PTAB

IPR2021-00347

Alzheon Inc v. Risen Suzhou Pharma Tech Co Ltd

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1. Case Identification

2. Patent Overview

  • Title: Isotope-Enriched Tramiprosate and Derivatives
  • Brief Description: The ’323 patent discloses compounds related to tramiprosate, a drug used for treating Alzheimer's disease, that are isotopically-enriched. The patent covers these compounds, compositions containing them, and methods of their use in therapeutic applications.

3. Grounds for Unpatentability

Ground 1: Obviousness over Kong and Czarnik - Claims 1-17 and 19-20 are obvious over Kong (Patent 8,748,656) in view of Czarnik (Application # 2009/0076167).

  • Prior Art Relied Upon: Kong (Patent 8,748,656) and Czarnik (’167 application).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Kong taught using tramiprosate and its prodrugs, specifically identifying L-valyl-3-aminopropanesulfonate (“Val-APS”) as a preferred lead compound for treating Alzheimer's disease. Critically, Kong also disclosed the metabolic pathways of tramiprosate, identifying the terminal amine and third carbon as the primary sites of metabolism. Czarnik taught the general concept of using deuterium-enriched tramiprosate to improve its pharmacokinetic profile by slowing metabolism. Petitioner asserted that the challenged claims, which cover isotopically-substituted Val-APS and tramiprosate, are rendered obvious by the combination of Kong’s specific lead compound and metabolic site disclosure with Czarnik’s general teaching of isotopic substitution for the same purpose. For example, D₂-Val-APS (Compound 4 of the ’323 patent) is merely Kong’s Val-APS with deuterium substituted at the third carbon, the precise location identified by Kong as a metabolic site.
    • Motivation to Combine: A Person of Ordinary Skill in the Art (POSA) would combine these references to solve a known problem. Kong expressly taught that minimizing the metabolism of tramiprosate was desirable to improve treatment. Czarnik provided a well-known solution for slowing drug metabolism: isotopic substitution to leverage the kinetic isotope effect (KIE). A POSA would have been motivated to apply Czarnik’s deuteration strategy to Kong’s preferred Val-APS prodrug, specifically targeting the third carbon as taught by Kong, to achieve the desired goal of reduced metabolism and improved therapeutic benefit.
    • Expectation of Success: Petitioner contended a POSA would have a reasonable expectation of success. The principle that isotopic substitution can slow metabolism via the KIE was well-established. Furthermore, Kong identified that tramiprosate metabolism is caused by transaminase and monoamine oxidase, enzymes known to be affected by the KIE. With Kong identifying the exact metabolic sites and Czarnik teaching the modification strategy, a POSA would reasonably expect that deuterating the third carbon of Val-APS would successfully slow its metabolism.

Ground 2: Obviousness over Tolar, Czarnik, and Kong - Claims 1-20 are obvious over Tolar (Patent 10,471,029) in view of Czarnik (Application # 2009/0076167) and Kong (Patent 8,748,656).

  • Prior Art Relied Upon: Tolar (Patent 10,471,029), Czarnik (’167 application), and Kong (’656 patent).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground presented an alternative but similar argument to Ground 1. Petitioner argued that Tolar, like Kong, disclosed Val-APS as an orally available prodrug of tramiprosate with improved properties (e.g., better tolerability, reduced nausea) for treating Alzheimer's disease, providing another strong basis for selecting it as a lead compound. The arguments for combining this lead compound with Czarnik and Kong remained the same as in Ground 1.
    • Motivation to Combine: A POSA would be motivated to select Val-APS as a lead compound based on Tolar's disclosure of its improved pharmacological profile and clinical results. The motivation to then modify Val-APS by applying Czarnik's isotopic substitution at the metabolic sites identified by Kong would be driven by the same desire to further improve therapeutic efficacy by slowing metabolism.
    • Expectation of Success: The expectation of success was based on the same reasoning as Ground 1: the known utility of the KIE, the specific enzymes involved, and the clear identification of the metabolic "hotspot" on the molecule provided by Kong.

Ground 3: Obviousness over Czarnik and Kong - Claims 3 and 19 are obvious over Czarnik (Application # 2009/0076167) in view of Kong (Patent 8,748,656).

  • Prior Art Relied Upon: Czarnik (’167 application) and Kong (’656 patent).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground targeted claims to isotopically-substituted tramiprosate itself, not its prodrugs. Claim 19 recites tramiprosate deuterated at the third carbon, and claim 3 recites tramiprosate with a nitrogen-15 (¹⁵N) isotope at the amine group. Petitioner argued that Czarnik disclosed deuterium-enriched tramiprosate generally as a lead compound.
    • Motivation to Combine: A POSA starting with Czarnik's deuterated tramiprosate would be motivated by Kong's metabolic analysis to place the deuterium specifically at the third carbon, as this is where C-H bond breaking occurs, in order to maximize the KIE. Similarly, because Kong’s analysis showed that metabolism involves the removal of the amine group, a POSA would be motivated to substitute the natural nitrogen with ¹⁵N to strengthen the N-C bond and slow this metabolic pathway, as recited in claim 3.
    • Expectation of Success: Success was reasonably expected because Czarnik already taught that deuterated tramiprosate was a viable therapeutic, and Kong provided the precise roadmap for where to place the isotopic substitution to achieve the greatest effect on the known metabolic pathways.

4. Key Technical Contentions (Beyond Claim Construction)

  • Predictability of the Kinetic Isotope Effect (KIE): A central technical argument was that the KIE is a well-understood and predictable tool in pharmaceutical chemistry used to slow drug metabolism. Petitioner argued that the enzymes responsible for metabolizing tramiprosate (transaminase and monoamine oxidase) were known to be susceptible to the KIE. Therefore, applying isotopic substitution to the specific metabolic sites of tramiprosate (as identified by Kong) was not an inventive step but a straightforward application of established scientific principles to achieve a predictable result.

5. Relief Requested

  • Petitioner requested institution of an inter partes review and cancellation of claims 1-20 of the ’323 patent as unpatentable.