DCT

1:17-cv-01790

Teva Pharma Intl GmbH v. Mylan Laboratories Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:17-cv-01790, D. Del., 12/12/2017
  • Venue Allegations: Venue is alleged to be proper because Mylan is a foreign company that may be sued in any judicial district where it is subject to personal jurisdiction. The complaint asserts personal jurisdiction based on Mylan's filing of an Abbreviated New Drug Application (ANDA) with intent to market its generic product in Delaware, its persistent course of conduct in placing goods into the U.S. stream of commerce, and its previous consent to jurisdiction in Delaware in prior ANDA-related cases.
  • Core Dispute: Plaintiffs allege that Defendant's submission of an ANDA to the FDA seeking approval to market a generic version of BENDEKA® (bendamustine hydrochloride) Injection constitutes an act of infringement of fifteen U.S. patents related to bendamustine compositions and methods of treatment.
  • Technical Context: The dispute centers on formulations of bendamustine, an alkylating drug used to treat chronic lymphocytic leukemia and non-Hodgkin lymphoma, which is historically unstable in aqueous solutions.
  • Key Procedural History: The lawsuit was triggered by a Paragraph IV Certification Notice Letter dated October 30, 2017, in which Mylan notified Plaintiffs of its ANDA filing and asserted that the Orange Book-listed patents would not be infringed or are invalid. The complaint notes that Mylan did not contest that its ANDA product is covered by at least some claims of the asserted patents.

Case Timeline

Date Event
2005-01-14 Earliest Priority Date ('270 Patent)
2010-01-28 Earliest Priority Date ('707, '831, '908, '021, '796, '797, '568, '887, '397, '398, '399, '384 Patents)
2013-12-17 U.S. Patent No. 8,609,707 Issues
2014-07-29 U.S. Patent No. 8,791,270 Issues
2015-02-13 Cephalon executes an exclusive license from Eagle for multiple patents-in-suit
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
2017-10-30 Mylan sends Paragraph IV Notice Letter to Teva and Eagle
2017-12-12 Complaint Filed

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

U.S. Patent No. 8,791,270 - "Bendamustine Pharmaceutical Compositions"

The Invention Explained

  • Problem Addressed: The patent describes that bendamustine, a nitrogen mustard drug, is unstable in aqueous solutions and is therefore supplied as a lyophilized (freeze-dried) powder. This lyophilized product is reportedly difficult and time-consuming for clinicians to reconstitute, requiring up to thirty minutes, which increases the risk of drug degradation due to water exposure ('270 Patent, col. 2:9-52).
  • The Patented Solution: The invention claims pharmaceutical compositions of bendamustine produced through a lyophilization process that uses an organic co-solvent, such as tertiary-butyl alcohol (TBA). This process results in a lyophilized product with specific, low levels of impurities (such as the hydrolysis product HP1) that is more stable and easier for clinicians to reconstitute than prior formulations ('270 Patent, col. 3:19-40; col. 5:1-9). The patent includes figures illustrating the improved solubility and stability profile achieved with alcohol/water co-solvents (e.g., '270 Patent, FIG. 1-4).
  • Technical Importance: This approach sought to improve the clinical utility and safety profile of bendamustine by creating a more stable and convenient-to-use formulation, reducing preparation time and minimizing degradation before administration ('270 Patent, col. 2:42-52).

Key Claims at a Glance

  • The complaint identifies independent claim 7 in its request for declaratory judgment (Compl. ¶193).
  • Claim 7:
    • A pharmaceutical composition of bendamustine hydrochloride,
    • containing less than or equal to 4.0% (area percent of bendamustine) of bendamustine degradants.
  • The complaint alleges infringement of "one or more claims" generally and reserves the right to assert other claims (Compl. ¶50).

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

The Invention Explained

  • Problem Addressed: The patent addresses the same core problem as the ’270 Patent: the instability of bendamustine in aqueous solutions, which necessitates inconvenient lyophilized formulations that are difficult to store and prepare for administration ('707 Patent, col. 2:47-54).
  • The Patented Solution: Rather than improving the lyophilization process, this invention provides a non-aqueous liquid formulation that is stable for long-term storage. The solution comprises bendamustine in a fluid containing polyethylene glycol (PEG), propylene glycol (PG), and a stabilizing antioxidant. This creates a "ready to use" formulation that avoids the need for reconstitution entirely ('707 Patent, Abstract; col. 2:50-58).
  • Technical Importance: This technology provided a path to a ready-to-use liquid bendamustine product, potentially eliminating the reconstitution step, improving long-term stability, and enhancing clinical convenience ('707 Patent, col. 2:5-12).

Key Claims at a Glance

  • The complaint identifies independent claim 1 as a claim that Mylan did not contest coverage of in its Notice Letter (Compl. ¶60, ¶206).
  • Claim 1:
    • A long term storage stable non-aqueous liquid bendamustine-containing composition, comprising:
    • a) bendamustine or a pharmaceutically acceptable salt thereof; and
    • b) 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 alleges infringement of "one or more claims" and reserves the right to assert others (Compl. ¶61).

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

  • Technology Synopsis: This patent is related to the ’707 Patent and describes long-term storage stable, non-aqueous liquid formulations of bendamustine. The solution claims a specific ratio of polyethylene glycol to propylene glycol and an antioxidant, designed to enhance stability and avoid the need for reconstitution.
  • Asserted Claims: The complaint identifies independent claim 1 (Compl. ¶71).
  • Accused Features: The composition of Mylan’s ANDA Product, specifically its alleged inclusion of bendamustine HCl, polyethylene glycol, propylene glycol, and an antioxidant (monothioglycerol), is accused of infringement (Compl. ¶¶36, 38).

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

  • Technology Synopsis: This patent is also related to the ’707 Patent family and covers long-term stable, non-aqueous liquid bendamustine compositions. It claims specific formulations containing bendamustine, a fluid of PEG and PG, and an antioxidant, aimed at providing a ready-to-use product.
  • Asserted Claims: The complaint identifies independent claim 1 (Compl. ¶82).
  • Accused Features: The formulation of Mylan’s ANDA Product, including its alleged active ingredient and excipients (polyethylene glycol, propylene glycol, monothioglycerol), is accused of infringement (Compl. ¶¶36, 38).

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

  • Technology Synopsis: Continuing in the ’707 Patent family, this patent claims long-term stable, non-aqueous liquid bendamustine compositions. The invention focuses on specific combinations of solvents (PEG, PG) and an antioxidant to create a stable, ready-to-use injectable product.
  • Asserted Claims: The complaint identifies independent claim 1 (Compl. ¶93).
  • Accused Features: The formulation of Mylan’s ANDA Product is accused of infringement based on its alleged composition of bendamustine HCl, polyethylene glycol, propylene glycol, and monothioglycerol (Compl. ¶¶36, 38).

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

  • Technology Synopsis: This patent relates to methods of treating bendamustine-responsive conditions by administering small-volume infusions (less than or equal to 325 ml) of bendamustine. The claimed method utilizes specific liquid formulations containing PEG and PG to enable administration in reduced volumes over shorter time periods.
  • Asserted Claims: The complaint identifies claim 1 as covering the use directed by Mylan’s proposed labeling (Compl. ¶104).
  • Accused Features: The proposed labeling for Mylan’s ANDA Product, which allegedly instructs administration in a volume of about 50 mL or less over a 10-minute period, is accused of infringing the claimed method (Compl. ¶43).

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

  • Technology Synopsis: This patent is directed to methods of treating bendamustine-responsive conditions using specific bendamustine formulations administered in small volumes (e.g., 100 ml or less). The formulation contains bendamustine in a solubilizer of PEG and PG, enabling rapid infusion.
  • Asserted Claims: The complaint identifies claim 1 as covering the use directed by Mylan’s proposed labeling (Compl. ¶115).
  • Accused Features: Mylan’s proposed labeling, which allegedly recommends administration in a volume of about 50 mL or less, is accused of infringing the claimed method of treatment (Compl. ¶43).

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

  • Technology Synopsis: This patent claims specific, stable, non-aqueous liquid formulations of bendamustine. The claimed composition includes bendamustine, a mixture of PEG and PG as a fluid, and an antioxidant, providing a ready-to-use formulation.
  • Asserted Claims: The complaint identifies independent claim 1 (Compl. ¶126).
  • Accused Features: The composition of Mylan's ANDA Product, with its alleged ingredients of bendamustine HCl, PEG, PG, and monothioglycerol, is accused of infringement (Compl. ¶¶36, 38).

U.S. Patent No. 9,597,397 - "Formulations of Bendamustine"

  • Technology Synopsis: This patent is directed to methods of treating cancer by administering a specific non-aqueous liquid bendamustine composition. The claimed method involves administering a formulation containing bendamustine, propylene glycol, polyethylene glycol, and an antioxidant.
  • Asserted Claims: The complaint identifies claim 1 as covering the use directed by Mylan’s proposed labeling (Compl. ¶137).
  • Accused Features: The instructions in Mylan's proposed labeling are alleged to induce infringement of the claimed method of treatment by directing use of the accused formulation (Compl. ¶¶39-43).

U.S. Patent No. 9,597,398 - "Formulations of Bendamustine"

  • Technology Synopsis: This patent claims methods of treating cancer by administering a bendamustine composition in a small volume (100 ml or less) over a short period (15 minutes or less). The method utilizes a liquid formulation containing bendamustine dissolved in a non-aqueous solubilizer.
  • Asserted Claims: The complaint identifies claim 1 as covering the use directed by Mylan’s proposed labeling (Compl. ¶148).
  • Accused Features: The instructions in Mylan’s proposed labeling, which allegedly recommend administration in a volume of about 50 mL or less over 10 minutes, are accused of inducing infringement of the claimed method (Compl. ¶43).

U.S. Patent No. 9,597,399 - "Formulations of Bendamustine"

  • Technology Synopsis: This patent covers methods of treating cancer using a bendamustine composition comprising specific concentrations of bendamustine, PEG, PG, and an antioxidant. The claimed method specifies administering this particular formulation to a patient.
  • Asserted Claims: The complaint identifies claim 1 as covering the use directed by Mylan’s proposed labeling (Compl. ¶159).
  • Accused Features: The use of Mylan's ANDA product, as directed by its proposed labeling, is alleged to infringe the claimed treatment method (Compl. ¶¶39-43).

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 of treating bendamustine-responsive conditions in patients who require restricted fluid or sodium intake. The method involves administering a small volume (about 120 ml or less) of a bendamustine composition containing PEG and PG solubilizers.
  • Asserted Claims: Although not specified by number, the complaint's allegations in Count XII map to the method claims of the patent (Compl. ¶¶168-178).
  • Accused Features: The alleged instructions in Mylan's proposed labeling to administer a small volume (about 50 mL) of the drug product are accused of inducing infringement of this method of treatment (Compl. ¶43).

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

  • Technology Synopsis: Similar to the ’021 Patent, this patent covers methods for treating patients requiring reduced administration volumes. The claimed method involves administering a small volume of a specific bendamustine formulation containing PEG and PG over a short time period.
  • Asserted Claims: The complaint identifies claim 1 as covering the use directed by Mylan’s proposed labeling (Compl. ¶181).
  • Accused Features: Mylan’s proposed labeling, which allegedly instructs for administration in a volume of about 50 mL over 10 minutes, is accused of inducing infringement (Compl. ¶43).

III. The Accused Instrumentality

Product Identification

"Mylan’s ANDA Product," identified as a generic Bendamustine Hydrochloride Injection, 100 mg/4 mL, with a proposed dosage strength of 25 mg/mL (Compl. ¶33, ¶37).

Functionality and Market Context

  • The accused product is a generic version of the branded drug BENDEKA® and is intended for use in treating chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma (Compl. ¶16, ¶33, ¶39, ¶41).
  • The complaint alleges, upon information and belief, that the accused product is a liquid formulation containing bendamustine hydrochloride as the active ingredient, along with propylene glycol, polyethylene glycol, and monothioglycerol as excipients (Compl. ¶36, ¶38).
  • The proposed labeling for Mylan’s product allegedly recommends, instructs, and/or promotes administration in a volume of about 50 mL or less over a 10-minute period (Compl. ¶43).
    No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

U.S. Patent No. 8,791,270 Infringement Allegations

The complaint does not provide a detailed claim chart or specific mapping of the accused product to the elements of any claim of the ’270 Patent. It alleges generally that the manufacture, use, or sale of Mylan’s ANDA Product would infringe one or more claims (Compl. ¶50). The complaint notes that in its Notice Letter, Mylan did not contest that claim 7 would cover its product (Compl. ¶49, ¶193). The infringement theory appears to rest on the final composition of Mylan's product meeting the purity limitations of claim 7, regardless of the manufacturing process used.

Identified Points of Contention

  • Scope Questions: A central question may be whether claims directed to a composition "reconstituted from a lyophilized preparation" (e.g., claim 1) can be asserted against a product that is allegedly a stable liquid formulation that does not require lyophilization or reconstitution. The complaint's focus on claim 7, which omits this "reconstituted from" language, may be an attempt to address this potential mismatch.
  • Technical Questions: What evidence does the complaint provide that Mylan's ANDA Product, a liquid formulation, is produced in a way that implicates a patent on lyophilization, or alternatively, that it meets the specific "bendamustine degradants" profile claimed in claim 7? The complaint does not specify the level of degradants in Mylan's product.

U.S. Patent No. 8,609,707 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A long term storage stable non-aqueous liquid bendamustine-containing composition, comprising: Mylan’s ANDA Product is a liquid Bendamustine Hydrochloride Injection. ¶33 col. 13:7-9
a) bendamustine or a pharmaceutically acceptable salt thereof, The active ingredient of Mylan's ANDA Product is alleged to be bendamustine hydrochloride. ¶36 col. 13:10-11
and b) a pharmaceutically acceptable fluid comprising i) about 90% polyethylene glycol and about 10% propylene glycol; Mylan’s ANDA Product is alleged to contain polyethylene glycol and propylene glycol. ¶38 col. 13:12-14
and ii) a stabilizing amount of an antioxidant. Mylan’s ANDA Product is alleged to contain monothioglycerol, which the patent specification identifies as an antioxidant. ¶38 col. 3:1-4

Identified Points of Contention

  • Scope Questions: The infringement analysis may turn on the meaning of "about 90%" and "about 10%." The complaint alleges Mylan’s product contains these components in the "same or equivalent amounts as BENDEKA®" (Compl. ¶38), which raises the factual question of whether those amounts fall within the scope of the claim terms.
  • Technical Questions: Does the monothioglycerol in the accused product function as a "stabilizing amount of an antioxidant" as required by the claim? The patent defines "stabilizing amount" as an amount that increases or enhances stability ('707 Patent, col. 3:49-52).

V. Key Claim Terms for Construction

For the ’270 Patent

  • The Term: "bendamustine degradants" (Claim 7)
  • Context and Importance: The scope of this term is central to infringement, as the claim requires the total amount of these degradants to be below a 4.0% threshold. Practitioners may focus on whether this term is limited to specific hydrolysis products mentioned in the specification (like HP1 and HP2) or if it covers any and all degradation products of bendamustine.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The plain language of the term suggests it covers all substances resulting from the degradation of bendamustine.
    • Evidence for a Narrower Interpretation: The specification primarily discusses specific hydrolysis byproducts like HP1 (monohydroxy bendamustine) and bendamustine dimer as the key impurities to be controlled ('270 Patent, col. 3:50-55; col. 4:21-23). A defendant may argue the term should be limited to these disclosed examples.

For the ’707 Patent

  • The Term: "about 90% polyethylene glycol and about 10% propylene glycol" (Claim 1)
  • Context and Importance: This term is critical, as infringement will depend on whether the specific ratio of excipients in Mylan’s product falls within its scope. The meaning of "about" will define the permissible range of deviation from the 90/10 ratio.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The use of "about" suggests the patentee did not intend to be limited to the exact 90/10 ratio. The specification describes various ratios, including 95:5 and 50:50, which may support an argument that the claims are not narrowly confined to the specific 90:10 example ('707 Patent, col. 3:29-38).
    • Evidence for a Narrower Interpretation: The claim explicitly recites the 90/10 ratio, distinguishing it from other ratios disclosed in the specification. A defendant may argue that "about" only accounts for minor experimental variance and does not extend to encompass other disclosed but unclaimed ratios like 85:15 or 75:25.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges active inducement for all asserted patents. The basis is Mylan’s proposed product labeling, which allegedly instructs and encourages medical professionals to administer the accused product in a manner that directly infringes the claims, particularly the method-of-use claims (e.g., Compl. ¶53, ¶64, ¶108). The complaint also alleges contributory infringement, stating Mylan knows its product is especially made for an infringing use and is not suitable for substantial noninfringing use (e.g., Compl. ¶54, ¶65).
  • Willful Infringement: The complaint alleges that Mylan acted with "full knowledge" of the patents-in-suit and "without a reasonable basis for believing that it would not be liable for infringing" (e.g., Compl. ¶56, ¶67). The basis for this knowledge appears to be the Paragraph IV Notice Letter sent by Mylan to the Plaintiffs prior to the suit (Compl. ¶33).

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

  • A core issue will be one of technological mismatch: can the claims of the '270 Patent family, which are rooted in an invention for an improved lyophilized product, be successfully asserted against Mylan's product, which is alleged to be a stable liquid formulation that seemingly does not require lyophilization? The viability of claims that omit process-specific language (like claim 7 of the '270 patent) will be central to this question.
  • A key evidentiary question will be one of compositional scope: for the '707 patent family, does the specific formulation of Mylan's ANDA Product, particularly its ratio of polyethylene glycol to propylene glycol, fall within the scope of the term "about 90% ... and about 10%" as recited in the claims? The construction of "about" and the factual evidence regarding the accused product's precise composition will likely be dispositive.
  • A third central question will be one of induced infringement for methods of administration: for the patents claiming methods of administering small-volume infusions, does Mylan's proposed product label contain instructions that are specific enough to actively encourage or instruct clinicians to perform all the steps of the claimed methods, thereby creating liability for indirect infringement?