Bristol Myers Squibb Co v. Lupin Ltd

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Bristol-Myers Squibb Company (Delaware) and Pfizer Inc. (Delaware)
  • Defendant: Lupin Ltd. (India)
  • Plaintiff’s Counsel: Farnan LLP
• Case Identification: 1:17-cv-00378, D. Del., 04/05/2017
• Venue Allegations: Defendant Lupin Ltd., through counsel, agreed not to contest personal jurisdiction or venue in the District of Delaware for this matter.
• Core Dispute: Plaintiffs allege that Defendant’s Abbreviated New Drug Application (ANDA) to market generic versions of the anticoagulant Eliquis® constitutes an act of infringement of a patent related to specific apixaban formulations.
• Technical Context: The technology concerns pharmaceutical formulations of apixaban, a poorly water-soluble drug, designed to achieve consistent absorption and bioavailability in patients by controlling the active ingredient's particle size.
• Key Procedural History: This case was initiated under the Hatch-Waxman Act following a notification letter from Lupin to Plaintiffs, dated February 23, 2017, which stated that Lupin had filed an ANDA containing a Paragraph IV certification asserting that the patent-in-suit is invalid, unenforceable, or will not be infringed by its proposed generic product.

Case Timeline

Date	Event
2010-02-25	Priority Date for U.S. Patent No. 9,326,945
2016-05-03	U.S. Patent No. 9,326,945 Issued
2017-02-23	Date of Lupin's ANDA Notice Letter sent to Plaintiffs
2017-04-05	Complaint Filing Date

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

U.S. Patent No. 9,326,945 - "Apixaban Formulations"

The Invention Explained

• Problem Addressed: The patent addresses the challenge of formulating apixaban, a Factor Xa inhibitor with low aqueous solubility. According to the patent’s background, standard biopharmaceutical models suggested that for the intended low-dose tablets, particle size should not be a critical factor for achieving consistent drug absorption. However, the inventors found that formulations using large particles of apixaban resulted in "less than optimal exposures," creating potential quality control and therapeutic consistency challenges ('’945 Patent, col. 1:47-62).
• The Patented Solution: The patent discloses the "surprising and unexpected" discovery that controlling the particle size of crystalline apixaban is, in fact, critical. The invention is a pharmaceutical composition where the apixaban particles have a D90 (meaning 90% of the particles by volume have a diameter less than this value) of 89 microns (µm) or less. This specific particle size control is claimed to produce "consistent in-vivo dissolution in humans," leading to predictable drug exposure and a reliable therapeutic effect ('945 Patent, col. 2:1-6).
• Technical Importance: For an anticoagulant like apixaban, predictable and consistent blood concentration is critical for safety and efficacy; this invention purports to provide a formulation method to achieve that reliability in a solid oral dosage form despite the drug's poor solubility ('945 Patent, col. 2:1-6).

Key Claims at a Glance

• The complaint asserts independent claims 1 and 12, among others (Compl. ¶19).
• Independent Claim 1 requires:
  • A solid pharmaceutical composition with crystalline apixaban particles.
  • The particles have a D90 equal to or less than about 89 µm.
  • At least 77 wt % of the apixaban dissolves within 30 minutes in a specific pH 6.8 phosphate buffer.
• Independent Claim 12 is similar to claim 1 but recites more specific dissolution testing conditions, requiring:
  • A solid pharmaceutical composition with crystalline apixaban particles.
  • The particles have a D90 equal to or less than about 89 µm.
  • At least 77 wt % of the apixaban dissolves within 30 minutes when measured with a USP Apparatus 2 at 75 rpm in 900 mL of a 0.05 M sodium phosphate buffer at pH 6.8 containing 0.05% sodium lauryl sulfate at 37° C.
• The complaint reserves the right to assert numerous dependent claims which add limitations such as specific dosages (2.5 mg and 5 mg) and formulation as a tablet (Compl. ¶19).

III. The Accused Instrumentality

Product Identification

The accused instrumentalities are the 2.5 mg and 5 mg tablets of apixaban for which Defendant Lupin seeks marketing approval in ANDA No. 210119 (the "Lupin ANDA product") (Compl. ¶2).

Functionality and Market Context

The complaint alleges that by filing its ANDA, Lupin has represented to the FDA that its proposed generic product has the same active ingredient, dosage form, and strength as Plaintiffs' Eliquis® product (Compl. ¶13). It is further alleged that Lupin's product is "bioequivalent to Eliquis®" and is intended for the same medical indications, which include reducing the risk of stroke and systemic embolism (Compl. ¶10, ¶13-14). The infringement action is based on the filing of this ANDA before the expiration of the '945 patent, an act of infringement defined under 35 U.S.C. § 271(e)(2)(A) (Compl. ¶1, ¶19).

IV. Analysis of Infringement Allegations

The complaint alleges that the submission of the ANDA is a technical act of infringement but does not contain a detailed claim chart mapping elements of the asserted claims to specific features of the Lupin ANDA product. The infringement theory, typical in ANDA litigation, rests on the allegation that to be an approvable generic, Lupin's product must be bioequivalent to the branded product (Eliquis®), and therefore will necessarily possess the characteristics recited in the claims of the '945 patent.

No probative visual evidence provided in complaint.

'945 Patent Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
A solid pharmaceutical composition comprising a therapeutically effective amount of crystalline apixaban particles...	Lupin seeks approval to market 2.5 mg and 5 mg solid tablets containing apixaban, the same active ingredient as Eliquis®.	¶2, ¶13	col. 11:49-51
wherein the crystalline apixaban particles have a D90 equal to or less than about 89 µm, and	The complaint alleges Lupin's product is bioequivalent to Eliquis®. The patent teaches that this specific particle size is required to achieve consistent in-vivo dissolution and exposure, a presumed necessary condition for the alleged bioequivalence.	¶13	col. 2:7-12
wherein at least 77 wt % of apixaban dissolves within 30 minutes in a pH 6.8 phosphate buffer containing 0.05% sodium lauryl sulfate.	The complaint's allegation of bioequivalence suggests the Lupin ANDA product must meet this dissolution profile, which the patent defines as the "threshold for achieving consistent exposure" and links to clinical performance.	¶13	col. 10:25-29

Identified Points of Contention

• Technical Questions: A central factual question is whether Lupin's proposed generic product, as detailed in its confidential ANDA filing, actually has a particle size distribution and dissolution profile that fall within the scope of the asserted claims. The complaint does not and cannot provide this evidence, which will be a focus of discovery.
• Scope Questions: The case may turn on whether Lupin's formulation meets the claimed limitations. For instance, if Lupin's product utilizes an amorphous form of apixaban rather than a "crystalline" form, or if its particle size D90 is demonstrably greater than 89 µm, it may raise a non-infringement defense.
• Validity Questions: Lupin has certified that the '945 patent is invalid (Compl. ¶15). A potential argument is that controlling the particle size of a poorly soluble drug is a well-known technique, rendering the claims obvious. Plaintiffs may counter this by pointing to the patent's own disclosure that standard pharmaceutical models predicted particle size would not be critical for apixaban, suggesting the discovery was non-obvious ('945 Patent, col. 1:51-58).

V. Key Claim Terms for Construction

"a D90 equal to or less than about 89 µm"

• Context and Importance: This term is the central technical limitation of the invention. The definition of "about" will be critical in determining the boundary of the claim and, therefore, whether Lupin's product infringes. Practitioners may focus on this term because even a small difference in measured particle size could decide the outcome of the case.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The use of the word "about" itself implies some degree of flexibility beyond the precise number 89. The patent also notes "typical variability" in dissolution results, which could be argued to support a less rigid numerical cutoff ('945 Patent, col. 10:43-46).
  • Evidence for a Narrower Interpretation: The patent repeatedly links the 89 µm value to a specific functional outcome: a dissolution rate of at least 77% in 30 minutes, which is defined as "the threshold for achieving consistent exposure" ('945 Patent, col. 10:25-29; Fig. 3-4). A party could argue that "about 89 µm" should be construed narrowly to mean the particle size that achieves this specific, clinically significant functional threshold.

"crystalline apixaban particles"

• Context and Importance: This term defines the required physical form of the active ingredient. A determination of infringement will depend on whether Lupin's ANDA product uses a form of apixaban that falls within the scope of "crystalline."
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: Independent claims 1 and 12 are not limited to a specific crystal form (polymorph). This suggests the term is meant to cover any form of apixaban that is crystalline, as opposed to amorphous.
  • Evidence for a Narrower Interpretation: The specification provides detailed characterization for specific crystalline forms, namely "Form N-1" and "Form H2-2" ('945 Patent, Table 1). A defendant might argue that the scope of "crystalline" should be limited to the forms actually disclosed and enabled by the patent specification, although the fact that dependent claim 2 explicitly recites "Form N-1" may weaken this argument for the broader independent claim 1.

VI. Other Allegations

Indirect Infringement

The complaint alleges that Lupin's future commercial manufacture, use, and sale of its ANDA product would induce and contribute to infringement by others (e.g., physicians and patients) (Compl. ¶20-21). The basis for this allegation is the act of seeking FDA approval for a product with a label that will instruct users to administer the drug for patented indications, thereby encouraging infringing acts (Compl. ¶14).

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, establish that Lupin had pre-suit knowledge of the '945 patent by citing the notice letter sent to Plaintiffs on February 23, 2017 (Compl. ¶11). The prayer for relief includes a request for relief under 35 U.S.C. § 285, which pertains to attorney's fees in exceptional cases (Compl. p. 6).

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

• A core issue will be one of obviousness: Was it obvious for a person of ordinary skill in the art to control apixaban's particle size to a D90 of less than 89 µm to achieve consistent bioavailability, especially when the patent asserts that established pharmaceutical models predicted such control would be unnecessary?
• The case will also turn on a question of claim scope and infringement: How will the court construe the term "about 89 µm"? The ultimate infringement determination will depend on whether the particle size of Lupin's proposed generic product, as specified in its confidential ANDA, falls within this potentially narrow boundary.
• A key evidentiary question will be one of bioequivalence as proof: To what extent can Plaintiffs rely on Lupin’s certification of "bioequivalence" to prove that the Lupin ANDA product necessarily meets the specific particle size and dissolution limitations of the asserted claims, especially in the absence of direct evidence from the ANDA itself in the initial pleadings?