DCT
1:17-cv-00379
Bristol Myers Squibb Co v. Mylan Pharma Inc
Key Events
Complaint
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Bristol-Myers Squibb Company (Delaware) and Pfizer Inc. (Delaware)
- Defendant: Mylan Pharmaceuticals Inc. (West Virginia)
- Plaintiff’s Counsel: Farnan LLP; Wilmer Cutler Pickering Hale and Dorr LLP
- Case Identification: 1:17-cv-00379, D. Del., 04/05/2017
- Venue Allegations: Venue is asserted based on Mylan being subject to personal jurisdiction in the District of Delaware, having committed acts of infringement there, and having a regular and established place of business in the district. The complaint further alleges Mylan is registered to do business in Delaware and derives substantial revenue from selling pharmaceutical products within the state.
- Core Dispute: Plaintiffs allege that Defendant’s submission of an Abbreviated New Drug Application (ANDA) to market generic versions of the anticoagulant drug Eliquis® constitutes an act of infringement of two patents covering the apixaban compound and specific pharmaceutical formulations thereof.
- Technical Context: The technology concerns apixaban, a Factor Xa inhibitor used as an oral anticoagulant for the treatment and prevention of thromboembolic disorders such as deep vein thrombosis and stroke.
- Key Procedural History: This lawsuit was initiated under the Hatch-Waxman Act following Mylan's notification to Plaintiffs, via a Paragraph IV certification letter, of its filing of ANDA No. 210128. This certification asserts that Plaintiffs' patents covering Eliquis® are invalid, unenforceable, or will not be infringed by Mylan's proposed generic product.
Case Timeline
| Date | Event |
|---|---|
| 2001-09-21 | U.S. Patent No. 6,967,208 Priority Date |
| 2005-11-22 | U.S. Patent No. 6,967,208 Issued |
| 2010-02-25 | U.S. Patent No. 9,326,945 Priority Date |
| 2016-05-03 | U.S. Patent No. 9,326,945 Issued |
| 2017-03-02 | Mylan sends Paragraph IV Notice Letter regarding its ANDA |
| 2017-04-05 | Complaint Filed |
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," issued November 22, 2005 (’208 Patent)
The Invention Explained
- Problem Addressed: The patent describes a need for new, effective, and orally bioavailable therapeutic agents for treating thromboembolic disorders. It specifically identifies a need for potent and selective inhibitors of Factor Xa, a critical enzyme in the blood coagulation cascade, that possess improved pharmacological properties compared to existing treatments (’208 Patent, col. 5:22-40).
- The Patented Solution: The invention provides a novel class of lactam-containing compounds, defined by a general chemical structure (Formula I), that function as inhibitors of Factor Xa (’208 Patent, Abstract; col. 5:53-60). The patent discloses numerous specific compounds that fall within this class, including the compound that would become known as apixaban, and methods for their use as anticoagulants.
- Technical Importance: This class of compounds provided a basis for developing new oral anticoagulants that could potentially offer more predictable dosing and safety profiles than older agents like warfarin, which require frequent monitoring (’208 Patent, col. 5:1-21).
Key Claims at a Glance
- The complaint asserts infringement of claims 8, 13, 26-27, and 55-61 (Compl. ¶28). The key independent claims appear to be Claim 1 (composition of matter) and Claim 55 (method of treatment).
- Independent Claim 1: A compound according to a specified chemical structure (Formula I) or a stereoisomer or pharmaceutically acceptable salt thereof, where the constituent parts of the formula (P, M, etc.) are defined by a large set of chemical groups (a Markush group).
- Independent Claim 55: A method for treating a thromboembolic disorder, which includes:
- administering to a patient in need thereof
- a therapeutically effective amount of a compound of claim 1
U.S. Patent No. 9,326,945 - "Apixaban Formulations," issued May 3, 2016 (’945 Patent)
The Invention Explained
- Problem Addressed: The patent notes that despite apixaban’s adequate aqueous solubility, formulations made with certain processes (wet granulation) or with large drug particles resulted in "less than optimal exposures" in humans, creating a challenge for ensuring consistent therapeutic effect (’945 Patent, col. 1:56-62).
- The Patented Solution: The invention is a solid pharmaceutical formulation of apixaban that solves the consistency problem by controlling the drug particle size. The patent claims crystalline apixaban particles with a size distribution where 90% of the particles by volume have a diameter of 89 micrometers (µm) or less (a D90 ≤ 89 µm), which yields a specific, rapid dissolution profile (’945 Patent, Abstract; col. 2:6-18). Figure 3 of the patent plots dissolution rates against particle size, illustrating that tablets made with drug substance particles having a D90 below approximately 89 µm meet the minimum dissolution requirement (’945 Patent, Fig. 3).
- Technical Importance: This invention provides a method to ensure that the oral dosage form of apixaban delivers the drug to the patient's bloodstream consistently and reliably, which is critical for an anticoagulant where both under-dosing (risk of clot) and over-dosing (risk of bleeding) are dangerous.
Key Claims at a Glance
- The complaint asserts infringement of claims 1, 9-12, 20-23, 25, 27, 29, 31, 33, 35, and 37 (Compl. ¶34). The key independent claims are Claim 1 and Claim 12.
- Independent Claim 1: A solid pharmaceutical composition that includes:
- a therapeutically effective amount of crystalline apixaban particles
- the particles having a D90 equal to or less than about 89 µm
- wherein at least 77 wt % of apixaban dissolves within 30 minutes in a specified buffer
- Independent Claim 12: A solid pharmaceutical composition that includes:
- crystalline apixaban particles with a D90 equal to or less than about 89 µm
- wherein, under specified USP Apparatus 2 test conditions, at least 77 wt % of apixaban dissolves within 30 minutes
III. The Accused Instrumentality
- Product Identification: The accused instrumentality is Mylan’s proposed 2.5 mg and 5 mg generic apixaban tablets, for which Mylan submitted ANDA No. 210128 to the FDA (Compl. ¶2).
- Functionality and Market Context: The complaint alleges that Mylan's ANDA product has the same active ingredient (apixaban), dosage form, strength, and is intended for the same medical indications as Plaintiffs' Eliquis® product (Compl. ¶19, ¶22-23). The product is designed to be a generic substitute for Eliquis®, functioning as a Factor Xa inhibitor for treating and preventing thromboembolic disorders (Compl. ¶19). By filing an ANDA, Mylan seeks to market a lower-cost version of Eliquis® upon receiving FDA approval (Compl. ¶21).
IV. Analysis of Infringement Allegations
The complaint alleges that Mylan’s submission of its ANDA constitutes a technical act of infringement under 35 U.S.C. § 271(e)(2) (Compl. ¶28, ¶34). The detailed specifications of Mylan’s product are contained within its confidential ANDA submission.
’208 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A compound of Formula I...or a stereoisomer or pharmaceutically acceptable salt thereof... | The complaint alleges that Mylan's ANDA product "has the same active ingredient as Eliquis®," which is the apixaban compound covered by the claims of the ’208 patent. The filing of the ANDA is alleged to be an act of infringement for this compound claim. | ¶22, ¶28 | col. 237:1-270:54 |
- Identified Points of Contention:
- Validity Question: In an ANDA case involving a compound patent, infringement is often not the main dispute if the generic contains the same active ingredient. The central conflict typically revolves around the defendant's assertion that the patent is invalid (Compl. ¶24). The details of Mylan's invalidity theories are not in the complaint.
- Method Claim Infringement: For method claims like Claim 55, the question is whether Mylan will induce infringement. The complaint alleges Mylan will do so by seeking approval to market its product for the same indications as Eliquis®, which will presumably be reflected on the product's label (Compl. ¶23, ¶30).
’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 | Mylan's ANDA No. 210128 seeks approval for 2.5 mg and 5 mg tablets of apixaban, which are solid pharmaceutical compositions (Compl. ¶2). | ¶2, ¶34 | col. 11:49-52 |
| having a D90 equal to or less than about 89 µm... | The complaint alleges Mylan's product "is bioequivalent to Eliquis®" (Compl. ¶22). Plaintiffs' infringement theory may depend on the argument that achieving bioequivalence necessarily requires Mylan's formulation to meet the claimed particle size and dissolution parameters taught by the ’945 patent as necessary for consistent bioavailability. | ¶22, ¶34 | col. 11:53-54 |
| wherein at least 77 wt % of apixaban dissolves within 30 minutes... | As with the particle size limitation, the complaint relies on the allegation of bioequivalence to infer that Mylan's product will meet the claimed dissolution profile (Compl. ¶22). | ¶22, ¶34 | col. 11:55-58 |
- Identified Points of Contention:
- Technical Question: A primary question for the court will be whether Mylan’s formulation, as described in its confidential ANDA, actually meets the D90 and dissolution rate limitations of the asserted claims. The complaint’s assertion of infringement relies on an inference from the allegation of bioequivalence rather than direct evidence of Mylan's formulation parameters.
- Scope Questions: The interpretation of the term "about 89 µm" may be a significant point of contention. The parties could dispute whether this term allows for any deviation from the 89 µm value and, if so, how much.
V. Key Claim Terms for Construction
Term from ’945 Patent, Claim 1: "about 89 µm"
- Context and Importance: This term defines the critical upper boundary for the particle size (D90) of the apixaban active ingredient. The patent ties this specific size to achieving a desired dissolution profile and consistent bioavailability. Whether Mylan's product literally infringes could depend entirely on how much, if any, flexibility the word "about" provides. Practitioners may focus on this term because its construction will determine the precise scope of the claim, a common battleground in pharmaceutical patent litigation.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: Plaintiffs may argue that "about" should be interpreted functionally, to encompass any particle size that achieves the patent's stated goal of consistent in-vivo dissolution, as shown by the dissolution rate of at least 77% in 30 minutes, also recited in the claim (’945 Patent, col. 11:55-58).
- Evidence for a Narrower Interpretation: Mylan may argue for a narrow construction, pointing to the patent's repeated and specific linkage of the 89 µm figure to data from clinical studies and dissolution graphs (’945 Patent, Fig. 3 & 4; col. 10:30-45). The specification states, "Since the tablets with 89 microns have >77% dissolved at 30 minutes, these tablets will also exhibit exposures that are equivalent..." suggesting 89 µm is not an arbitrary number but a specific, experimentally derived threshold (’945 Patent, col. 10:35-39).
VI. Other Allegations
- Indirect Infringement: The complaint alleges that Mylan's future commercial activities will induce and/or contribute to infringement by others (e.g., physicians and patients) (Compl. ¶29-31, ¶35-36). The basis for this is the allegation that Mylan will sell its ANDA product with a label instructing its use for the patented methods of treatment, which are the same indications for which Eliquis® is approved (Compl. ¶23).
- Willful Infringement: The complaint does not contain an explicit count for willful infringement. However, it alleges that Mylan was aware of the patents-in-suit, as evidenced by its sending of the Paragraph IV notice letter on March 2, 2017 (Compl. ¶20, ¶24). This alleged knowledge could form the basis for a later claim of post-suit willfulness or a motion for enhanced damages if infringement is found.
VII. Analyst’s Conclusion: Key Questions for the Case
- Validity of the Compound: For the ’208 patent covering the apixaban compound itself, the central issue is unlikely to be infringement but rather validity. The case will turn on whether Mylan can prove, by clear and convincing evidence, its assertion that the patent's claims to the apixaban molecule are invalid, likely on grounds such as obviousness or lack of enablement.
- Evidentiary Proof of Formulation: For the ’945 formulation patent, a key question will be evidentiary. Does the technical data within Mylan's confidential ANDA demonstrate that its proposed generic product meets the specific D90 particle size and dissolution rate limitations recited in the claims? Plaintiffs' allegation is premised on an inference from bioequivalence, which will need to be substantiated with direct technical proof.
- Definitional Scope of "About": A critical legal issue for the ’945 patent will be the claim construction of "about 89 µm." The court’s interpretation of this term—whether it is a precise, data-driven cutoff or allows for a range of functional equivalents—could be dispositive on the question of literal infringement.