Bristol Myers Squibb Co v. Micro Labs USA Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Bristol-Myers Squibb Company (Delaware) and Pfizer Inc. (Delaware)
  • Defendant: Micro Labs USA Inc. (New Jersey) and Micro Labs, Ltd. (India)
  • Plaintiff’s Counsel: Farnan, LLP
• Case Identification: 1:17-cv-00406, D. Del., 04/10/2017
• Venue Allegations: Venue is alleged to be proper under 28 U.S.C. §§ 1391 and/or 1400(b). The complaint notes that Defendants, through counsel, agreed not to contest jurisdiction or venue.
• Core Dispute: Plaintiffs allege that Defendants’ submission of an Abbreviated New Drug Application (ANDA) to market generic apixaban tablets infringes two patents covering the apixaban compound and specific formulations of it.
• Technical Context: The technology concerns oral anticoagulants, specifically Factor Xa inhibitors, which are used for the treatment and prevention of thromboembolic disorders such as deep vein thrombosis and stroke.
• Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiffs’ receipt of a notice letter from Micro Labs on March 7, 2017. The letter included a Paragraph IV certification asserting that Plaintiffs’ patents are invalid, unenforceable, or will not be infringed by the proposed generic product. This complaint, filed within 45 days of that notice, triggers an automatic 30-month stay of FDA approval for the generic product.

Case Timeline

Date	Event
2001-09-21	’208 Patent Priority Date
2005-11-22	’208 Patent Issue Date
2010-02-25	’945 Patent Priority Date
2016-05-03	’945 Patent Issue Date
2017-03-07	Plaintiffs receive Eliquis Notice Letter from Defendants
2017-04-10	Complaint Filing Date

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

U.S. Patent No. 6,967,208 - "Lactam-Containing Compounds and Derivatives thereof as Factor Xa Inhibitors"

The Invention Explained

• Problem Addressed: The patent describes a need for effective and specific inhibitors of Factor Xa, a critical enzyme in the blood coagulation cascade, to treat thromboembolic disorders. The background highlights a need for new agents with improved pharmacological properties compared to existing therapies ('208 Patent, col. 5:23-41).
• The Patented Solution: The invention provides a novel class of lactam-containing compounds, defined by a general chemical structure, that are described as potent Factor Xa inhibitors. The patent discloses numerous specific compounds encompassed by this class, including the compound that would become known as apixaban, and methods for their synthesis ('208 Patent, col. 5:51-65, col. 6:1-3).
• Technical Importance: The invention provided a new chemical entity for use as an oral anticoagulant, targeting a key chokepoint in the biological pathway responsible for blood clot formation ('208 Patent, col. 5:6-14).

Key Claims at a Glance

• The complaint asserts independent compound claims 8 and 13, and independent method of use claim 55 (Compl. ¶¶ 22-24).
• Independent Claim 8: A claim to a specific compound:
  • "A compound according to claim 1, wherein the compound is 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-7-one; or a pharmaceutically acceptable salt form thereof."
• Independent Claim 55: A claim to a method of treatment:
  • "A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof."
• The complaint also asserts dependent claims 26-27 and 56-61 (Compl. ¶¶ 22-24).

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

The Invention Explained

• Problem Addressed: The patent discloses the unexpected finding that apixaban formulations, despite the compound's adequate aqueous solubility, exhibited inconsistent patient exposure when made with larger drug particles or via certain manufacturing processes. This created "quality control challenges" for ensuring a consistent therapeutic effect ('945 Patent, col. 1:45-62).
• The Patented Solution: The invention claims pharmaceutical compositions of crystalline apixaban where the drug particles have a specific, controlled size distribution—specifically, a D90 of less than or equal to 89 µm. This particle size control, preferably combined with a dry granulation manufacturing process, is taught to achieve consistent in-vivo dissolution and predictable patient exposure ('945 Patent, Abstract; col. 2:8-16).
• Technical Importance: The invention addresses a critical drug formulation challenge by linking a specific particle size threshold to consistent bioavailability, a non-obvious relationship according to the patent's description of apixaban's properties ('945 Patent, col. 2:44-59).

Key Claims at a Glance

• The complaint asserts independent claims 1 and 12 (Compl. ¶28).
• Independent Claim 1: A claim to a solid pharmaceutical composition with specific particle size and dissolution properties:
  • A solid pharmaceutical composition comprising a therapeutically effective amount of crystalline apixaban particles and a pharmaceutically acceptable diluent or carrier,
  • wherein the crystalline apixaban particles have a D90 equal to or less than about 89 µm, and
  • 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 also asserts dependent claims 9-12, 20-23, 25, 27, 29, 31, 33, 35, and 37 (Compl. ¶28).

III. The Accused Instrumentality

Product Identification

• The accused instrumentality is the "Micro Labs ANDA product," which the complaint identifies as 2.5 mg and 5 mg tablets of apixaban intended as generic versions of Plaintiffs' Eliquis® drug product (Compl. ¶2).

Functionality and Market Context

• As a proposed generic drug submitted for approval via an ANDA, the accused product has necessarily been represented to the FDA as having the same active ingredient (apixaban), dosage form, strength, and route of administration as Eliquis®. The complaint further states that the ANDA filing represents the proposed generic product is bioequivalent to Eliquis® and is intended for the same approved indications (Compl. ¶¶ 16-17).
  No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint’s infringement allegations are based on the statutory act of filing the ANDA under 35 U.S.C. § 271(e)(2)(A), which treats the submission as an act of infringement if the proposed product would infringe the patent upon commercialization.

'208 Patent Infringement Allegations

Claim Element (from Independent Claim 8)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
A compound...which is 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-7-one...	The complaint alleges that by filing its ANDA, Micro Labs has represented to the FDA that its proposed generic product contains the same active ingredient as Eliquis®, which is the specific chemical compound apixaban.	¶16	col. 266:40-44

• Identified Points of Contention:
  • Scope Questions: For the ’208 Patent's compound claim, the infringement analysis appears straightforward. The central allegation is that the ANDA product contains apixaban. The dispute is therefore less likely to be about the structure of the accused compound and more likely to be about the validity of the patent claim covering that structure.

'945 Patent Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
A solid pharmaceutical composition comprising...crystalline apixaban particles	The complaint alleges the ANDA product contains apixaban and is bioequivalent to Eliquis®, which is formulated with crystalline apixaban.	¶16	col. 10:50-52
wherein the crystalline apixaban particles have a D90 equal to or less than about 89 µm	The complaint does not contain specific allegations about the particle size in the ANDA product. Infringement is asserted based on the representation of bioequivalence, which the patent teaches is achieved by meeting this particle size limitation.	¶16	col. 10:53-55
wherein at least 77 wt % of apixaban dissolves within 30 minutes...	The complaint does not provide dissolution data for the ANDA product. The allegation relies on the representation of bioequivalence, which the patent links to this dissolution rate threshold.	¶16	col. 10:56-59

• Identified Points of Contention:
  • Technical Questions: A key question is whether Micro Labs's proposed generic product, in fact, has a D90 particle size of ≤ 89 µm and the claimed dissolution profile. The complaint infers these properties from the ANDA's certification of bioequivalence. The court will need to examine the actual characteristics of the ANDA product, which will be a central focus of discovery.
  • Scope Questions: This raises the question of whether a product can be bioequivalent to Eliquis® without meeting the specific particle size and dissolution limitations of the ’945 Patent claims. Defendants may argue their formulation achieves bioequivalence through alternative means, thereby avoiding literal infringement.

V. Key Claim Terms for Construction

• The Term: "a D90 equal to or less than about 89 µm" (from claim 1 of the ’945 Patent)
• Context and Importance: This limitation is the core of the asserted claims of the ’945 Patent. The patentability of the formulation and the question of infringement both hinge on the meaning and scope of this specific particle size threshold. Practitioners may focus on this term because it is a numerical boundary that defines the invention over prior art and distinguishes it from formulations that allegedly provide inconsistent results.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The use of the word "about" suggests the 89 µm value is not an absolute, rigid cutoff. A party could argue the term should be interpreted functionally to mean any particle size that achieves the patent's stated goal of "consistent in-vivo dissolution" ('945 Patent, col. 2:62-64). The patent itself shows dissolution rates above the 77% threshold for particle sizes up to 119 µm, which could be used to argue for a wider range ('945 Patent, Fig. 4).
  • Evidence for a Narrower Interpretation: The specification repeatedly identifies 89 µm as a key threshold. The abstract states the invention comprises particles having a D90 "equal to or less than about 89 µm," and the summary of invention states "it has surprisingly been found, however, that the particle size that impacts apixaban absorption rate is about a D90 of 89 µm" ('945 Patent, Abstract; col. 2:52-54). A party could argue "about" only accounts for standard measurement variability and does not extend the claimed range to include particle sizes that the patent itself distinguishes as problematic.

VI. Other Allegations

• Indirect Infringement: The complaint alleges that upon approval, Micro Labs's commercial manufacture, use, and sale of its ANDA product would actively induce and contribute to infringement by others (e.g., doctors and patients) ('Compl. ¶¶ 23-25, 29-30). This allegation is supported by the fact that the generic product is intended for the same indications as Eliquis®, and its label would instruct users to administer the drug in a manner that would infringe the method claims of the ’208 Patent.
• Willful Infringement: The complaint does not explicitly use the word "willful," but it alleges that Micro Labs had knowledge of the patents-in-suit, as evidenced by its Paragraph IV certification letter sent to Plaintiffs ('Compl. ¶¶ 14, 18). This establishes the pre-suit knowledge element required for a later claim of enhanced damages or attorney fees under 35 U.S.C. § 285.

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

• A primary question for the ’208 patent will be one of validity: Given that the ANDA filing effectively concedes that the generic product is the chemical compound apixaban, the defense will likely center on whether the patent’s claim to that compound is valid over the prior art.
• A key evidentiary and legal question for the ’945 patent will be one of infringement by equivalence: Does Micro Labs's certification of bioequivalence legally and factually necessitate that its formulation meets the specific D90 ≤ 89 µm particle size and dissolution rate limitations of the claims, or can bioequivalence be achieved by other means that fall outside the literal scope of the claims?
• A final core issue will be the validity of the formulation patent: The case will likely examine whether the claimed 89 µm particle size threshold in the ’945 patent represents a non-obvious invention or is an arbitrary or obvious-to-try parameter for a skilled formulator seeking to optimize drug dissolution and bioavailability.