DCT
1:17-cv-00374
Bristol Myers Squibb Co v. Aurobindo Pharma USA Inc
Key Events
Complaint
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Bristol-Myers Squibb Company (Delaware) and Pfizer Inc. (Delaware)
- Defendant: Aurobindo Pharma USA Inc. (Delaware)
- Plaintiff’s Counsel: Farnan LLP; Wilmer Cutler Pickering Hale and Dorr LLP
- Case Identification: 1:17-cv-00374, D. Del., 04/05/2017
- Venue Allegations: Venue is asserted to be proper based on Defendant's incorporation in Delaware and its consent, communicated via e-mail, not to contest jurisdiction or venue.
- Core Dispute: Plaintiffs allege that Defendant’s filing of an Abbreviated New Drug Application (ANDA) to market a generic version of the anticoagulant drug Eliquis® (apixaban) constitutes an act of infringement of two patents covering the apixaban compound and its specific formulations.
- Technical Context: The case involves Factor Xa inhibitors, a class of anticoagulant medications used to treat and prevent thromboembolic disorders such as deep vein thrombosis and stroke in patients with atrial fibrillation.
- Key Procedural History: This action was triggered by Aurobindo’s submission of ANDA No. 210026 to the FDA, seeking approval to market a generic version of Eliquis®. The complaint states that Aurobindo’s notification letter included a "Paragraph IV certification," asserting that the patents-in-suit are invalid, unenforceable, and/or will not be infringed by its proposed generic product. This filing under the Hatch-Waxman Act provides the statutory basis for the infringement suit prior to the actual marketing of the generic drug.
Case Timeline
| Date | Event |
|---|---|
| 2002-08-09 | '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 |
| 2017-02-27 | Aurobindo sent Eliquis Notice Letter |
| 2017-02-28 | Plaintiffs received Eliquis Notice Letter (earliest date) |
| 2017-03-15 | Aurobindo agreed not to contest venue |
| 2017-04-05 | 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," issued November 22, 2005
The Invention Explained
- Problem Addressed: The patent addresses the need for effective and specific inhibitors of Factor Xa, a critical enzyme in the blood coagulation cascade, for the treatment and prevention of thromboembolic disorders ('208 Patent, col. 5:21-26). The background notes a desire for compounds with improved pharmacological characteristics over existing agents, such as better selectivity, bioavailability, and safety profiles ('208 Patent, col. 5:27-52).
- The Patented Solution: The patent discloses a genus of novel lactam-containing compounds, defined by a general chemical structure (Formula I), that are effective as inhibitors of Factor Xa ('208 Patent, Abstract; col. 5:53-65). The invention covers the chemical compounds themselves, pharmaceutical compositions containing them, and methods of using them to treat thromboembolic disorders ('208 Patent, col. 5:53-6:21). The active ingredient in Eliquis®, apixaban, is one such compound disclosed in the patent.
- Technical Importance: The invention provided a new class of chemical entities for use as direct oral anticoagulants, offering a potential alternative to older treatments that required frequent monitoring or had less favorable side-effect profiles.
Key Claims at a Glance
- The complaint asserts infringement of claims including 8, 13, 26-27, and 55-61 (Compl. ¶20). The independent claims in this set are composition of matter claims (e.g., Claim 8) and method of treatment claims (e.g., Claim 55).
- Claim 8 (representative composition claim):
- A compound according to claim 1, wherein the compound is 1-(4-methoxyphenyl)-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.
- Claim 55 (representative method claim):
- 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 asserts infringement of multiple claims, including dependent claims, and reserves the right to assert others (Compl. ¶¶ 20-23).
U.S. Patent No. 9,326,945 - "Apixaban Formulations," issued May 3, 2016
The Invention Explained
- Problem Addressed: The patent addresses the challenge of achieving consistent in-vivo dissolution and patient exposure for apixaban formulations ('945 Patent, col. 1:45-56). While apixaban's aqueous solubility suggested particle size should not be critical, the inventors found that formulations made with larger particles or through certain manufacturing processes (wet granulation) resulted in "less than optimal exposures" ('945 Patent, col. 1:56-62).
- The Patented Solution: The invention is a specific solid pharmaceutical formulation of apixaban that ensures consistent drug absorption. This is achieved by controlling the particle size of the crystalline apixaban, specifically requiring that 90% of the volume of particles have a diameter (D90) of less than or equal to 89 micrometers (µm) ('945 Patent, col. 2:8-12). This specific particle size distribution is disclosed to lead to a reliable dissolution rate and, consequently, consistent therapeutic effect ('945 Patent, col. 2:1-6).
- Technical Importance: This invention provided a method to overcome the unexpected bioavailability issues with apixaban, enabling the creation of a reliable and commercially viable oral tablet formulation with consistent patient outcomes.
Key Claims at a Glance
- The complaint asserts infringement of claims including 1, 9-12, 20-23, 25, 27, 29, 31, 33, 35, and 37 (Compl. ¶26). Claim 1 is an independent claim.
- Claim 1:
- 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 reserves the right to assert additional claims (Compl. ¶26).
III. The Accused Instrumentality
Product Identification
- The accused instrumentality is the "Aurobindo ANDA product," which is described as 2.5 mg and 5 mg tablets of apixaban, a generic version of Plaintiffs' Eliquis® drug product (Compl. ¶2).
Functionality and Market Context
- The complaint alleges that Aurobindo's product has the same active ingredient (apixaban), dosage form, and strength as Eliquis®, and is bioequivalent to Eliquis® (Compl. ¶14). The product is intended for the same approved indications as Eliquis®, which include reducing the risk of stroke and systemic embolism, prophylaxis of deep vein thrombosis, and treatment of DVT and pulmonary embolism (PE) (Compl. ¶¶ 11, 15). The complaint alleges that Aurobindo intends to engage in the commercial manufacture, use, and sale of this product promptly upon receiving FDA approval (Compl. ¶13).
IV. Analysis of Infringement Allegations
The complaint does not provide a detailed claim chart or specific evidence mapping the features of Aurobindo's ANDA product to the elements of the asserted claims. The infringement allegation is statutory, based on the act of filing an ANDA under 35 U.S.C. § 271(e)(2) for a drug claimed in a patent. The core of the allegation rests on the representation to the FDA that the proposed generic product is bioequivalent and has the same active ingredient, dosage form, and strength as the branded product, Eliquis® (Compl. ¶14).
'208 Patent Infringement Allegations
| Claim Element (from Independent Claim 8) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A compound... which is 1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-7-one [apixaban]... | The Aurobindo ANDA product contains apixaban as its active ingredient. | ¶14 | col. 62:38-46 |
| or a pharmaceutically acceptable salt form thereof. | The complaint does not specify if the Aurobindo ANDA product is a salt form, but alleges it is a generic version of Eliquis®. | ¶2 | col. 5:53-62 |
'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... | The Aurobindo ANDA product is a solid tablet formulation containing apixaban. | ¶2, ¶14 | col. 2:8-12 |
| wherein the crystalline apixaban particles have a D90 equal to or less than about 89 µm... | The complaint alleges the ANDA product is a generic version of and bioequivalent to Eliquis®, which Plaintiffs allege is covered by the '945 patent. An explicit allegation regarding particle size is not present. | ¶2, ¶14 | col. 2:9-12 |
| 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 does not provide data on the dissolution profile of the ANDA product but relies on the bioequivalence representation to allege infringement. | ¶14, ¶26 | col. 10:14-26 |
- Identified Points of Contention:
- Technical Questions: A primary question for the litigation will be evidentiary: does Aurobindo’s proposed generic product, in fact, meet the specific limitations of the ’945 Patent claims? The complaint does not provide test data for the particle size (D90) or the dissolution rate of the Aurobindo ANDA product. This information will be a central focus of discovery.
- Scope Questions: For the '945 Patent, the interpretation of "about 89 µm" may become a point of contention, particularly if Aurobindo's product has a D90 value very close to, but not exactly at or below, 89 µm. The complaint does not provide sufficient detail for analysis of this specific element.
- Figure 3 from the '945 patent, incorporated into the complaint as part of Exhibit B, shows a graph of dissolution rates for 2.5-mg apixaban tablets as a function of drug substance particle size (D90), illustrating the claimed relationship between smaller particle size and faster dissolution (Compl. ¶10; '945 Patent, Fig. 3). The litigation may focus on whether Aurobindo's product falls on the compliant side of the performance curve depicted.
V. Key Claim Terms for Construction
For the '208 Patent, a composition of matter patent for a specific chemical entity, the infringement analysis is typically straightforward and may not require extensive claim construction. The dispute will likely focus on the formulation claims of the '945 Patent.
- The Term: "a D90 equal to or less than about 89 µm" (from Claim 1 of the '945 Patent)
- Context and Importance: This term is the central technical limitation of the '945 Patent, distinguishing the invention from prior art formulations. The definition of "about" will determine the effective boundary of the claim. Practitioners may focus on this term because even a small deviation in measured particle size could determine the outcome of infringement.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The use of the word "about" itself suggests the patentee did not intend the 89 µm value to be an absolute, precise limit. A party could argue it is meant to encompass values that are technically equivalent and achieve the same result of consistent bioavailability ('945 Patent, col. 2:1-6).
- Evidence for a Narrower Interpretation: The specification repeatedly and consistently recites "about 89 µm" as the cutoff that "impacts apixaban absorption rate" ('945 Patent, col. 1:57-59). The patent presents this as a surprising discovery, which might suggest the number itself is critical. Further, Figure 4 shows data for a 119 µm particle size, suggesting the patentee could have claimed a higher number but chose not to, potentially limiting the scope of "about."
VI. Other Allegations
- Indirect Infringement: The complaint alleges that Aurobindo's commercial manufacture, use, and sale of its ANDA product would induce and/or contribute to infringement by others (e.g., doctors and patients) (Compl. ¶¶ 21-22, 27). This is based on the allegation that Aurobindo is seeking approval to market the product for the same treatments for which Eliquis® is prescribed (Compl. ¶15).
VII. Analyst’s Conclusion: Key Questions for the Case
- A primary issue will be one of evidentiary proof: Will discovery and testing confirm that Aurobindo’s proposed generic product has crystalline apixaban particles with a D90 of less than or equal to 89 µm and dissolves at a rate of at least 77% in 30 minutes, as required by the asserted claims of the '945 patent? The complaint rests on the legal presumption of infringement from the ANDA filing, but this will need to be substantiated with technical evidence.
- A second issue will be one of claim scope: Should Aurobindo's product fall near the claimed 89 µm boundary, the case may turn on the construction of the term "about." The court's interpretation will determine whether the claim encompasses only values strictly at or below 89 µm, or if it allows for a margin of variability that still achieves the patent's stated goal of consistent bioavailability.