Bayer Healthcare LLC v. Apotex Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Bayer HealthCare LLC, Bayer HealthCare Pharmaceuticals Inc., and Onyx Pharmaceuticals, Inc. (Delaware, New Jersey, California)
  • Defendant: Apotex Inc. and Apotex Corp. (Canada, Florida)
  • Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP
• Case Identification: 1:18-cv-01539, D. Del., 10/04/2018
• Venue Allegations: Venue is alleged to be proper in the District of Delaware based on Defendant Apotex Corp. being a Delaware corporation and both defendants having previously consented to jurisdiction in the district in other ANDA-related lawsuits.
• Core Dispute: Plaintiffs allege that Defendant’s submission of an Abbreviated New Drug Application (ANDA) to market a generic version of the cancer drug NEXAVAR® constitutes an act of infringement of two patents covering a specific crystalline form and a high-load pharmaceutical formulation of the active ingredient, sorafenib tosylate.
• Technical Context: The technology relates to pharmaceutical chemistry, specifically the identification of a thermodynamically stable crystalline polymorph and the formulation of a high-concentration, immediate-release tablet for an oral kinase inhibitor used in cancer therapy.
• Key Procedural History: The litigation was initiated under the Hatch-Waxman Act following Plaintiffs' receipt of a Notice Letter from Apotex, which included a Paragraph IV certification challenging the patents-in-suit. The complaint notes that Apotex has been a party to numerous prior patent litigations in the District of Delaware, which Plaintiffs assert as a basis for jurisdiction.

Case Timeline

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

U.S. Patent No. 8,877,933 - "Thermodynamically Stable Form of a Tosylate Salt," issued November 4, 2014

The Invention Explained

• Problem Addressed: The patent's background explains that the active pharmaceutical ingredient, sorafenib tosylate, can exist in different crystalline structures, known as polymorphs. The initially discovered form, Polymorph II, is described as "metastable," meaning it could convert into a different, more stable form during manufacturing or storage (’933 Patent, col. 2:21-22). Such a conversion can alter critical drug properties like solubility and bioavailability, posing a risk to the quality, safety, and consistency of the final pharmaceutical product (’933 Patent, col. 2:40-46).
• The Patented Solution: The invention is a new, "thermodynamically stable" crystalline form of sorafenib tosylate, designated "Polymorph I" (’933 Patent, Abstract). This form is described as being storage-stable, which prevents undesired conversions and ensures that the drug's physical properties remain consistent over time (’933 Patent, col. 2:31-34). The patent provides detailed characterization of Polymorph I through distinct analytical data, including its unique X-ray diffraction pattern and melting point, which differentiate it from other forms (’933 Patent, col. 2:47-59, FIGs. 1-6).
• Technical Importance: The discovery and isolation of a thermodynamically stable polymorph is a crucial step in pharmaceutical development, as it ensures product uniformity, predictable performance, and long-term shelf-life, which are essential for regulatory approval and patient safety (’933 Patent, col. 2:44-46).

Key Claims at a Glance

• The complaint asserts independent claims 1 (composition) and 16 (method of treatment) (Compl. ¶45).
• Independent Claim 1 recites:
  • A compound of formula (I) (sorafenib tosylate);
  • in the polymorph I form;
  • which shows in the X-ray diffractometry peak maxima of the 2 theta angle of 4.4, 14.8 and 20.5.
• The complaint reserves the right to assert additional claims.

U.S. Patent No. 9,737,488 - "Pharmaceutical Composition for the Treatment of Cancer," issued August 22, 2017

The Invention Explained

• Problem Addressed: The patent addresses the challenge of creating an oral drug formulation that contains a high dose of an active ingredient while remaining easy for patients to swallow, a key factor in patient compliance (’488 Patent, col. 1:52-65). Increasing the drug concentration can often lead to manufacturing difficulties and poor dissolution characteristics, while lowering it requires larger tablets that are difficult to ingest.
• The Patented Solution: The patent discloses a specific "immediate release" tablet formulation that contains a high concentration of sorafenib tosylate—at least 40% by weight—in combination with at least one pharmaceutically acceptable excipient (’488 Patent, col. 11:19-24, Abstract). This formulation successfully balances a high drug load with rapid release properties, enabling the delivery of a therapeutically effective dose in a reasonably sized tablet (’488 Patent, col. 4:1-15, Table 1).
• Technical Importance: Developing a high-load, solid oral dosage form that also provides immediate release of the active ingredient is a significant technical achievement in pharmaceutical formulation, directly addressing the practical challenges of patient adherence and effective drug delivery for high-dose medicines.

Key Claims at a Glance

• The complaint asserts independent claims 40 and 70, among others (Compl. ¶65).
• Independent Claim 40 recites:
  • An immediate release pharmaceutical composition;
  • comprising the active agent [sorafenib tosylate];
  • in a portion of at least 40% by weight of the composition;
  • and at least one pharmaceutically acceptable excipient;
  • wherein the pharmaceutical composition is an immediate release tablet.
• The complaint reserves the right to assert additional claims.

III. The Accused Instrumentality

• Product Identification: The accused instrumentality is "Apotex's ANDA Product," a generic version of NEXAVAR® (sorafenib tosylate) 200 mg tablets, for which Apotex submitted ANDA No. 212228 to the FDA for marketing approval (Compl. ¶¶1-2, 31).
• Functionality and Market Context: The product is an oral tablet intended as a generic substitute for Plaintiffs' branded NEXAVAR®, a kinase inhibitor used for treating certain types of cancer (Compl. ¶¶2, 24). The complaint alleges, on information and belief, that the accused product is an "immediate release" tablet that contains sorafenib tosylate in the specific "polymorph I form" and comprises at least 40% of the active ingredient by weight of the composition (Compl. ¶¶42, 64). Apotex is a generic pharmaceutical company that intends to manufacture and sell the product in the United States upon receiving FDA approval (Compl. ¶¶6-7, 13).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

• U.S. Patent No. 8,877,933 Infringement Allegations

• U.S. Patent No. 9,737,488 Infringement Allegations

• Identified Points of Contention:
  • Factual Question ('933 Patent): The primary point of contention regarding the '933 patent will be factual: does chemical analysis of Apotex's ANDA product confirm that it contains sorafenib tosylate in the claimed "polymorph I form"? The complaint's allegation is based on "information and belief," and the case will likely turn on expert analysis of the actual product samples and confidential ANDA data obtained during discovery.
  • Factual Question ('488 Patent): Similarly, the dispute over the '488 patent will center on factual questions about the product's composition. Does the accused tablet contain the active ingredient at a concentration of "at least 40% by weight," and does its dissolution profile meet the patent's definition of an "immediate release tablet"? These questions can only be resolved by examining the confidential formulation information in Apotex's ANDA.

V. Key Claim Terms for Construction

• Term: "polymorph I form" (’933 Patent)

  • Context and Importance: This term is the central limitation of the '933 patent's composition claims. The infringement analysis will depend entirely on whether the accused product falls within the definition of this specific crystalline form.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Narrower Interpretation: The patent provides extensive and specific defining characteristics for "polymorph I," including a precise melting point under decomposition at 223-231° C. and a unique X-ray diffraction pattern with enumerated peaks (’933 Patent, col. 2:47-54, Table 2). Claim 1 itself recites specific characteristic peaks, suggesting the term is tied to this specific analytical fingerprint.
    • Evidence for a Broader Interpretation: A party might argue that the term should be understood in the context of the invention's purpose—to claim the thermodynamically stable form of the salt (’933 Patent, col. 2:31-34). This could support an argument that the term covers forms that are functionally equivalent in stability, even if their analytical data is not identical to the examples.

• Term: "immediate release" (’488 Patent)

  • Context and Importance: The "immediate release" character of the tablet is a key functional limitation. While infringement appears to be a factual question, any ambiguity in the definition of this term could become a focus of claim construction.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Narrower Interpretation: The specification provides a clear, quantitative definition: "immediate release administration forms having a Q-value (30 minutes) of 75% due to USP-release method with device 2 (paddle, 75 rpm, in 0.1M HCl+1% sodium dodecylsulfate)" (’488 Patent, col. 4:64-68). This explicit definition provides strong evidence for a narrow construction limited to this specific performance standard under these precise testing conditions.
    • Evidence for a Broader Interpretation: A party could argue that this definition is merely a preferred embodiment and that the term's plain and ordinary meaning—a formulation not designed for delayed, extended, or modified release—should control, potentially capturing a wider range of dissolution profiles.

VI. Other Allegations

• Indirect Infringement: The complaint alleges active inducement and contributory infringement. The inducement allegation is based on the assertion that Apotex's proposed product labeling will instruct physicians and patients to use the generic drug to treat cancer, thereby directing the infringement of Plaintiffs' method-of-use claims (Compl. ¶¶44, 47, 67). The contributory infringement allegation is based on the assertion that the accused product is especially made for infringing uses and has no substantial non-infringing use (Compl. ¶48).
• Willful Infringement: The complaint alleges that Apotex had knowledge of the patents-in-suit prior to filing its ANDA, as demonstrated by its service of a Paragraph IV certification that explicitly referenced the patents (Compl. ¶¶33, 58). This alleged pre-suit knowledge forms the basis for the claim of willful infringement.

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

• A central evidentiary question will be one of compositional identity: Will discovery and analysis of Apotex’s confidential ANDA information and product samples confirm that the generic product contains the specific "Polymorph I" crystalline structure, as defined by the analytical data in the ’933 patent?
• A second key evidentiary question will concern formulation parameters: Does the Apotex product meet the quantitative limitations of the ’488 patent, specifically the "at least 40% by weight" drug load and the "immediate release" dissolution profile as strictly defined in the specification?
• A potential legal and factual question will be one of infringement scope: If the accused product is found to have characteristics that differ slightly from the claimed invention (e.g., a mixture of polymorphs, a drug load just under 40%, or a dissolution rate near but not exceeding the "immediate release" threshold), the case may turn on whether these differences are sufficient to avoid literal infringement and whether the doctrine of equivalents can bridge the gap.