DCT
1:17-cv-00407
Bristol Myers Squibb Co v. Sandoz Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Bristol-Myers Squibb Company (Delaware) and Pfizer Inc. (Delaware)
- Defendant: Sandoz Inc. (Colorado)
- Plaintiff’s Counsel: Farnan, LLP; Wilmer Cutler Pickering Hale and Dorr LLP
- Case Identification: 1:17-cv-00407, D. Del., 04/10/2017
- Venue Allegations: Venue is alleged to be proper in the District of Delaware because Sandoz committed a statutory act of infringement by filing its Abbreviated New Drug Application (ANDA) with the intent to market its product in Delaware, and because Sandoz allegedly maintains systematic and continuous business contacts within the state.
- Core Dispute: Plaintiffs allege that Defendant’s filing of an ANDA to market generic versions of the anticoagulant drug Eliquis® (apixaban) constitutes an act of infringement of two patents covering the apixaban chemical compound and specific pharmaceutical formulations thereof.
- Technical Context: The patents relate to Factor Xa inhibitors, a class of anticoagulant medications used for the treatment and prevention of thromboembolic disorders such as stroke, deep vein thrombosis, and pulmonary embolism.
- Key Procedural History: This lawsuit was initiated under the Hatch-Waxman Act following Plaintiffs' receipt of a notice letter from Sandoz. The letter contained a Paragraph IV certification asserting that the patents-in-suit are invalid, unenforceable, and/or will not be infringed by Sandoz's proposed 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 |
| 2017-03-09 | Sandoz sends Eliquis® Notice Letter |
| 2017-03-10 | Plaintiffs receive Eliquis® Notice Letter |
| 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"
- Patent Identification: U.S. Patent No. 6,967,208, titled "Lactam-Containing Compounds and Derivatives thereof as Factor Xa Inhibitors," issued November 22, 2005 (Compl. ¶13).
The Invention Explained
- Problem Addressed: The patent describes a need for effective and specific inhibitors of Factor Xa, a key enzyme in the blood coagulation cascade, to treat and prevent thromboembolic disorders. The background implies a need for alternatives to existing anticoagulants with potentially improved pharmacological properties (Compl. ¶13; ’208 Patent, col. 5:22-34).
- The Patented Solution: The invention provides a novel class of lactam-containing chemical compounds that are potent inhibitors of Factor Xa. The patent discloses a broad genus of related compounds and specific, preferred embodiments, including the compound that would become known as apixaban (’208 Patent, Abstract; col. 5:53-57).
- Technical Importance: The discovery of this class of compounds provided a new molecular entity for direct Factor Xa inhibition, offering a novel mechanism for oral anticoagulant therapy (’208 Patent, col. 5:5-15).
Key Claims at a Glance
- The complaint asserts infringement of claims 8, 13, 26-27, and 55-61 (Compl. ¶24). Claim 8 is a compound claim that recites the specific chemical structure of apixaban.
- Essential Elements 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-1H-pyrazolo[3,4-c]pyridine-3-carboxamide,
- or a stereoisomer or a pharmaceutically acceptable salt thereof.
- The complaint reserves the right to assert other claims, including dependent claims (Compl. ¶24).
U.S. Patent No. 9,326,945 - "Apixaban Formulations"
- Patent Identification: U.S. Patent No. 9,326,945, titled "Apixaban Formulations," issued May 3, 2016 (Compl. ¶14).
The Invention Explained
- Problem Addressed: The patent explains the unexpected discovery that, despite apixaban’s adequate aqueous solubility, formulations made with large particles of the drug substance or through a wet granulation process resulted in inconsistent and "less than optimal" drug exposure in patients (’945 Patent, col. 1:45-62).
- The Patented Solution: The invention is a solid pharmaceutical formulation of apixaban that solves the exposure problem by controlling the particle size of the crystalline drug substance. The patent teaches that ensuring at least 90% of the particles by volume (D90) are no larger than 89 microns results in consistent in-vivo dissolution and reliable bioavailability (’945 Patent, col. 2:6-18; col. 2:63-col. 3:3).
- Technical Importance: This finding was critical for developing a commercially viable oral tablet for apixaban, as it provided a method to ensure patients receive a consistent and predictable therapeutic dose, a crucial safety factor for an anticoagulant (’945 Patent, col. 2:1-5).
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. ¶30). Claims 1 and 12 are independent.
- Essential Elements of Independent 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 other claims, including dependent claims (Compl. ¶30).
III. The Accused Instrumentality
- Product Identification: The accused instrumentality is the "Sandoz ANDA product," identified as 2.5 mg and 5 mg tablets of apixaban for which Sandoz seeks FDA approval under ANDA No. 209981 (Compl. ¶2).
- Functionality and Market Context: The complaint alleges that the Sandoz ANDA product has the same active ingredient, dosage form, and strength as Plaintiffs' Eliquis® product and is bioequivalent to it (Compl. ¶18). Sandoz is allegedly seeking approval to market its product for the same indications as Eliquis®, which is used to treat and prevent thromboembolic disorders (Compl. ¶19). Eliquis® is described as a "revolutionary" pharmaceutical product for serious diseases (Compl. ¶5).
- No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
The complaint does not contain detailed infringement allegations or claim charts, as is common in initial complaints filed in ANDA litigation prior to discovery of the confidential ANDA contents. The infringement theory must be inferred from the claims and the nature of the accused product.
- '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]pyridine-3-carboxamide, or a stereoisomer or a pharmaceutically acceptable salt thereof. | The Sandoz ANDA product is alleged to contain apixaban as its active pharmaceutical ingredient. By filing its ANDA, Sandoz has represented to the FDA that its product contains the same active ingredient as Eliquis®, which is the compound recited in claim 8. | ¶18 | col. 265:39-46 |
Identified Points of Contention:
- Scope Questions: For a compound claim in an ANDA case, where the generic must contain the "same" active ingredient, there is limited room for a non-infringement argument based on chemical structure. Any dispute will likely center on the validity or enforceability of the patent, as asserted by Sandoz in its Paragraph IV certification (Compl. ¶20).
'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 and a pharmaceutically acceptable diluent or carrier, | The Sandoz ANDA product is a solid tablet containing apixaban, and is alleged to be bioequivalent to Eliquis®, thereby containing a therapeutically effective amount. | ¶2, ¶18 | col. 11:1-2 |
| wherein the crystalline apixaban particles have a D90 equal to or less than about 89 µm, | The complaint does not provide specific data but alleges that the Sandoz ANDA product infringes. This implies that the product described in Sandoz's confidential ANDA meets this particle size limitation. | ¶30 | col. 11:2-4 |
| 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 specific data but alleges that the Sandoz ANDA product infringes. This implies that the product described in Sandoz's confidential ANDA meets this in-vitro dissolution profile limitation. | ¶30 | col. 11:5-8 |
- Identified Points of Contention:
- Technical Questions: A primary issue will be factual: do the apixaban particles in the Sandoz ANDA product, as specified in its application, actually have a D90 of less than or equal to about 89 µm and meet the claimed dissolution rate? The resolution will depend on evidence from the ANDA itself.
- Scope Questions: The construction of "about 89 µm" may be a key point of dispute. The parties may contest the degree of numerical flexibility this term affords and whether the Sandoz product's particle size falls within that scope.
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 term is the central technical limitation of the ’945 Patent's claims and defines the boundary of the invention. The interpretation of "about" will determine the literal scope of the claim and could be dispositive of infringement if the Sandoz product has a D90 value close to, but not exactly at or below, 89 µm.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: A party arguing for a broader scope may point to the specification’s characterization of the invention as a surprising discovery that particle size mattered at all, with the 89 µm threshold being the point at which consistent exposure was achieved. The use of "about" may be argued to cover any particle size that achieves this functional result (’945 Patent, col. 2:50-54).
- Evidence for a Narrower Interpretation: A party arguing for a narrower scope may highlight that the 89 µm value is consistently and specifically recited throughout the patent, including in the abstract, summary, and claims, suggesting it is a critical and deliberate ceiling (’945 Patent, Abstract; col. 2:9-10). The specification's discussion of allowing for "typical variability" by claiming less than 89 microns could be used to argue the term "about" is intended to cover only minor experimental or measurement variance (’945 Patent, col. 11:40-45).
VI. Other Allegations
- Indirect Infringement: The complaint alleges both induced and contributory infringement for both patents. The factual basis alleged is that Sandoz intends to market its ANDA product for the same approved indications as Eliquis®, and its product label will instruct physicians and patients to use the drug in an infringing manner (i.e., infringing the asserted method of treatment claims) (Compl. ¶¶ 25-26, 31).
- Willful Infringement: The complaint does not contain an explicit allegation of willful infringement.
VII. Analyst’s Conclusion: Key Questions for the Case
- A primary issue for the ’208 patent will be one of validity. Given that the accused generic product must contain the same active ingredient (apixaban), infringement of the compound claim appears direct. The case will likely turn on Sandoz's defenses, asserted in its Paragraph IV certification, that the patent is invalid (e.g., anticipated or obvious) or otherwise unenforceable.
- For the ’945 patent, a central question is one of factual proof and claim scope. The dispute will focus on whether the specific formulation characteristics of the Sandoz product, as detailed in its confidential ANDA, fall within the boundaries of the asserted claims, particularly the "about 89 µm" particle size limitation.
- A broader question underlying the dispute is whether the formulation improvements of the ’945 patent constitute a non-obvious invention over the foundational compound disclosed in the ’208 patent. The court will need to determine if controlling apixaban's particle size to achieve consistent bioavailability was an inventive step or a routine optimization that a person of ordinary skill in the art would have been motivated to perform.