PTAB

IPR2021-01507

Apotex Inc v. AuSPEX Pharmaceuticals Inc

Log In
Key Events
Petition

1. Case Identification

2. Patent Overview

  • Title: Benzoquinoline Inhibitors of Vesicular Monoamine Transporter 2
  • Brief Description: The ’733 patent claims the compound deutetrabenazine, a deuterated form of the known drug tetrabenazine, and pharmaceutical compositions thereof. The invention involves replacing hydrogen atoms with deuterium atoms on the two methoxy groups of tetrabenazine to treat movement disorders.

3. Grounds for Unpatentability

Ground 1: Obviousness over Zheng, Naicker ’921, and Kohl - Claims 1-3 are obvious over Zheng in view of Naicker ’921 and Kohl.

  • Prior Art Relied Upon: Zheng (a 2006 journal article), Naicker ’921 (Patent 6,503,921), and Kohl (WO 2007/012650).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Zheng established tetrabenazine as an effective but flawed lead compound. Zheng taught it was used for hyperkinetic movement disorders but had significant side effects and a short half-life. Crucially, Zheng identified the methoxy groups at positions 9 and 10 as essential for the drug's activity, which would direct a skilled artisan (POSITA) to focus modifications there to preserve efficacy. Naicker ’921 taught the specific benefits of deuterating therapeutically important methoxy groups to improve pharmacokinetics, slow metabolism, increase potency, and reduce toxicity, providing an explicit roadmap. Kohl provided further data showing a ~50% reduction in metabolism from deuterating a methoxy group in a different compound (pantoprazole). Kohl also explicitly disclosed the claimed deuterium enrichment levels of at least 90% (claim 1) and a preference for at least 96% (near the 98% of claim 2), as well as the use of a pharmaceutically acceptable carrier (claim 3).
    • Motivation to Combine: A POSITA would combine these references as part of a predictable drug development strategy. Zheng provided the motivation to improve tetrabenazine due to its known drawbacks. Naicker ’921 provided the specific solution—deuteration of methoxy groups—to achieve predictable improvements in metabolism and safety. Kohl confirmed the benefits and provided the specific enrichment levels and formulation requirements recited in the dependent claims.
    • Expectation of Success: A POSITA would have had a high expectation of success because deuteration was a well-established technique for slowing metabolism at C-H bonds, such as those in methoxy groups. The references showed this was a routine modification that yielded predictable results, not an unexpected discovery.

Ground 2: Obviousness over Zheng, Foster AB, and Kohl - Claims 1-3 are obvious over Zheng in view of Foster AB and Kohl.

  • Prior Art Relied Upon: Zheng (a 2006 journal article), Foster AB (a 1974 journal article), and Kohl (WO 2007/012650).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground largely mirrored Ground 1, with Foster AB substituting for Naicker ’921 as the primary teaching for deuterating methoxy groups. As before, Zheng identified tetrabenazine as a lead compound with known flaws and highlighted the importance of its methoxy groups. Foster AB disclosed that "isotope effects of ~2" (i.e., a two-fold or 50% reduction in the rate of metabolism) were found for the O-demethylation of compounds with methoxy groups structurally analogous to those in tetrabenazine. This reference explicitly linked a predictable, quantitative outcome to the deuteration of these specific functional groups. Kohl’s contribution remained the same, teaching the claimed enrichment levels and pharmaceutical carrier limitations.
    • Motivation to Combine: The motivation was identical to Ground 1: to improve the known drug tetrabenazine. A POSITA, motivated by Zheng, would have looked to known methods for slowing O-demethylation. Foster AB provided a direct, decades-old teaching that deuterating methoxy groups achieves this effect with a predictable magnitude, making it an obvious modification to pursue.
    • Expectation of Success: The expectation of success was high, reinforced by Foster AB’s disclosure of a consistent, two-fold isotope effect for O-demethylation of methoxy groups. This suggested that slowing the metabolism of tetrabenazine by deuterating its methoxy groups was a straightforward application of a known principle with predictable results.

Ground 3: Obviousness over Gano, Schwartz, and Gant ’991 - Claims 1-3 are obvious over Gano in view of Schwartz and Gant ’991.

  • Prior Art Relied Upon: Gano (Patent 8,039,627), Schwartz (a 1966 journal article), and Gant ’991 (Application # 2008/0280991).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground presented a different combination of art to reach the same conclusion. Gano taught that there was a specific need for tetrabenazine analogs with a longer half-life to improve upon its low bioavailability and frequent dosing schedule. Schwartz, a reference cited in the ’733 patent itself, taught that the metabolic pathways of tetrabenazine involve the O-demethylation of its methoxy groups. Gant ’991 taught that deuteration is a proven approach to improve pharmacokinetics, specifically teaching the deuteration of methoxy groups to increase a drug’s half-life. Gant ’991 explicitly disclosed the claimed enrichment levels (at least 90% and 98%) and formulation with a carrier.
    • Motivation to Combine: A POSITA, starting with the problem identified in Gano (the need for a longer-lasting tetrabenazine analog), would have been motivated by Schwartz to identify the methoxy groups as the site of metabolic breakdown. With this knowledge, the POSITA would have been motivated to apply the solution taught in Gant ’991: deuterate the methoxy groups to predictably increase the drug's half-life and obtain other therapeutic benefits.
    • Expectation of Success: Success was reasonably expected because the combination represented a textbook "problem-and-solution" approach. Gano and Schwartz defined the problem and its biochemical location, while Gant ’991 provided the well-known, targeted solution with clear instructions, including the specific claim limitations for enrichment and formulation.

4. Key Technical Contentions (Beyond Claim Construction)

  • Predictability of Results: Petitioner's central technical contention across all grounds was that the prior art rendered the benefits of deuterating tetrabenazine’s methoxy groups entirely predictable, not just in kind but also in degree. References like Foster AB and Kohl taught that a roughly 50% reduction in metabolic rate and a two-fold increase in bioavailability were expected outcomes, directly undermining the Patent Owner’s arguments of unexpected results during prosecution.
  • Legally Irrelevant Comparison for Unexpected Results: Petitioner argued that the Patent Owner overcame prosecution rejections by presenting evidence of reduced side effects that was based on a legally irrelevant comparison. The study compared a 15 mg extended-release formulation of deutetrabenazine with a 25 mg immediate-release formulation of tetrabenazine. Petitioner contended that any observed benefits could be due to the different dosages and release profiles, not the claimed compound itself, and thus the evidence lacked the required nexus to the invention.

5. Relief Requested

  • Petitioner requested institution of an inter partes review and cancellation of claims 1-3 of the ’733 patent as unpatentable under 35 U.S.C. §103.