Neptune Generics LLC v. Nektar Therapeutics

1. Case Identification

• Case #: IPR2016-00049
• Patent #: 7,786,133
• Filed: October 15, 2015
• Petitioner(s): Neptune Generics, LLC
• Patent Owner(s): AstraZeneca PLC.
• Challenged Claims: 1-4

2. Patent Overview

• Title: Chemically Modified Small Molecules
• Brief Description: The ’133 patent discloses conjugates of a small molecule drug, specifically the opioid antagonist naloxone or its reduced form naloxol, covalently attached to a water-soluble polyethylene glycol (PEG) oligomer. The claimed invention is a specific naloxol-PEG conjugate intended to exhibit a reduced rate of crossing biological membranes.

3. Grounds for Unpatentability

Ground 1: Anticipation of Claims 1-4 under 35 U.S.C. §102

• Prior Art Relied Upon: Bentley (Application # 2003/0124086).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that Bentley expressly described each element of the challenged claims. Bentley disclosed a generic formula for polymer conjugates of opioid antagonists, R-POLY-X-Ao, and provided preferred embodiments for each component that directly read on the claimed invention. Specifically, Bentley taught that R is preferably a methoxy capping group, POLY is preferably poly(ethylene glycol), X is preferably a stable ether linkage, and the opioid antagonist (Ao) is preferably naloxone. Bentley further disclosed that the number of PEG monomer units typically ranges from 2 to 20, a range that encompasses the seven units required by the challenged claims. Petitioner contended this disclosure described a sufficiently defined and limited class of compounds that a person of ordinary skill in the art (POSITA) would have at once envisioned the claimed structure. For dependent claims 2 and 3, Bentley taught that its conjugates exist as a mixture of α and β epimers that can be separated. For claim 4, Bentley explicitly disclosed formulating its conjugates with a pharmaceutically acceptable carrier or excipient.
  • Key Aspects: The core of this argument rested on the assertion that Bentley's preferred embodiments, when combined, created a very small genus that a POSITA could immediately visualize, thereby anticipating the specific compound of claim 1.

Ground 2: Obviousness of Claims 1-4 under 35 U.S.C. §103

• Prior Art Relied Upon: Bentley (Application # 2003/0124086), Ouchi (a 1987 journal article on PEGylating 5-fluorouracil), and Erez (a 1982 journal article on PEGylating a narcotic antagonist).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner asserted that Bentley provided the foundational disclosure for a naloxone/naloxol molecule conjugated to a PEG polymer through an ether linkage. While Bentley disclosed a range of PEG lengths, it did not specify exactly seven units. The secondary references, Ouchi and Erez, were argued to supply the motivation to select a seven-unit PEG chain and provide a reasonable expectation of success.
  • Motivation to Combine: A POSITA would combine these references to optimize the properties of the drug conjugate disclosed in Bentley. Ouchi taught that PEGylating small molecule drugs was a known method to modify their biological properties and demonstrated that varying the PEG chain length was a routine technique for optimization. Notably, Ouchi prepared and tested conjugates with PEG lengths of n=1, 4, 7, 15, and 110, explicitly teaching the use of a seven-unit chain. Erez reinforced this by demonstrating the successful conjugation of a PEG unit to an opioid antagonist (β-naltrexamine) that is structurally very similar to naloxol, confirming the suitability of this approach for the specific drug class. Therefore, a POSITA would have been motivated to apply the routine optimization strategy from Ouchi to the base conjugate from Bentley.
  • Expectation of Success: A POSITA would have had a high expectation of success because the underlying chemistry (ether synthesis) was well-established and predictable. The teachings of Ouchi and Erez demonstrated that PEGylation was a viable and effective strategy for modifying the properties of small molecule drugs in general and structurally similar opioid antagonists in particular. Petitioner argued that preparing a series of derivatives with different PEG lengths, including the claimed seven-unit version, was a standard and obvious step in drug development.

4. Key Claim Construction Positions

• "6-CH3-(OCH2CH2)7-O-Naloxol": Petitioner argued this term should be understood by its chemical structure, representing a naloxol molecule where an ether linkage at the 6-position of the bicyclohexane ring connects it to a seven-unit methoxy-capped polyethylene glycol oligomer (m-PEG7).
• "pharmaceutically acceptable excipient": Relying on the patent’s specification, Petitioner proposed this term be construed to mean "a substance that can be included in the compositions of the invention and that causes no significant adverse toxicological effects to the patient." This construction was presented as consistent with the understanding of a POSITA.

5. Relief Requested

• Petitioner requested the institution of an inter partes review and the cancellation of claims 1-4 of Patent 7,786,133 as unpatentable.