PTAB

IPR2021-01136

Sarepta Therapeutics Inc v. National Center Of Neurology Psychiatry

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Key Events
Petition
petition

1. Case Identification

2. Patent Overview

  • Title: Antisense Nucleic Acids
  • Brief Description: The ’461 patent relates to a phosphorodiamidate morpholino oligomer (PMO) antisense oligomer designed to cause skipping of exon 53 of the human dystrophin pre-mRNA. The technology is intended for therapeutic use in treating Duchenne muscular dystrophy (DMD).

3. Grounds for Unpatentability

Ground 1: Claims 1 and 2 are obvious over Popplewell in view of Sazani.

  • Prior Art Relied Upon: Popplewell (a 2010 journal article titled “Comparative Analysis of Antisense Oligonucleotide Sequences Targeting Exon 53 of the Human DMD Gene”) and Sazani (a 2010 journal article titled “Safety Pharmacology and Genotoxicity Evaluation of AVI-4658”).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that the combination of Popplewell and Sazani discloses all limitations of the challenged claims.
      • Claim 1 (PMO): Popplewell taught that exon 53 was a critical target for treating DMD and disclosed extensive testing of PMOs to induce its skipping. The reference identified a "hotspot" target region spanning nucleotides +30 to +65 of exon 53 where PMOs were highly effective. Popplewell specifically disclosed a high-performing 25-mer PMO, designated PMO-A, which targets nucleotides +35 to +59. The PMO of claim 1 is also a 25-mer and targets nucleotides +36 to +60, a sequence that is shifted by only one nucleotide from Popplewell’s PMO-A and falls entirely within the disclosed +30 to +65 hotspot. Sazani disclosed PMOs with the same monomeric subunit structure recited in the claim.
      • Claim 2 (TEG Moiety): Claim 2 adds a limitation requiring a specific triethylene glycol (TEG) moiety attached to the 5' end of the PMO. Sazani explicitly disclosed this exact structure in the context of AVI-4658, a PMO for exon skipping that was in clinical trials. The addition of a TEG moiety to improve solubility and other properties was a well-known and routine modification in the art.
    • Motivation to Combine: A person of ordinary skill in the art (POSITA) would combine these references to arrive at the claimed invention.
      • A POSITA, starting with Popplewell’s disclosure of the highly effective PMO-A (+35 to +59) and the broader +30 to +65 hotspot, would have been motivated to optimize the sequence to find the most effective compound for clinical development. Petitioner argued it was routine practice to perform "oligonucleotide walks" by creating and testing oligomers targeting sequences shifted by single nucleotides around a known lead candidate. This routine optimization of Popplewell's PMO-A would have led directly to the claimed PMO targeting +36 to +60.
      • A POSITA would have been further motivated to add the TEG moiety disclosed by Sazani to the 5' end of the optimized PMO. This was a common and well-understood modification used to improve the pharmaceutical properties of PMOs, such as solubility, and was part of the structure of a leading clinical candidate (AVI-4658) at the time.
    • Expectation of Success: A POSITA would have had a reasonable expectation of success.
      • Popplewell demonstrated that every PMO tested within the broader +29 to +74 region induced exon 53 skipping, and that PMOs within the +30 to +65 hotspot were particularly effective. Therefore, a POSITA would reasonably expect that an oligomer targeting a sequence shifted by only one nucleotide from a highly effective PMO (PMO-A) and still within the hotspot would also be effective.
      • The conjugation of a TEG moiety as taught by Sazani was a standard, predictable chemical modification with known benefits, giving a POSITA a high expectation of successfully creating the molecule of claim 2 and improving its properties without losing its exon-skipping activity.
    • Key Aspects: Petitioner contended that the claimed invention is merely the result of routine, predictable optimization of a known lead compound (Popplewell's PMO-A) using conventional techniques and modifications (Sazani's TEG moiety) that were well-established in the field of antisense therapy for DMD.

4. Arguments Regarding Discretionary Denial

  • Petitioner argued that the Board should not exercise its discretion to deny institution under 35 U.S.C. §325(d). The asserted combination of Popplewell and Sazani presents arguments and evidence that were not before the Office during prosecution.
  • Specifically, Sazani was never considered by the examiner and is not cumulative to the art of record, as it provides unique disclosures about the complete chemical structure and safety data for a clinical-stage PMO.
  • While a related publication was of record, the specific Popplewell reference contains more complete data, including the critical identification of the 25-mer PMO-A as a "viable alternative" for clinical development. Petitioner argued the examiner overlooked this teaching and erroneously allowed the patent based on the Patent Owner's flawed "unexpected results" arguments made during prosecution of the grandparent '361 patent.

5. Relief Requested

  • Petitioner requests institution of an inter partes review and cancellation of claims 1 and 2 of the ’461 patent as unpatentable under 35 U.S.C. §103.