DCT
1:23-cv-01008
Celgene Corp v. Teva Pharma Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Celgene Corporation (Delaware), Celgene International Sàrl (Switzerland), and Bristol-Myers Squibb Company (Delaware)
- Defendant: Teva Pharmaceuticals, Inc. (Delaware)
- Plaintiff’s Counsel: Farnan LLP; Wilmer Cutler Pickering Hale and Dorr LLP
- Case Identification: 1:23-cv-01008, D. Del., 09/13/2023
- Venue Allegations: Venue is alleged to be proper as Defendant is a Delaware corporation.
- Core Dispute: Plaintiff alleges that Defendant’s Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff’s Onureg® drug product infringes two patents related to oral formulations of azacitidine.
- Technical Context: The technology concerns pharmaceutical compositions for the oral delivery of azacitidine, a nucleoside metabolic inhibitor used as a cancer treatment, particularly for acute myeloid leukemia.
- Key Procedural History: This Hatch-Waxman litigation was initiated in response to a Notice Letter from Teva, which informed Plaintiff of Teva’s ANDA filing. The Notice Letter included a Paragraph IV certification asserting that the patents-in-suit are invalid as obvious under 35 U.S.C. § 103, but did not contest infringement of the asserted claims should they be found valid.
Case Timeline
| Date | Event |
|---|---|
| 2008-05-15 | Priority Date for ’628 and ’436 Patents |
| 2014-09-30 | U.S. Patent No. 8,846,628 Issues |
| 2023-02-07 | U.S. Patent No. 11,571,436 Issues |
| 2023-08-08 | Teva sends Notice Letter regarding ANDA filing |
| 2023-09-13 | Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
No probative visual evidence provided in complaint.
U.S. Patent No. 8,846,628 - “Oral Formulations of Cytidine Analogs and Methods of Use Thereof” (Issued Sep. 30, 2014)
The Invention Explained
- Problem Addressed: The patent describes the difficulty of developing an oral dosage form for cytidine analogs like 5-azacytidine due to their chemical instability in the acidic environment of the stomach (’436 Patent, col. 4:10-15). Prior art approaches consequently focused on enteric coatings designed to protect the active pharmaceutical ingredient (API) from the stomach and release it in the lower gastrointestinal tract (’436 Patent, col. 4:15-24).
- The Patented Solution: The invention is a pharmaceutical composition that releases the 5-azacytidine API "substantially in the stomach upon oral administration" (’436 Patent, col. 4:45-49). This approach is counter-intuitive to the problem description, challenging the accepted belief that such a formulation would lead to therapeutically unacceptable hydrolysis of the drug (’436 Patent, col. 4:15-24). The claimed solution is a "non-enteric coated tablet," which allows for immediate release in the stomach.
- Technical Importance: This design simplifies the formulation, avoids organic solvents often required for enteric coatings, and enables different pharmacokinetic profiles and dosing regimens compared to subcutaneous injections or enteric-coated oral forms (’436 Patent, col. 4:30-40).
Key Claims at a Glance
- The complaint asserts independent claims 1 (a composition claim) and 28 (a method of treatment claim) as representative (Compl. ¶¶32, 37).
- Independent Claim 1:
- A pharmaceutical composition for oral administration
- comprising a therapeutically effective amount of 5-azacytidine and at least one pharmaceutically acceptable excipient,
- wherein the composition is a non-enteric coated tablet.
- Independent Claim 28:
- A method for treating one or more symptoms of a disease associated with abnormal cell proliferation,
- comprising orally administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of 5-azacytidine and at least one pharmaceutically acceptable excipient,
- wherein the composition is a non-enteric coated tablet,
- and wherein the disease is myelodysplastic syndrome or acute myelogenous leukemia.
- The complaint asserts infringement of claims 1-9, 11, 13-26, 28-36, 38, and 40-43, thereby including dependent claims (Compl. ¶28).
U.S. Patent No. 11,571,436 - “Oral Formulations of Cytidine Analogs and Methods of Use Thereof” (Issued Feb. 7, 2023)
The Invention Explained
- Problem Addressed: As with its parent, the ’436 Patent addresses the challenges of creating a stable and effective oral formulation for cytidine analogs like 5-azacytidine (’436 Patent, col. 4:10-15).
- The Patented Solution: The ’436 Patent claims a specific oral formulation of 5-azacytidine that is not only a non-enteric coated tablet, but is also characterized by a negative limitation: "a therapeutically effective amount of 5-azacytidine is not absorbed through oral mucosa upon administration to a human subject" (’436 Patent, Abstract; claim 1). This limitation directs absorption to the gastrointestinal tract, rather than the mouth, to ensure a specific type of systemic delivery.
- Technical Importance: By preventing significant absorption through the oral mucosa, the invention seeks to achieve more consistent and predictable pharmacokinetic profiles, avoiding variability that could arise from buccal or sublingual absorption (’436 Patent, col. 10:51-54).
Key Claims at a Glance
- The complaint identifies claim 1 as the sole independent claim and representative of the patent's infringement allegations (Compl. ¶51).
- Independent Claim 1:
- A pharmaceutical composition for oral administration
- comprising 180 mg to 360 mg of 5-azacytidine and at least one pharmaceutically acceptable excipient,
- wherein the composition is a non-enteric coated tablet,
- and wherein a therapeutically effective amount of 5-azacytidine is not absorbed through oral mucosa upon administration to a human subject.
- The complaint asserts infringement of all claims 1-22 (Compl. ¶47).
III. The Accused Instrumentality
- Product Identification: The accused product is Teva Pharmaceuticals, Inc.'s proposed generic version of Onureg®, described as 200 mg and 300 mg tablets of azacitidine for oral use (the "Teva ANDA Product") (Compl. ¶2, ¶34).
- Functionality and Market Context: The Teva ANDA Product is the subject of ANDA No. 218751, filed to obtain FDA approval for marketing prior to the expiration of the patents-in-suit (Compl. ¶1-2). By filing its ANDA, Teva has represented to the FDA that its product has the same active ingredient, dosage form, route of administration, and strength as Onureg®, and is bioequivalent to it (Compl. ¶23). The complaint alleges that Teva is seeking approval for the same indications as Onureg®, which is used for the continued treatment of adult patients with acute myeloid leukemia (Compl. ¶19, ¶24, ¶40).
IV. Analysis of Infringement Allegations
’628 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A pharmaceutical composition for oral administration | The Teva ANDA Product is described as "co-packaged tablets for oral use." | ¶33, ¶34 | ’436 Patent, col. 4:45-49 |
| comprising a therapeutically effective amount of 5-azacytidine | The Teva ANDA Product contains 200 mg and 300 mg dosage strengths of azacitidine, which the complaint alleges is a therapeutically effective amount. | ¶33, ¶34 | ’436 Patent, col. 6:9-12 |
| and at least one pharmaceutically acceptable excipient, | The Teva ANDA Product is a tablet formulation and is alleged to contain at least one such excipient. | ¶33, ¶35 | ’436 Patent, col. 5:65 |
| wherein the composition is a non-enteric coated tablet. | The Teva ANDA Product is alleged to be a non-enteric coated tablet, based on its asserted bioequivalence to Onureg®, which is a non-enteric coated tablet. | ¶33, ¶35 | ’436 Patent, col. 5:3-4 |
’436 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A pharmaceutical composition for oral administration comprising 180 mg to 360 mg of 5-azacytidine | The Teva ANDA Product is offered in 200 mg and 300 mg dosage strengths, which fall within the claimed range. | ¶52, ¶53 | ’436 Patent, col. 38:45-50 |
| and at least one pharmaceutically acceptable excipient, wherein the composition is a non-enteric coated tablet, | The Teva ANDA Product is alleged to be a non-enteric coated tablet containing at least one excipient, based on its asserted bioequivalence to Onureg®. | ¶52, ¶54 | ’436 Patent, col. 5:3-4 |
| and wherein a therapeutically effective amount of 5-azacytidine is not absorbed through oral mucosa upon administration to a human subject. | The complaint alleges that because the Teva ANDA Product is bioequivalent to Onureg®, it necessarily does not result in absorption of a therapeutically effective amount of the drug through the oral mucosa. | ¶52, ¶54 | ’436 Patent, col. 10:51-54 |
- Identified Points of Contention:
- Scope Questions: The complaint notes that Teva's Notice Letter does not contest infringement of the asserted claims to the extent they are valid, instead challenging their validity under 35 U.S.C. § 103 (Compl. ¶25). While the primary dispute will likely concern validity, the infringement case for the ’436 Patent raises the question of whether bioequivalence legally and factually satisfies the negative limitation "not absorbed through oral mucosa."
- Technical Questions: A key evidentiary question for the ’436 Patent infringement claim is what proof, beyond the assertion of bioequivalence, the complaint provides to demonstrate that the Teva ANDA Product meets the specific negative limitation of claim 1. The plaintiff's theory appears to rest entirely on the legal implications of Teva's ANDA filing (Compl. ¶54).
V. Key Claim Terms for Construction
The Term: "non-enteric coated tablet"
Context and Importance: This term is central to the asserted claims of both patents and captures the core departure from prior art, which favored protecting the API from the stomach. Practitioners may focus on this term because its construction will define the boundary between the patented invention and prior art formulations that used coatings to delay release until after the stomach.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification defines the invention in the negative, stating that certain embodiments provide compositions that "do not have an enteric coating (i.e., are non-enteric-coated)" (’436 Patent, col. 6:14-15). This suggests the term broadly covers any tablet lacking a coating specifically designed to resist gastric fluid.
- Evidence for a Narrower Interpretation: The specification also states that tablets may "optionally further contain a coating of the drug core" (’436 Patent, col. 5:24-26). A defendant might explore whether specific embodiments or statements in the prosecution history (not provided in the complaint) limit the types of permissible non-enteric coatings.
The Term: "a therapeutically effective amount of 5-azacytidine is not absorbed through oral mucosa"
Context and Importance: This negative limitation in claim 1 of the ’436 Patent is critical for distinguishing it from other oral dosage forms and is a key element of the infringement allegation. The dispute will turn on what level of absorption, if any, is permissible under this claim.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The phrase "therapeutically effective amount" suggests that a de minimis or therapeutically insignificant amount of absorption through the oral mucosa might not negate infringement. This interpretation would focus on whether the primary therapeutic effect is derived from gastrointestinal, not mucosal, absorption.
- Evidence for a Narrower Interpretation: The patent does not appear to explicitly define a quantitative threshold for what constitutes a "therapeutically effective amount" absorbed through the oral mucosa. A defendant may argue that the term is indefinite or that any detectable mucosal absorption falls outside the claim's scope, raising questions of both non-infringement and invalidity.
VI. Other Allegations
- Indirect Infringement: The complaint alleges inducement of infringement against Teva. The factual basis is that Teva's proposed product label will instruct medical practitioners and patients to administer the Teva ANDA Product for the FDA-approved indication of treating acute myeloid leukemia, which is a method of treatment covered by claim 28 of the ’628 Patent (Compl. ¶29, ¶38, ¶40, ¶42). The complaint alleges Teva has knowledge of the patents based on the FDA's Orange Book listing and Teva's own Notice Letter (Compl. ¶43).
- Willful Infringement: While not using the term "willful infringement" in a heading, the complaint alleges that "Teva is aware, has knowledge, and/or is willfully blind to the fact that patients will administer and/or medical practitioners will prescribe and/or administer the Teva ANDA Product in accordance with its proposed label indications" (Compl. ¶44). This allegation is based on pre-suit knowledge derived from the Orange Book listing and the Notice Letter sent by Teva itself (Compl. ¶43).
VII. Analyst’s Conclusion: Key Questions for the Case
While the complaint indicates that patent validity will be the central battleground of the litigation, the infringement allegations themselves present key questions for the court.
- A core issue will be one of evidentiary sufficiency: In the context of ANDA litigation, does a defendant’s representation of bioequivalence legally suffice to prove infringement of a negative claim limitation, such as the requirement in the ’436 Patent that a "therapeutically effective amount...is not absorbed through oral mucosa"?
- A second key question will be one of definitional scope: How will the court construe "non-enteric coated tablet"? The answer will determine whether the invention is narrowly confined to specific immediate-release formulations or broadly covers any oral tablet that is not designed to bypass the stomach, which will be critical for both infringement and the inevitable validity challenge.