Teva Pharma Intl GmbH v. Fresenius Kabi USA LLC

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Teva Pharmaceuticals International GmbH (Switzerland), Cephalon, Inc. (Delaware), and Eagle Pharmaceuticals, Inc. (Delaware)
  • Defendant: Fresenius Kabi USA, LLC (Delaware) and Mylan Laboratories Ltd. (India)
  • Plaintiff’s Counsel: Shaw Keller LLP (representing all Plaintiffs); Williams & Connolly LLP and Latham & Watkins LLP (Of Counsel)
• Case Identification: 1:18-cv-01586, D. Del., 10/15/2018
• Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant Fresenius Kabi is incorporated in Delaware, and Defendant Mylan is a foreign company subject to personal jurisdiction in the district.
• Core Dispute: Plaintiffs allege that Defendants' proposed generic versions of the cancer drug BENDEKA®, for which they have filed Abbreviated New Drug Applications (ANDAs) with the FDA, will infringe two patents covering stable, ready-to-use formulations and methods of administering bendamustine hydrochloride.
• Technical Context: The patents relate to liquid formulations of the alkylating drug bendamustine, used to treat certain leukemias and lymphomas, which are designed to overcome the chemical instability of the drug in aqueous solutions and allow for administration in smaller volumes over shorter infusion times.
• Key Procedural History: The action was triggered by Defendants Fresenius Kabi and Mylan filing ANDAs with Paragraph IV certifications, asserting that their proposed generic products would not infringe the patents-in-suit or that the patents are invalid. Plaintiffs are exercising their rights under the Hatch-Waxman Act to sue for infringement based on these ANDA filings. The complaint also notes that Plaintiff Eagle granted an exclusive license to Cephalon, which was subsequently assigned to Teva Pharmaceuticals, covering the patents-in-suit.

Case Timeline

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

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

• Issued: July 3, 2018

The Invention Explained

• Problem Addressed: The patent describes that bendamustine is unstable in water and degrades rapidly, which makes long-term storage in liquid form unsuitable. Commercially available products at the time were lyophilized (freeze-dried) powders that required inconvenient and time-consuming reconstitution before administration, introducing risks of chemical instability (’533 Patent, col. 1:36-60).
• The Patented Solution: The invention provides a long-term, storage-stable liquid formulation of bendamustine that is "ready to use" or ready for dilution, avoiding the need for reconstitution. This is achieved by dissolving bendamustine in a non-aqueous, pharmaceutically acceptable fluid, specifically a mixture of polyethylene glycol (PEG) and propylene glycol (PG), and adding a stabilizing amount of an antioxidant, such as thioglycerol (’533 Patent, Abstract; col. 2:59-col. 3:5).
• Technical Importance: This approach provides a clinically more convenient product that enhances stability and simplifies the administration process for a known, but difficult-to-formulate, chemotherapy agent (’533 Patent, col. 1:55-60).

Key Claims at a Glance

• The complaint asserts "one or more claims" of the patent (Compl. ¶50). Independent claim 1 is representative of the composition claims.
• The essential elements of independent claim 1 include:
  • A liquid bendamustine-containing composition comprising bendamustine or a salt thereof;
  • A pharmaceutically acceptable fluid comprising about 5% to about 10% propylene glycol and polyethylene glycol, where the PEG:PG ratio is selected from a group including 95:5, 90:10, 85:15, 80:20, and 75:25;
  • A stabilizing amount of an antioxidant selected from a specified list that includes thioglycerol and monothioglycerol; and
  • The composition has less than or equal to 0.11% total propylene glycol (PG) esters after one month of storage at about 5° C.
• The complaint implicitly reserves the right to assert other claims, including dependent claims.

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

• Issued: August 21, 2018

The Invention Explained

• Problem Addressed: The patent notes that existing bendamustine treatments require dilution into large infusion volumes (e.g., 500 mL) and administration over long periods (30-60 minutes). This is due to the drug's limited solubility and the need to minimize side effects at the injection site. These large volumes and long infusion times are inconvenient for patients and healthcare providers (’385 Patent, col. 3:25-45).
• The Patented Solution: The invention is a method for treating cancer by administering bendamustine in a much smaller volume (e.g., about 100 mL or less) over a significantly shorter time (e.g., about 15 minutes or less). This is made possible by a specific formulation using a nonaqueous solubilizer (a PEG and PG blend) that maintains the drug's solubility at higher concentrations, preventing precipitation during administration in smaller diluent volumes (’385 Patent, col. 3:49-col. 4:15).
• Technical Importance: This method improves the quality of life for patients by reducing time spent in infusion clinics and decreases the administrative burden on healthcare facilities (’385 Patent, col. 3:55-64).

Key Claims at a Glance

• The complaint asserts "one or more claims" of the patent (Compl. ¶60). Independent claim 1 is representative of the method claims.
• The essential elements of independent claim 1 include:
  • A method of treating chronic lymphocytic leukemia or indolent B-cell non-Hodgkin's lymphoma;
  • Parenterally administering to a subject, over a period of less than or equal to about 15 minutes;
  • About 100 mL or less of a liquid composition comprising;
  • A specific concentration of bendamustine (0.96-5.59 mg/mL);
  • A specific volume percentage of a nonaqueous component (3.8-22.4 vol %) comprising PEG and PG;
  • A parenterally acceptable diluent; and
  • Optionally an antioxidant.
• The complaint implicitly reserves the right to assert other claims, including dependent claims.

III. The Accused Instrumentality

Product Identification

• The accused instrumentalities are the generic bendamustine hydrochloride injection products for which Defendants Fresenius Kabi and Mylan filed ANDA No. 210410 and ANDA No. 210827, respectively (Compl. ¶1).

Functionality and Market Context

• The complaint alleges that Defendants' ANDA products are generic versions of Plaintiffs' BENDEKA® product, containing bendamustine hydrochloride at a proposed dosage strength of 25 mg/mL (Compl. ¶¶34, 43).
• The products are alleged to contain the same or equivalent key non-active ingredients as BENDEKA®, specifically propylene glycol, polyethylene glycol, and monothioglycerol (Compl. ¶¶35, 44).
• Critically, the complaint alleges that the proposed labeling for the ANDA products instructs administration in a volume of "about 50 mL or less over a 10-minute period" for the treatment of chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma (Compl. ¶¶36-38, 45-47).
• The commercial context is an attempt by generic drug manufacturers to market a bioequivalent version of a branded drug prior to the expiration of patents listed in the FDA's Orange Book for that drug (Compl. ¶¶1, 26-27).
• No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

’533 Patent Infringement Allegations

’385 Patent Infringement Allegations

Identified Points of Contention

• Scope Questions: For the ’533 Patent, a potential point of dispute is whether the precise formulation of the ANDA products meets the specific claimed ratios of PEG to PG and the functional limitation on impurity levels (e.g., less than 0.11% PG esters). The complaint's allegation is based on "information and belief," which will require factual development.
• Technical Questions: For the ’385 Patent, the infringement case appears to hinge on the content of the Defendants' proposed drug labels. A key question for the court will be whether the instructions on the label are sufficient to prove that Defendants will induce medical professionals to perform the patented method. The allegation that the label recommends a 50 mL/10-minute infusion seems to map directly onto the claim limitations.

V. Key Claim Terms for Construction

For the ’533 Patent

• The Term: "stabilizing amount" (of an antioxidant)
• Context and Importance: This term is a functional limitation that defines a required characteristic of the antioxidant component. The infringement analysis depends on whether the amount of monothioglycerol in the accused products performs the claimed stabilizing function. Practitioners may focus on this term because its construction will determine the breadth of the claim and whether a specific quantity of antioxidant, which might otherwise be considered a standard amount, falls within the patent's scope.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The specification defines "stabilizing amount" functionally as "those amounts which increase or enhance the stability of the bendamustine in the compositions described herein" (’533 Patent, col. 5:60-63). This suggests any amount that provides a measurable stability benefit could be infringing.
  • Evidence for a Narrower Interpretation: The patent also provides specific exemplary concentration ranges, such as "from about 2.5 mg/mL to about 35 mg/mL" (’533 Patent, col. 4:1-2). A defendant may argue that these specific embodiments should guide the interpretation of the term, limiting it to such ranges.

For the ’385 Patent

• The Term: "about" (as in "about 15 minutes" and "about 100 ml")
• Context and Importance: This term defines the boundaries of the claimed administration time and volume. Its construction is critical because it determines whether an administration protocol that deviates slightly from the exact numbers on the proposed label still constitutes infringement.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: Generally, "about" is used to afford some flexibility beyond the precise number stated. Parties might argue it should be interpreted in light of the understanding of one of skill in the art.
  • Evidence for a Narrower Interpretation: The specification provides an explicit definition: "the word 'about' when used to modify infusion volumes or concentrations shall be understood to include values which may vary by amounts of about +/-10% or 15%" (’385 Patent, col. 4:51-54). This express definition provides very strong intrinsic evidence that will likely be adopted by the court, creating a clear, numerical boundary for the claim scope.

VI. Other Allegations

Indirect Infringement

• The complaint alleges both induced and contributory infringement against both defendants for both patents. The inducement allegation is primarily based on the assertion that the Defendants' proposed product labeling "recommends, instructs, and/or promotes" the infringing use of the formulations and methods (Compl. ¶¶36-38, 53, 63, 97, 107). The contributory infringement allegation is based on the claim that the ANDA products are "especially made or adapted for use in infringing" the patents and are "not suitable for substantial noninfringing use" (Compl. ¶¶54, 64, 98, 108).

Willful Infringement

• The complaint alleges that Defendants have acted with "full knowledge" of the patents-in-suit and "without a reasonable basis for believing" they would not be liable for infringement (Compl. ¶¶56, 66, 100, 110). This allegation is supported by the fact that Defendants sent Paragraph IV Notice Letters to Plaintiffs, which serves as direct evidence of pre-suit knowledge of the patents.

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

• A central issue will be one of validity, particularly obviousness: Given that bendamustine's instability was known, a key question for the court will be whether combining it with a known class of non-aqueous solubilizers (PEG/PG) and a known class of antioxidants to create a stable, ready-to-use formulation, as claimed in the ’533 Patent, would have been obvious to a person of ordinary skill in pharmaceutical formulation at the time of the invention.
• A second core issue is one of induced infringement based on labeling: For the ’385 method patent, the case will likely turn on whether the instructions in the Defendants' proposed drug labels are sufficient to prove that they will inevitably induce healthcare providers to administer the generic drug using the patented low-volume, short-duration method.
• Finally, a key evidentiary question will concern the exact product composition: While the case is at the pleading stage, discovery will focus on whether the precise concentrations and ratios of excipients in the Defendants' ANDA products fall within the literal scope of the ’533 Patent's claims, or if Plaintiffs will need to argue infringement under the doctrine of equivalents.