PTAB

IPR2023-00512

Apotex Inc v. Celgene Corp

Key Events

Petition

petition

Title: Oral Formulations of Cytidine Analogs and Methods of Use Thereof
Brief Description: The ’628 patent discloses pharmaceutical compositions of cytidine analogs, specifically non-enteric coated (NEC) oral tablets of 5-azacytidine, and methods for using them to treat diseases associated with abnormal cell proliferation, such as myelodysplastic syndrome (MDS).

Prior Art Relied Upon: Ionescu (WO 2004/082619).
Core Argument for this Ground:
- Prior Art Mapping: Petitioner argued that Ionescu expressly discloses all limitations of the challenged claims. Specifically, Ionescu taught a pharmaceutical composition for oral administration comprising a therapeutically effective amount of 5-azacytidine in a non-enteric coated tablet (specifically, a sugar-coated tablet) for treating MDS. Ionescu also disclosed the use of claimed excipients like mannitol and microcrystalline cellulose, and dosage ranges (e.g., "about 5 mg to about 200 mg") that overlap with or encompass the claimed dosage limitations. For claims reciting pharmacokinetic (PK) properties (AUC, Cmax, Tmax), Petitioner contended these properties are inherently disclosed as they are the natural result of administering the Ionescu formulation. This inherency was allegedly confirmed by in silico modeling.

Prior Art Relied Upon: Ionescu (WO 2004/082619), Atadja (WO 2004/103358), and Gibson (a 2001 textbook, Oral Solid Dosage Forms).
Core Argument for this Ground:
- Prior Art Mapping: Petitioner asserted that Ionescu provided the foundational teaching of an oral NEC tablet of 5-azacytidine. Atadja taught using oral formulations of 5-azacytidine to treat the same diseases and disclosed broader, overlapping dosage ranges (100 to 1500 mg daily). Gibson, identified in the ’628 patent as a "pertinent textbook," taught that NEC tablets were the default and most preferred oral dosage form for reasons of stability, taste-masking, and predictable bioavailability compared to enteric-coated forms.
- Motivation to Combine: A POSA would combine these references to create a predictable and effective oral therapy for MDS. The motivations included improving patient convenience over injectable forms, improving the biological effect of 5-azacytidine by enabling continuous low-dose regimens, and using a well-understood, default oral dosage form (an NEC tablet) with known excipients and manufacturing techniques.
- Expectation of Success: A POSA would have had a reasonable expectation of success because 5-azacytidine was known to be orally bioavailable and well-tolerated. The proposed formulation used conventional methods and materials described in standard textbooks like Gibson, ensuring predictability.

Prior Art Relied Upon: Ionescu (WO 2004/082619), Atadja (WO 2004/103358), Gibson (a 2001 textbook), and Pharmion-PR (a 2007 press release).
Core Argument for this Ground:
- Prior Art Mapping: This ground built upon the combination in Ground 2, adding the teachings of Pharmion-PR. Pharmion-PR disclosed positive clinical data from a pilot study demonstrating the bioavailability and tolerability of an oral 5-azacytidine formulation in MDS patients.
- Motivation to Combine: The positive clinical results disclosed in Pharmion-PR would have strongly motivated a POSA to pursue the development of an oral NEC tablet of 5-azacytidine. It confirmed the viability of the oral route of administration for this specific drug and patient population, reducing the uncertainty and risk associated with development.
- Expectation of Success: The expectation of success was further heightened by Pharmion-PR, which provided direct clinical evidence that an oral 5-azacytidine formulation was well-tolerated and quantifiable in plasma, reinforcing the teachings of the other references.

"about": Petitioner argued that for PK parameters, the term "about" should be construed broadly (e.g., ±30%) based on disclosures in the ’628 patent specification showing high variability in measured PK values. This broad construction supported Petitioner's contention that the PK results from its modeling of prior art formulations fell within the claimed ranges.

In Silico Modeling for Inherency: A central technical argument was that the claimed PK limitations are not patentable because they are merely the inherent, natural results of administering an anticipated or obvious formulation. Petitioner used widely available prior art software (GastroPlus) to conduct in silico modeling, which allegedly confirmed that administering the 200 mg NEC tablet disclosed in Ionescu would necessarily result in the AUC, Cmax, and Tmax values recited in the dependent claims.

Petitioner argued that discretionary denial under §325(d) would be improper. The petition presented new art (Atadja, Gibson, Pharmion-PR) and new arguments not previously before the Examiner. Petitioner contended that while Ionescu was cited in an IDS, there was no evidence the Examiner substantively considered it, constituting a material error. Furthermore, new evidence, particularly the in silico modeling results, was presented to demonstrate the inherency of the claimed PK properties, warranting reconsideration.

Petitioner requests institution of an inter partes review and cancellation of claims 1, 2, 6-9, 11-28, 32-36, and 38-43 of the ’628 patent as unpatentable.