ingredient of the accused ANDA Product is bendamustine hydrochloride. ¶41 col. 4:62-63
b) a pharmaceutically acceptable fluid comprising; i) about 5% to about 10% by volume propylene glycol... The accused ANDA Product contains propylene glycol. ¶43 col. 3:30-34
...ii) polyethylene glycol... The accused ANDA Product contains polyethylene glycol. ¶43 col. 3:30-34
...and iii) a stabilizing amount of an antioxidant selected from the group consisting of thioglycerol, monothioglycerol... The accused ANDA Product contains monothioglycerol, which is an antioxidant listed in the claim. ¶43 col. 4:9-16
  • Identified Points of Contention:
    • Scope Questions: Similar to the '707 patent, the term "about" in the range "about 5% to about 10% by volume propylene glycol" will likely be a point of contention. The analysis will question whether the precise percentage of propylene glycol in Lupin's product falls within the scope of this claimed range.
    • Technical Questions: The complaint does not provide the specific percentage of propylene glycol in the accused product. Discovery will be required to establish the exact composition of Lupin's ANDA product to determine if it meets this quantitative limitation.

V. Key Claim Terms for Construction

  • The Term: "stabilizing amount of an antioxidant" (from '707 Patent, Claim 1)
  • Context and Importance: This term is critical because infringement requires the presence of an antioxidant in an amount that performs a "stabilizing" function. Practitioners may focus on this term because the parties will likely dispute whether the quantity of monothioglycerol in Lupin's product is sufficient to meet this functional requirement, or if it is present for other reasons.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification states that "stabilizing amount" shall be understood to include "those amounts which increase or enhance the stability of the bendamustine in the compositions described herein" ('707 Patent, col. 3:60-64). This functional language could support a broad reading where any measurable increase in stability suffices.
    • Evidence for a Narrower Interpretation: The specification provides specific concentration ranges for suitable antioxidants, such as "from about 2.5 mg/mL to about 35 mg/mL" ('707 Patent, col. 3:65-col. 4:1). A defendant may argue that a "stabilizing amount" must fall within or be commensurate with the exemplary ranges disclosed in the patent's detailed description.
  • The Term: "about 5% to about 10% by volume propylene glycol" (from '831 Patent, Claim 1)
  • Context and Importance: This quantitative limitation is a core element of the asserted composition claim. The infringement analysis for the '831 patent will turn on whether the concentration of propylene glycol in Lupin's product falls within the scope of this range, making the definition of "about" highly dispositive.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The term "about" is used throughout the patent when describing component ratios (e.g., "about 95:5 to about 50:50" for PEG:PG ratios) ('831 Patent, col. 3:39-40), suggesting the patentee intended some flexibility beyond the precise numerical values stated, consistent with the general understanding of the term in patent law.
    • Evidence for a Narrower Interpretation: The patent provides numerous specific working examples with precise percentages, such as Example 5, which details formulations with 10%, 25%, and 50% propylene glycol ('831 Patent, Table 5). A defendant may argue that "about" should be interpreted narrowly in light of these specific examples and should not be expanded to cover formulations that are materially different from those explicitly disclosed and tested.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges active inducement of infringement against Lupin, asserting that Lupin's proposed product labeling will recommend, instruct, and promote the administration of its ANDA product in a manner that directly infringes the asserted method patents (Compl. ¶55, ¶88, ¶99). The complaint also pleads contributory infringement, alleging that Lupin's product and its labeling are especially made or adapted for infringing the patents and are not suitable for substantial noninfringing use (Compl. ¶56, ¶89, ¶100).
  • Willful Infringement: The complaint alleges that Lupin has acted with full knowledge of the patents-in-suit and without a reasonable basis for believing it would not be liable for infringement (Compl. ¶58, ¶69, ¶80). This allegation is based on Lupin's filing of a Paragraph IV certification and its pre-suit notice letter, which Plaintiffs contend establish pre-suit knowledge of the patents and the alleged infringement.

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

  • A core issue will be one of quantitative scope: does the term "about," as applied to the claimed percentages of polyethylene glycol and propylene glycol in the asserted composition claims, encompass the precise concentrations used in Lupin's proposed generic formulation? The outcome of the literal infringement analysis for several patents will likely depend on the construction of this single term.
  • A central validity question, though not detailed in the complaint, will be obviousness: can Lupin demonstrate with clear and convincing evidence that a person of ordinary skill in the art would have been motivated to combine the known elements of bendamustine, a PEG/PG solvent system, and an antioxidant to arrive at the claimed stable, low-volume formulations with a reasonable expectation of success?
  • A key evidentiary question for the method claims will be one of induced infringement: does Lupin's proposed product label provide sufficient instruction and encouragement to healthcare professionals to administer the generic product in a way that practices all steps of the claimed methods, thereby demonstrating Lupin's specific intent to induce infringement?