DCT
1:23-cv-00699
Celgene Corp v. MSN Laboratories Pvt Ltd
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Celgene Corporation (Delaware), Celgene International Sàrl (Switzerland), and Bristol-Myers Squibb Company (Delaware)
- Defendant: MSN Laboratories Private Limited (India) and MSN Pharmaceuticals, Inc. (Delaware)
- Plaintiff’s Counsel: Farnan LLP
- Case Identification: 1:23-cv-00699, D. Del., 06/27/2023
- Venue Allegations: Venue is alleged to be proper as to MSN Pharmaceuticals, Inc. due to its incorporation in Delaware and as to MSN Laboratories Private Limited because it is not a U.S. resident. The complaint notes that the Defendants agreed not to contest venue.
- Core Dispute: Plaintiffs allege that Defendants’ Abbreviated New Drug Application (ANDA) to market a generic version of the cancer drug Onureg® (azacitidine) infringes patents related to oral formulations of azacitidine.
- Technical Context: The technology concerns oral pharmaceutical compositions of azacitidine, a nucleoside metabolic inhibitor used for the continued treatment of acute myeloid leukemia (AML).
- Key Procedural History: This action arises under the Hatch-Waxman Act, triggered by Defendants' submission of ANDA No. 218435 containing a Paragraph IV certification that the patents-in-suit are invalid. Plaintiffs' patents are listed in the U.S. Food and Drug Administration's "Orange Book" as covering their Onureg® product.
Case Timeline
| Date | Event |
|---|---|
| 2008-05-15 | Priority Date for U.S. Patent No. 8,846,628 |
| 2008-05-15 | Priority Date for U.S. Patent No. 11,571,436 |
| 2014-09-30 | U.S. Patent No. 8,846,628 Issued |
| 2023-02-07 | U.S. Patent No. 11,571,436 Issued |
| 2023-05-16 | Date of Defendants' Notice Letter to Plaintiffs |
| 2023-06-27 | Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
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 delivering cytidine analogs like 5-azacytidine orally due to their chemical instability in the acidic environment of the stomach, enzymatic instability, and poor permeability (’628 Patent, col. 4:9-15). Prior art approaches often involved enteric coatings designed to bypass the stomach entirely (’628 Patent, col. 4:15-24).
- The Patented Solution: The invention provides pharmaceutical compositions, specifically "non-enteric coated" tablets, that release the 5-azacytidine active ingredient "substantially in the stomach" (’628 Patent, col. 4:45-48). This approach is presented as a solution that enables effective oral administration for treating diseases associated with abnormal cell proliferation, such as myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) (’628 Patent, col. 3:51-60).
- Technical Importance: This approach provided a more convenient oral dosage form for a cancer therapy previously limited to subcutaneous or intravenous administration, potentially improving patient compliance and eliminating injection-site reactions (’628 Patent, col. 4:5-9).
Key Claims at a Glance
- The complaint asserts claims 1-9, 11, 13-26, 28-36, 38, and 40-43, with claims 1 and 28 identified as representative (Compl. ¶¶40, 44, 49).
- Independent Claim 1 (Composition Claim):
- 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 (Method Claim):
- A method for treating one or more symptoms of a disease associated with abnormal cell proliferation,
- comprising orally administering a pharmaceutical composition with a therapeutically effective amount of 5-azacytidine and an excipient,
- wherein the composition is a non-enteric coated tablet,
- and wherein the disease is myelodysplastic syndrome or acute myelogenous leukemia.
- The complaint does not explicitly reserve the right to assert dependent claims, but asserts a wide range of them (Compl. ¶40).
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: The patent addresses the same challenges as its parent ’628 Patent: the chemical and enzymatic instability and poor permeability that have historically made oral delivery of cytidine analogs difficult (’436 Patent, col. 4:9-30).
- The Patented Solution: This patent claims an oral formulation designed for release in the stomach, but refines the invention by claiming a specific dosage range of 5-azacytidine and adding a negative limitation that the drug is not absorbed through the oral mucosa (’436 Patent, Abstract; ’436 Patent, cl. 1). This further specifies the formulation as one intended for gastrointestinal, rather than sublingual or buccal, absorption.
- Technical Importance: The invention refines the oral dosage form to a specific therapeutic window and delivery pathway, providing a more targeted approach for achieving desired pharmacokinetic profiles with oral azacitidine (’436 Patent, col. 6:9-12).
Key Claims at a Glance
- The complaint asserts claims 1-22, with claim 1 identified as the sole independent claim (Compl. ¶¶59, 63).
- Independent Claim 1 (Composition Claim):
- 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 all dependent claims 2-22 (Compl. ¶59).
III. The Accused Instrumentality
Product Identification
- The accused instrumentality is the "MSN ANDA Product," which are proposed 200 mg and 300 mg tablets of azacitidine for oral administration (Compl. ¶2).
Functionality and Market Context
- The complaint alleges that the MSN ANDA Product is a generic version of Plaintiffs' Onureg® product (Compl. ¶2). It is alleged to have the same active ingredient, dosage form, route of administration, and strength as Onureg®, and to be bioequivalent (Compl. ¶35). The complaint further alleges that MSN is seeking approval to market its product for the same indications as Onureg®, which is used for the continued treatment of adult patients with acute myeloid leukemia (AML) (Compl. ¶¶31, 36).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint.
’628 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A pharmaceutical composition for oral administration | The MSN ANDA Product is an oral tablet. | ¶46 | col. 4:44-48 |
| comprising a therapeutically effective amount of 5-azacytidine | The MSN ANDA Product contains 200 mg and 300 mg of azacitidine (also known as 5-azacytidine), which is alleged to be a therapeutically effective amount. | ¶46 | col. 6:9-12 |
| and at least one pharmaceutically acceptable excipient | The MSN ANDA Product contains at least one excipient, as it is a tablet form bioequivalent to Onureg®. | ¶47 | col. 5:6-8 |
| wherein the composition is a non-enteric coated tablet | The MSN ANDA Product is alleged to be a non-enteric coated tablet because it is bioequivalent to Plaintiffs' Onureg® product, which is a non-enteric coated tablet. | ¶47 | col. 5:3-4 |
- Identified Points of Contention:
- Scope Questions: A central question may be the construction of "non-enteric coated tablet." The dispute may focus on whether this term simply means the absence of a conventional enteric coating or if it requires an affirmative technical design for immediate release substantially in the stomach.
- Technical Questions: The complaint's infringement theory for this claim rests heavily on the allegation that the MSN ANDA Product is bioequivalent to Onureg® (Compl. ¶47). A key question for the court will be what factual evidence supports the assertion that the accused product is, in fact, a "non-enteric coated tablet," beyond the representation of bioequivalence.
’436 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A pharmaceutical composition for oral administration | The MSN ANDA Product is an oral tablet. | ¶66 | col. 4:44-48 |
| comprising 180 mg to 360 mg of 5-azacytidine | The MSN ANDA Product is available in 200 mg and 300 mg dosage strengths, which falls within the claimed range. | ¶65 | col. 6:9-12 |
| and at least one pharmaceutically acceptable excipient | The MSN ANDA Product is a tablet formulation and therefore contains at least one excipient. | ¶66 | col. 5:6-8 |
| wherein the composition is a non-enteric coated tablet | The MSN ANDA Product is alleged to be a non-enteric coated tablet due to its asserted bioequivalence to Onureg®. | ¶66 | 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 | This property is alleged based on the MSN product's bioequivalence to Onureg®, which is asserted to not be absorbed through the oral mucosa. | ¶66 | col. 4:9-14 |
- Identified Points of Contention:
- Scope Questions: The construction of the negative limitation "not absorbed through oral mucosa" will be critical. The parties may dispute the level of absorption that this term permits (e.g., zero, negligible, or simply not the primary pathway).
- Technical Questions: The infringement allegation for the final limitation is based on an inference from bioequivalence (Compl. ¶66). A key evidentiary question will be whether the facts supporting bioequivalence are sufficient to prove this negative limitation or if direct evidence of the accused product's absorption profile is required.
V. Key Claim Terms for Construction
The Term: "non-enteric coated tablet" (asserted in both patents)
Context and Importance: This term is the central point of novelty, distinguishing the invention from prior art that sought to protect acid-labile cytidine analogs by bypassing the stomach with enteric coatings. Its definition will determine the scope of both patents.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification defines a non-enteric-coated composition as one that "does not comprise a coating intended to release the active ingredient(s) beyond the stomach (e.g., in the intestine)" (’628 Patent, col. 11:39-43). This language could support a construction that focuses on the absence of a specific type of coating.
- Evidence for a Narrower Interpretation: The specification repeatedly states that the inventive compositions "release the API substantially in the stomach" (’628 Patent, col. 4:45-48). This could support a narrower construction requiring not just the absence of an enteric coat but also an affirmative functional characteristic of stomach-based release.
The Term: "not absorbed through oral mucosa" (’436 Patent)
Context and Importance: This negative limitation distinguishes the claimed invention from other oral delivery routes, such as sublingual or buccal tablets, by specifying a gastrointestinal absorption pathway. Infringement of the ’436 Patent hinges on this element.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent's background focuses on the challenges of gastrointestinal delivery after swallowing, contrasting the invention with intravenous or subcutaneous administration (’436 Patent, col. 4:5-24). This context suggests the term is meant to exclude formulations designed for absorption in the mouth.
- Evidence for a Narrower Interpretation: The claim language is absolute ("is not absorbed"). A defendant may argue this requires proof of zero absorption through this pathway. The specification does not provide a quantitative threshold or test method for determining what level of absorption satisfies this negative limitation, potentially creating ambiguity.
VI. Other Allegations
- Indirect Infringement: The complaint alleges inducement of infringement based on Defendants' intent to market the MSN ANDA Product with a label that will encourage use for treating AML, which is covered by the method claims of the ’628 Patent (Compl. ¶¶52, 54). Contributory infringement is also alleged, based on the assertion that the MSN ANDA Product is not a staple article of commerce and is especially adapted for the infringing use, as its only FDA-approved indication would be the patented method (Compl. ¶57). Similar allegations are made for the ’436 Patent (Compl. ¶60).
- Willful Infringement: The complaint alleges that MSN had pre-suit knowledge of the ’628 Patent because it is listed in the FDA's Orange Book and was cited in MSN's Notice Letter (Compl. ¶55). The complaint also alleges MSN is willfully blind to the fact that its product will be used to directly infringe (Compl. ¶56).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of definitional scope: How will the court construe "non-enteric coated tablet"? Will it be defined simply by the absence of a specific coating structure, or will it require affirmative functional proof of drug release "substantially in the stomach," potentially narrowing the patents' scope?
- A key evidentiary question will be one of infringement by inference: Will Defendants' representation of bioequivalence to Onureg® be sufficient evidence to prove that the accused product meets every claim limitation, particularly the negative limitation in the ’436 Patent that the drug is "not absorbed through oral mucosa"?