DCT
1:17-cv-00399
Bristol Myers Squibb Co v. Apotex Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Bristol-Myers Squibb Company (Delaware) and Pfizer Inc. (Delaware)
- Defendant: Apotex, Inc. (Canada) and Apotex Corp. (Delaware)
- Plaintiff’s Counsel: Farnan, LLP; Wilmer Cutler Pickering Hale and Dorr LLP
- Case Identification: 1:17-cv-00399, D. Del., 04/10/2017
- Venue Allegations: Venue is based on Defendant Apotex's agreement, communicated through counsel, not to contest jurisdiction or venue in the District of Delaware.
- Core Dispute: Plaintiffs allege that Defendant's filing of an Abbreviated New Drug Application (ANDA) for generic apixaban tablets constitutes an act of infringement of three patents covering the apixaban compound and its pharmaceutical formulations.
- Technical Context: The case concerns apixaban (marketed as Eliquis®), a direct Factor Xa inhibitor used as an anticoagulant for the treatment and prevention of thromboembolic disorders.
- Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiffs' receipt of a notice letter from Apotex on or after March 13, 2017. The letter contained a Paragraph IV certification asserting that the patents-in-suit are invalid, unenforceable, and/or will not be infringed by Apotex's proposed generic product.
Case Timeline
| Date | Event |
|---|---|
| 1998-12-23 | ’980 Patent Earliest Priority Date |
| 2001-09-21 | ’208 Patent Earliest Priority Date |
| 2002-07-02 | ’980 Patent Issued |
| 2005-11-22 | ’208 Patent Issued |
| 2010-02-25 | ’945 Patent Earliest Priority Date |
| 2016-05-03 | ’945 Patent Issued |
| 2017-03-13 | Apotex sent Eliquis Notice Letter to Plaintiffs |
| 2017-04-10 | Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 6,413,980 - "Nitrogen Containing Heterobicycles as Factor Xa Inhibitors," issued 07/02/2002
The Invention Explained
- Problem Addressed: The patent addresses the medical need for potent and selective inhibitors of Factor Xa, a critical enzyme in the blood coagulation cascade, to treat and prevent thromboembolic disorders (e.g., blood clots) ('980 Patent, col. 2:18-38).
- The Patented Solution: The invention provides a novel genus of "nitrogen containing heterobicycles," which are complex chemical compounds designed to act as inhibitors of Factor Xa ('980 Patent, Abstract; col. 2:40-44). The patent describes a core bicyclic chemical structure and a wide array of possible substituent groups, defining a large family of potential therapeutic compounds ('980 Patent, col. 3:5-6:65).
- Technical Importance: The invention disclosed a new class of chemical structures for selectively targeting Factor Xa, offering a potential therapeutic pathway for anticoagulation distinct from previous, less specific agents ('980 Patent, col. 2:33-38).
Key Claims at a Glance
- The complaint asserts claims 5-8, 10, and 16 (Compl. ¶23). The lead independent claim appears to be claim 1, on which other asserted claims depend.
- Essential elements of Independent Claim 1:
- A compound selected from a large Markush group defined by general formulas I or II, which describe a bicyclic core with numerous specified substituent groups.
- The complaint reserves the right to assert additional claims.
U.S. Patent No. 6,967,208 - "Lactam-Containing Compounds and Derivatives thereof as Factor Xa Inhibitors," issued 11/22/2005
The Invention Explained
- Problem Addressed: The patent seeks to identify new Factor Xa inhibitors with improved pharmacological characteristics, such as enhanced potency, selectivity, solubility, and bioavailability, which are desirable for developing an effective oral anticoagulant drug ('208 Patent, col. 5:26-52).
- The Patented Solution: The invention discloses novel "lactam-containing compounds" that function as Factor Xa inhibitors. Crucially, the patent specifically identifies and claims the compound apixaban by its chemical name and provides methods for its synthesis ('208 Patent, Abstract; col. 62:38-44; col. 158:34-64, Example 1-1).
- Technical Importance: This patent claims the specific active pharmaceutical ingredient, apixaban, that was successfully developed and commercialized as the drug Eliquis®.
Key Claims at a Glance
- The complaint asserts claims 8, 13, 26-27, and 55-61 (Compl. ¶28). Claim 8 is an independent claim directed to the specific compound.
- Essential element of Independent Claim 8:
- A compound which is 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one.
- The complaint reserves the right to assert additional claims.
U.S. Patent No. 9,326,945 - "Apixaban Formulations," issued 05/03/2016
- Patent Identification: U.S. Patent No. 9,326,945, "Apixaban Formulations," issued 05/03/2016 (Compl. ¶13).
- Technology Synopsis: The patent addresses the problem of inconsistent drug absorption observed in early apixaban formulations, which could compromise therapeutic consistency ('945 Patent, col. 1:45-62). The invention is based on the discovery that formulating apixaban with crystalline particles having a particle size distribution where 90% of the particles are no larger than 89 micrometers (D90 ≤ 89 µm) leads to consistent in-vivo dissolution and predictable bioavailability ('945 Patent, Abstract; col. 2:9-17).
- Asserted Claims: The complaint asserts claims 1, 9-12, 20-23, 25, 27, 29, 31, 33, 35, and 37, including independent claim 1 (Compl. ¶34).
- Accused Features: The complaint alleges that Apotex's ANDA product, in order to be bioequivalent to Plaintiffs' Eliquis® product as required by the FDA, must necessarily be formulated with the claimed particle size characteristics (Compl. ¶¶ 17, 34).
III. The Accused Instrumentality
- Product Identification: The accused instrumentality is Apotex's proposed generic 2.5 mg and 5 mg apixaban tablets, for which Apotex seeks FDA approval via ANDA No. 210091 (the "Apotex ANDA product") (Compl. ¶2).
- Functionality and Market Context: The Apotex ANDA product is intended as a generic substitute for Plaintiffs' branded drug, Eliquis® (Compl. ¶2). By filing its ANDA, Apotex has represented to the FDA that its product contains the same active ingredient (apixaban), has the same dosage form and strength, is bioequivalent, and is intended for the same medical indications as Eliquis®, including the treatment of thromboembolic disorders (Compl. ¶¶ 14, 17-18). The product is designed to compete directly with Eliquis® upon receiving FDA approval (Compl. ¶16).
No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
The complaint does not contain detailed claim charts. The infringement allegations are based on the nature of the Apotex ANDA filing itself.
'980 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A compound selected from the group: [of nitrogen-containing heterobicycles defined by Formula I or II] | The active pharmaceutical ingredient, apixaban, in the Apotex ANDA product is alleged to be a chemical compound that falls within the genus of structures defined by the claim. | ¶17, ¶23 | col. 220:30-221:20 |
'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-7H-pyrazolo[3,4-c]pyridin-7-one. | The active pharmaceutical ingredient in the Apotex ANDA product is apixaban. The complaint alleges that Apotex's product contains this exact chemical structure as its active ingredient. | ¶17, ¶28 | col. 266:39-44 |
- Identified Points of Contention:
- Scope Questions: For the '980 Patent, a primary question will be whether apixaban is properly encompassed by the broad Markush genus claimed in claim 1. This raises the question of whether the patent's specification provides adequate written description and enablement for the specific apixaban compound, which is one of many thousands of theoretical compounds covered by the claim language.
- Technical Questions: For the '208 Patent, infringement of compound claim 8 appears to be a direct consequence of Apotex using apixaban as the active ingredient. Therefore, the central dispute will likely focus on Apotex's asserted defenses of invalidity (Compl. ¶19), questioning whether claim 8 was anticipated or rendered obvious by prior art, which could include Plaintiffs' own earlier '980 patent.
V. Key Claim Terms for Construction
- The Term: "A compound selected from the group" (referring to the Markush group of Formula I in claim 1 of the '980 patent).
- Context and Importance: The construction and validity of this broad genus claim in the '980 Patent are critical. The infringement case for this patent depends entirely on whether apixaban falls within this genus and whether the claim is valid as written. Practitioners may focus on this term because successfully invalidating this genus claim for lack of written description or enablement could eliminate the earliest-expiring patent from the dispute.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification provides extensive lists of variables for the substituent groups (A, B, G, etc.) that can be combined to form the claimed compounds, suggesting an intent to claim a wide chemical space ('980 Patent, col. 7:24-9:66). This breadth may be argued to cover all combinations, including apixaban.
- Evidence for a Narrower Interpretation: The specification discloses a finite number of synthesized examples ('980 Patent, col. 84-214). A party challenging the patent could argue that the disclosure does not adequately describe or enable the "vast" genus claimed and that the invention is limited to the actually synthesized compounds or a much smaller, more clearly described subset that may not include apixaban.
VI. Other Allegations
- Indirect Infringement: The complaint alleges that Apotex will induce and contribute to infringement of the patents-in-suit (Compl. ¶¶ 24, 29-30, 35). The factual basis for this allegation is Apotex's filing of an ANDA for its product with proposed labeling that will instruct physicians and patients to use the generic apixaban tablets for the same patented indications as Eliquis®, thereby infringing method-of-use claims upon approval (Compl. ¶¶ 18, 25, 30-31, 36).
- Willful Infringement: The complaint does not contain an explicit allegation of "willful infringement." However, it pleads facts that could support a later argument for enhanced damages, such as Apotex's knowledge of the patents via their listing in the FDA's Orange Book and its receipt of the Paragraph IV notice letter prior to the filing of the lawsuit (Compl. ¶¶ 14, 15, 19).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central issue for the court will be one of validity: Since infringement of the '208 patent's claim to the apixaban compound appears direct, Apotex’s defense will likely depend on its ability to prove that the asserted patent claims are invalid as anticipated or obvious, as asserted in its Paragraph IV certification. The relationship between the broad genus in the '980 patent and the specific compound in the later '208 patent will be a key focus of this analysis.
- A key evidentiary question for the '945 patent will be one of infringement by bioequivalence: Will the evidence show that in order for Apotex's product to meet the FDA's bioequivalence standard relative to Eliquis® (Compl. ¶17), it must necessarily be formulated using the specific particle size limitations recited in the '945 patent claims?