PTAB

IPR2022-00402

Synthego Corp v. Agilent Technologies Inc

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Petition
petition

1. Case Identification

2. Patent Overview

  • Title: Guide RNA with Chemical Modifications
  • Brief Description: The ’001 patent discloses synthetic guide RNAs (gRNAs) for CRISPR-Cas gene editing systems. The invention focuses on incorporating chemical modifications into the gRNA molecules, particularly within five nucleotides of the 5' or 3' ends, to enhance properties like stability and resistance to cellular degradation.

3. Grounds for Unpatentability

Ground 1: Claims 1-7, 9-10, 12-15, 17-18, 20-25, and 27-30 are anticipated by Pioneer Hi-Bred.

  • Prior Art Relied Upon: Pioneer Hi-Bred (WO 2015/026885).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Pioneer Hi-Bred discloses every element of the challenged claims under 35 U.S.C. §102. The reference teaches using chemically modified gRNAs, including both single-molecule (sgRNA) and double-molecule forms, within CRISPR-Cas9 systems for gene editing. Petitioner asserted that Tables 7 and 8 of Pioneer Hi-Bred explicitly disclose gRNAs with 2’-O-methyl (a sugar modification) and phosphorothioate (a phosphodiester linkage modification) nucleotides located at their 5’ and 3’ ends. This disclosure was argued to meet the core limitations of independent claims 1 and 12, which require a synthetic CRISPR guide RNA with one or more modified nucleotides at or near its ends. Pioneer Hi-Bred also was shown to teach the required gRNA functionality of associating with a Cas protein to target and cleave a polynucleotide.

Ground 2: Claims 9, 18, and 25 are obvious over Pioneer Hi-Bred in view of Krutzfeldt, Deleavey, Soutschek, or Yoo.

  • Prior Art Relied Upon: Pioneer Hi-Bred (WO 2015/026885), Krutzfeldt (a 2007 journal article), Deleavey (a 2012 review article), Soutschek (a 2004 journal article), and Yoo (a 2004 journal article).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground asserted that even if Pioneer Hi-Bred does not anticipate claims 9, 18, and 25, they are obvious under 35 U.S.C. §103. Pioneer Hi-Bred provides the foundational teaching of using modified gRNAs in a CRISPR system. The secondary references were cited to demonstrate that the specific 2’-O-methyl-3’-phosphorothioate modification recited in these claims was a well-known, conventional, and successful strategy for stabilizing other analogous RNA molecules (e.g., siRNA, anti-miRNA, AONs) by protecting their ends from nuclease degradation.
    • Motivation to Combine: A POSITA would combine the teachings to improve the stability and efficacy of the gRNAs taught in Pioneer Hi-Bred. The secondary references provided established and successful methods for achieving such stability in functionally similar RNA molecules using the exact modifications claimed. Petitioner argued that applying these known stability-enhancing modifications from other RNA contexts to the CRISPR gRNA platform was a simple and predictable design choice to solve a known problem of RNA degradation.
    • Expectation of Success: A POSITA would have a high expectation of success. Pioneer Hi-Bred itself teaches combining different modifications and states that "other possible combinations may be envisioned." The secondary art confirmed the effectiveness of 2’-O-methyl-3’-phosphorothioate modifications in increasing stability without disrupting the function of other therapeutic RNAs. Furthermore, the petition noted that standard synthesis techniques for creating such modified RNAs were well-established and commercially available.

Ground 3: Claims 8, 11, 16, 19, and 26 are obvious over Pioneer Hi-Bred in view of Threlfall or Deleavey.

  • Prior Art Relied Upon: Pioneer Hi-Bred (WO 2015/026885), Threlfall (a 2012 journal article), and Deleavey (a 2012 review article).

  • Core Argument for this Ground:

    • Prior Art Mapping: This ground targeted claims reciting phosphonoacetate (PACE) and phosphonothioacetate (thioPACE) modifications. As in the other grounds, Petitioner relied on Pioneer Hi-Bred for the fundamental CRISPR gRNA framework. The secondary references, Threlfall and Deleavey, were used to show that PACE and thioPACE modifications were known in the art for use at the ends of RNA oligonucleotides to increase nuclease resistance, improve cellular uptake, and enhance thermal melting temperatures.
    • Motivation to Combine: A POSITA would be motivated to incorporate the PACE and thioPACE modifications taught by Threlfall and Deleavey into the gRNAs of Pioneer Hi-Bred to achieve the same predictable benefits. Since Pioneer Hi-Bred sought to improve gRNA properties like stability and cellular permeability, and the secondary art taught that these specific modifications accomplished those goals in other RNA molecules, the combination was presented as an obvious path to an improved gRNA.
    • Expectation of Success: The petition argued for a reasonable expectation of success because the functional benefits of PACE/thioPACE modifications were well-documented. Threlfall provided established synthesis protocols, and the petition asserted that such methods were commercially available. Given the widespread use and known benefits of these modifications in the broader field of gene regulation, a POSITA would reasonably expect them to be functional and beneficial when applied to gRNAs in the Cas system.

  • Additional Grounds: Petitioner asserted further obviousness challenges (Grounds 4 and 5) against claims 2, 9, 18, 25, 29, and 30, based on Pioneer Hi-Bred in view of the general knowledge of a POSA, arguing that creating single guide RNAs (sgRNAs), making libraries, or performing methods outside a cell were routine and predictable variations of the disclosed art.

4. Relief Requested

  • Petitioner requests institution of an inter partes review and cancellation of claims 1-30 of Patent 10,337,001 as unpatentable.