DCT

1:17-cv-01493

Bristol Myers Squibb Co v. Apotex Inc

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Key Events
Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:17-cv-01493, D. Del., 10/24/2017
  • Venue Allegations: Venue is alleged to be proper as Defendant Apotex Corp. is a Delaware corporation and because Defendants, through counsel, agreed to be sued in the District of Delaware for this matter.
  • Core Dispute: Plaintiff alleges that Defendant's Abbreviated New Drug Application (ANDA) to market a generic version of the HIV drug Reyataz® constitutes an act of infringement of a patent covering the specific bisulfate salt form of the active ingredient, atazanavir.
  • Technical Context: The patent relates to pharmaceutical chemistry, specifically creating a salt form of an active drug compound (an HIV protease inhibitor) to improve its solubility and oral bioavailability, thereby making it suitable for an effective oral medication.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiff's receipt of a notice letter from Defendant regarding its ANDA filing. The letter contained a Paragraph IV certification, asserting that the patent-in-suit is invalid, unenforceable, or will not be infringed. The patent is listed in the FDA's "Orange Book" for the brand-name drug Reyataz® and benefits from a period of pediatric exclusivity.

Case Timeline

Date Event
1998-01-20 '383 Patent Priority Date
2000-07-11 '383 Patent Issue Date
2017-09-12 Apotex sends notice letter to Plaintiff
2017-10-24 Complaint Filing Date
2018-12-21 '383 Patent Original Expiration Date
2019-06-21 '383 Patent Pediatric Exclusivity Expiration

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

U.S. Patent No. 6,087,383 - "Bisulfate Salt of HIV Protease Inhibitor"

The Invention Explained

  • Problem Addressed: The patent's background section explains that the "free base" form of a particular azapeptide HIV protease inhibitor (referred to as Compound I) is a weak organic base with an aqueous solubility of less than 1 µg/mL. This extremely low solubility results in "poor oral bioavailability in animals," rendering it unsuitable for an effective oral drug. (’383 Patent, col. 2:39-43).
  • The Patented Solution: The invention is the specific bisulfate salt of Compound I. The specification describes how other common acid addition salts (e.g., hydrochloride, methanesulfonate, and even the simple sulfate) were evaluated but proved inadequate, exhibiting either lower solubility or physical instability that caused them to convert back to the insoluble free base in water (’383 Patent, col. 2:48-62). The bisulfate salt, in contrast, is described as having "unexpectedly superior aqueous solubility" (approximately 4-5 mg/mL) and, critically, is stabilized by an "extra proton" that "prevents the conversion to the free base," thus overcoming the bioavailability problem. (’383 Patent, col. 2:28-34; col. 2:62-64).
  • Technical Importance: The creation of this specific, stable, and more soluble salt form was a key step in enabling the development of an effective oral dosage form for a potent HIV protease inhibitor. (’383 Patent, col. 2:44-47).

Key Claims at a Glance

  • The complaint asserts independent claim 1 and dependent claim 2. (Compl. ¶20).
  • Independent Claim 1:
    • The bisulfate salt having the formula [shown as formula II in the patent]
  • Dependent Claim 2:
    • A pharmaceutical dosage form comprising the bisulfate salt of claim 1
    • and a pharmaceutically acceptable carrier

III. The Accused Instrumentality

Product Identification

The accused instrumentalities are the "Apotex ANDA Products" described in Abbreviated New Drug Application No. 210400. These products are 100 mg, 150 mg, 200 mg, and 300 mg capsules of atazanavir sulfate. (Compl. ¶2).

Functionality and Market Context

The Apotex ANDA Products are intended to be generic versions of Plaintiff's Reyataz® drug product. (Compl. ¶2). The complaint alleges that by filing its ANDA, Apotex has represented to the FDA that its products have the same active ingredient, method of administration, dosage form, and strengths as Reyataz®, and are bioequivalent to Reyataz®. (Compl. ¶14). The core technical allegation is that, upon information and belief, the "Apotex ANDA Products contain atazanavir bisulfate." (Compl. ¶15).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

Claim Chart Summary

The complaint’s infringement theory rests on the chemical composition of the product described in the ANDA.

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
The bisulfate salt having the formula [II] The product described in Apotex's ANDA No. 210400 is alleged to contain "atazanavir bisulfate," which is the bisulfate salt of the compound of formula I, corresponding to the claimed formula II. The submission of the ANDA seeking approval for this product is the alleged act of infringement. ¶15, ¶20 col. 6:35-51

Identified Points of Contention

  • Technical Questions: The central dispute will likely be factual: what is the precise chemical composition of the substance in the Apotex ANDA Products? Does the active pharmaceutical ingredient meet the definition of the claimed "bisulfate salt," or is it a different salt (e.g., a simple sulfate), a different polymorph, or an amorphous form that falls outside the patent’s claims? The complaint's allegation that the product contains "atazanavir bisulfate" (Compl. ¶15) will be the subject of discovery and expert chemical analysis.
  • Scope Questions: A potential dispute may arise over the proper construction of the term "bisulfate salt." Does the claim cover any compound meeting the recited chemical structure, or is it implicitly limited to the specific crystalline forms (e.g., "Type-II crystals") and performance characteristics (e.g., solubility of ~4-5 mg/mL, stability against conversion) that the specification touts as the invention's "unexpected" advantages? (’383 Patent, col. 5:1-6; col. 2:55-57).

V. Key Claim Terms for Construction

  • The Term: "bisulfate salt"
  • Context and Importance: This term, which appears in the sole independent claim, is the entire basis of the patent. The outcome of the infringement analysis is entirely dependent on its definition. Practitioners may focus on this term because Apotex's primary non-infringement defense would likely involve arguing that its product, while chemically related, does not fall within the proper scope of "bisulfate salt" as defined by the patent.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: A party could argue for the plain and ordinary meaning, asserting that the term covers any salt formed from the reaction of one molecule of the base compound (atazanavir) with one molecule of sulfuric acid, as depicted in the chemical structure in claim 1. (’383 Patent, col. 6:35-51).
    • Evidence for a Narrower Interpretation: A party could argue that the specification defines the term by implication, limiting it to a salt that exhibits the specific, "unexpected" properties described as the invention. This could include the "unusual solubility behavior" of approximately 4-5 mg/mL and the stability that "prevents the conversion to the free base," which the patent distinguishes from other salts. (’383 Patent, col. 2:55-57, col. 2:62-64). Further, the patent discusses specific crystalline forms, which could be used to argue the claim is limited to those embodiments. (’383 Patent, col. 5:1-6).

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that Apotex's future commercial manufacture and sale would induce and contribute to infringement by others under 35 U.S.C. § 271(b) and (c). (Compl. ¶21, ¶22). The factual basis for this allegation is Apotex's stated intent to market its ANDA products for use by patients upon receiving FDA approval. (Compl. ¶13).
  • Willful Infringement: The complaint does not contain an explicit allegation of "willful" infringement or a request for enhanced damages under 35 U.S.C. § 284. It does, however, plead facts establishing Apotex’s pre-suit knowledge of the ’383 patent, citing the Paragraph IV notice letter sent by Apotex to BMS. (Compl. ¶12, ¶17).

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

  • A core issue will be one of chemical identity: is the active ingredient in the Apotex generic product, as specified in its ANDA, the exact "bisulfate salt" claimed in the '383 patent? Discovery and chemical analysis will focus on determining if Apotex has designed around the patent by using a different, non-infringing salt form, polymorph, or formulation.
  • The case may also turn on a question of definitional scope: does the term "bisulfate salt" in claim 1 simply refer to a compound with the recited chemical structure, or is its meaning implicitly limited by the patent's specification to a salt that also exhibits the specific solubility and stability characteristics that the inventors described as the "unexpected" and superior solution to the prior art's problem?