DCT

1:23-cv-01019

Celgene Corp v. Natco Pharma Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:23-cv-01019, D. Del., 09/18/2023
  • Venue Allegations: Plaintiff alleges venue is proper because Defendant is a foreign corporation and subject to personal jurisdiction in the district based on its business activities and actions directed toward seeking approval to market its generic product in the United States, including Delaware.
  • Core Dispute: Plaintiff alleges that Defendant’s filing of an Abbreviated New Drug Application to market a generic version of Plaintiff’s Onureg® (azacitidine) tablets constitutes an act of infringement of two patents related to oral formulations of azacitidine.
  • Technical Context: The technology concerns oral pharmaceutical formulations of the anti-cancer drug azacitidine, designed to treat hematologic disorders such as acute myeloid leukemia.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following a Notice Letter from Defendant, dated August 24, 2023, which included a Paragraph IV certification. The complaint alleges that Defendant’s letter asserts the patents-in-suit are invalid but does not contest that the proposed generic product would infringe the asserted claims if they are valid. Both patents-in-suit are listed in the U.S. Food and Drug Administration’s "Orange Book" as covering the Onureg® product.

Case Timeline

Date Event
2008-05-15 Earliest 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
2023-08-24 Date of Defendant's Notice Letter
2023-09-18 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”

  • Patent Identification: U.S. Patent No. 8,846,628, “Oral Formulations of Cytidine Analogs and Methods of Use Thereof,” issued September 30, 2014.

The Invention Explained

  • Problem Addressed: The patent addresses the difficulty of creating an oral dosage form for cytidine analogs like 5-azacytidine (Compl. ¶2). The specification notes that these compounds have been considered "acid labile and unstable in the acidic gastric environment," which led previous development efforts to focus on enteric coatings that protect the drug from the stomach and release it in the small intestine (’628 Patent, col. 3:11-21).
  • The Patented Solution: The invention is a pharmaceutical composition that releases the cytidine analog "substantially in the stomach" upon oral administration (’628 Patent, col. 4:44-50). This approach runs counter to the prior art's focus on avoiding the stomach and is embodied in claims directed to a "non-enteric coated tablet" (’628 Patent, col. 82:46-47).
  • Technical Importance: This solution provides a more convenient oral dosage form for patients, eliminating the need for subcutaneous or intravenous administration and the potential for injection-site reactions (’628 Patent, col. 3:5-10).

Key Claims at a Glance

  • The complaint asserts independent claims 1 and 28 as representative of the composition and method claims, respectively (Compl. ¶34, 39).
  • Independent Claim 1 (Composition):
    • 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):
    • A method for treating a disease associated with abnormal cell proliferation (myelodysplastic syndrome or acute myelogenous leukemia)
    • comprising orally administering to a subject a pharmaceutical composition
    • which comprises a therapeutically effective amount of 5-azacytidine and an excipient
    • wherein the composition is a non-enteric coated tablet.
  • The complaint asserts claims 1-9, 11, 13-26, 28-36, 38, and 40-43 (Compl. ¶30).

U.S. Patent No. 11,571,436 - “Oral Formulations of Cytidine Analogs and Methods of Use Thereof”

  • Patent Identification: U.S. Patent No. 11,571,436, “Oral Formulations of Cytidine Analogs and Methods of Use Thereof,” issued February 7, 2023.

The Invention Explained

  • Problem Addressed: As a continuation of the application leading to the ’628 Patent, the ’436 Patent addresses the same technical problem: the perceived instability of cytidine analogs in the stomach, which historically discouraged the development of oral formulations that release the drug in that environment (’436 Patent, col. 3:11-20).
  • The Patented Solution: The ’436 Patent also claims a solution based on stomach-release formulations, but its claims are more specific than those in the parent patent (’436 Patent, col. 4:44-50). Claim 1 adds limitations directed to a specific dosage range of 5-azacytidine and clarifies that a therapeutically effective amount of the drug is "not absorbed through oral mucosa," thereby ensuring delivery to the gastrointestinal tract (’436 Patent, col. 84:1-8).
  • Technical Importance: This invention further refines the oral dosage form by defining specific dosage amounts and clarifying the administration pathway to ensure proper delivery and therapeutic effect.

Key Claims at a Glance

  • The complaint asserts independent claim 1 (Compl. ¶53).
  • Independent Claim 1 (Composition):
    • 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 claims 1-22 (Compl. ¶49).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentality is the "Natco ANDA Product," identified as 200 mg and 300 mg tablets of azacitidine for which Natco seeks FDA approval (Compl. ¶2).

Functionality and Market Context

  • The complaint alleges that the Natco ANDA Product is a generic version of Plaintiffs' Onureg® drug product (Compl. ¶2). As such, it allegedly has the same active ingredient, dosage form (oral tablet), route of administration, and strength as Onureg®, and is bioequivalent (Compl. ¶25, 37). The complaint further alleges that the Natco ANDA Product is intended for the same approved indications as Onureg®, which is used for the treatment of adult patients with acute myeloid leukemia (Compl. ¶21, 26). No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint alleges that Defendant’s Notice Letter does not contest that its ANDA Product will infringe the asserted claims of the patents-in-suit to the extent those claims are valid (Compl. ¶27, 49). The infringement theory is based on the ANDA product's alleged identity to the commercial Onureg® product.

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A pharmaceutical composition for oral administration... The Natco ANDA Product is an oral tablet. ¶36 col. 82:43-44
...comprising a therapeutically effective amount of 5-azacytidine... The 200 mg and 300 mg tablets allegedly include a therapeutically effective amount of 5-azacytidine. ¶36 col. 82:44-45
...and at least one pharmaceutically acceptable excipient... The Natco ANDA Product is alleged to contain at least one pharmaceutically acceptable excipient. ¶37 col. 82:45-46
...wherein the composition is a non-enteric coated tablet. The Natco ANDA Product is alleged to be a non-enteric coated tablet. ¶37 col. 82:46-47
Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A pharmaceutical composition for oral administration... The Natco ANDA Product is an oral tablet. ¶55 col. 84:1-2
...comprising 180 mg to 360 mg of 5-azacytidine... The proposed 200 mg and 300 mg dosage strengths fall within the claimed range. ¶55 col. 84:2-3
...and at least one pharmaceutically acceptable excipient... The Natco ANDA Product is alleged to contain at least one pharmaceutically acceptable excipient. ¶56 col. 84:3-4
...wherein the composition is a non-enteric coated tablet... The Natco ANDA Product is alleged to be a non-enteric coated tablet. ¶56 col. 84:5-6
...and wherein a therapeutically effective amount of 5-azacytidine is not absorbed through oral mucosa upon administration to a human subject. The complaint alleges bioequivalence to Onureg®, which Plaintiffs assert has this characteristic. ¶56 col. 84:6-8
  • Identified Points of Contention:
    • Scope Questions: Given the allegation that Defendant does not contest infringement, the primary dispute is likely to be over validity rather than claim scope. However, a question may arise regarding the evidence needed to prove the negative limitation in claim 1 of the ’436 Patent—that a therapeutically effective amount "is not absorbed through oral mucosa"—for the accused product. The complaint's reliance on bioequivalence may be challenged.
    • Technical Questions: A factual question for the court could be whether the record supports the complaint's assertion that Defendant's Notice Letter concedes infringement for all asserted claims, as this would significantly narrow the issues for trial.

V. Key Claim Terms for Construction

  • The Term: "non-enteric coated tablet" (’628 Patent, Claim 1; ’436 Patent, Claim 1)
  • Context and Importance: This term is central to the patents' novelty and non-obviousness, as it defines the invention in opposition to prior art that taught using enteric coatings to protect 5-azacytidine from stomach acid. Practitioners may focus on this term because Defendant’s invalidity defense will likely argue that creating a simple non-enteric coated tablet was an obvious formulation choice, making the precise scope of this term critical.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patents appear to use the term to mean any tablet lacking a coating designed for intestinal release. The ’436 Patent specification states that compositions "do not have an enteric coating (i.e., are non-enteric-coated)" (’436 Patent, col. 6:14-15), suggesting the term's meaning is simply the absence of an enteric coat.
    • Evidence for a Narrower Interpretation: A party could argue the term should be limited by the specification's objective of releasing the drug "substantially in the stomach" (’436 Patent, col. 4:45-47). This might be used to argue that a "non-enteric coated tablet" must not only lack an enteric coat but must also be formulated for immediate or controlled release specifically in the stomach, potentially excluding other types of non-enteric formulations.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges induced infringement, stating that Defendant’s proposed product label will encourage and instruct physicians and patients to administer the Natco ANDA Product for the patented methods of treatment (Compl. ¶44, 46).
  • Willful Infringement: The complaint alleges that Defendant has knowledge of the patents-in-suit, citing their listing in the FDA’s Orange Book and their inclusion in Defendant’s own Notice Letter (Compl. ¶45). Based on this alleged knowledge, the complaint asserts that Defendant is "willfully blind" to the infringing acts that will occur upon the product's launch (Compl. ¶46).

VII. Analyst’s Conclusion: Key Questions for the Case

As the complaint alleges infringement is not contested, the litigation will likely focus almost exclusively on the validity of the asserted patents. The central questions for the court appear to be:

  1. A core issue will be one of obviousness: Was it obvious to a person of ordinary skill in the art to formulate 5-azacytidine in a simple "non-enteric coated tablet" for stomach release, despite a widely held belief, described in the patent, that the drug was unstable in stomach acid and required protection via an enteric coating?
  2. A secondary question for the ’436 Patent will be non-obviousness of the combination: Even if a basic non-enteric tablet was deemed obvious, do the additional claimed limitations—specifically the dosage range of "180 mg to 360 mg" and the negative limitation that the drug is "not absorbed through oral mucosa"—render the claims of the ’436 Patent non-obvious over the prior art?