PTAB

IPR2021-01140

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 ’322 patent relates to solid-phase methods for making a specific 25-mer phosphorodiamidate morpholino oligomer (PMO) that is 100% complementary to nucleotides +36 to +60 of exon 53 of the human dystrophin pre-mRNA. This antisense oligomer (AO) is intended for use in exon-skipping therapies for Duchenne muscular dystrophy (DMD).

3. Grounds for Unpatentability

Ground 1: Claims 1-10 are obvious over Popplewell in view of Sazani and Reeves.

  • Prior Art Relied Upon: Popplewell (a 2010 journal article titled "Comparative Analysis of Antisense Oligonucleotide Sequences Targeting Exon 53..."), Sazani (a 2010 journal article titled "Safety Pharmacology and Genotoxicity Evaluation of AVI-4658"), and Reeves (Application # 2009/0131624).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that the combination of references taught all elements of the challenged claims. Popplewell identified a "hotspot" target region (+30 to +65) within exon 53 of the dystrophin gene for effective AOs. Popplewell specifically disclosed several highly effective PMOs in this region, including a 25-mer designated PMO-A that targets the +35 to +59 sequence—a sequence shifted by only one nucleotide from the sequence claimed in the ’322 patent. Sazani disclosed the exact chemical structure of a different clinical candidate AO (AVI-4658), which used the same phosphorodiamidate morpholino monomers and 5’ triethylene glycol (TEG) moiety recited in the challenged claims. Finally, Reeves disclosed a detailed, stepwise solid-phase synthesis method for making PMOs, including the incorporation of a 5' TEG moiety, that maps directly onto the method steps recited in claims 1 and 6. The dependent claims recite specific, well-known reagents for this synthesis (e.g., trifluoroacetic acid, N-ethylmorpholine), all of which were also taught by Reeves or known in the art for their recited purpose.
    • Motivation to Combine: A Person of Ordinary Skill in the Art (POSA), starting with Popplewell's promising results, would have been motivated to optimize the highly effective PMO-A sequence. Petitioner asserted that a standard and routine optimization technique in the field was to perform an "oligonucleotide walk"—testing sequences shifted by one or more nucleotides. A one-nucleotide shift from Popplewell’s PMO-A (+35+59) would have immediately led a POSA to the claimed +36+60 sequence. To synthesize this optimized AO for potential clinical use, a POSA would have been motivated to use the exact PMO chemistry (monomers and 5' TEG moiety) from Sazani, which was already part of a successful clinical candidate (AVI-4658), and to employ the routine and well-established solid-phase synthesis methods detailed in Reeves.
    • Expectation of Success: Petitioner argued a POSA would have had a high expectation of success. Popplewell demonstrated that nearly every AO tested within the +30 to +65 "hotspot" region successfully induced exon skipping, and that PMO-A was a "viable alternative" for clinical development. Therefore, a minor, one-nucleotide shift to the claimed sequence was highly likely to retain this function. Furthermore, the synthesis methods taught by Reeves and the chemical components from Sazani were well-characterized and known to be effective and predictable, providing a high probability of successfully creating the desired oligomer.

4. Key Technical Contentions (Beyond Claim Construction)

  • Refutation of Unexpected Results: During prosecution of a related patent, the Patent Owner argued for patentability based on unexpected results, alleging its claimed AO was superior to the prior art. Petitioner contended this argument was flawed and that the Patent Owner's own data, presented in Figures 16 and 17 of the ’322 patent specification, directly contradicted this claim. This data, which Petitioner argued was overlooked by the Examiner, showed that an AO targeting the claimed +36+60 sequence performed no better, and perhaps worse, than an AO targeting the prior art +35+59 sequence (PMO-A) when directly compared under identical conditions.
  • Near-Simultaneous Invention: As objective evidence of obviousness, Petitioner pointed to a provisional application filed by a third party (Prosensa) within five months of the patent's priority date. This application disclosed a PMO targeting the exact same +36+60 sequence of exon 53, demonstrating that the claimed invention was the product of ordinary skill in the art at the time.

5. Arguments Regarding Discretionary Denial

  • Petitioner argued that discretionary denial under 35 U.S.C. §325(d) was inappropriate because the Office made material errors during prosecution. The petition relied on references and arguments that were not previously before the Examiner. Specifically, Sazani was a new reference not cumulative to the art of record. While Popplewell and Reeves were cited in the patent specification, they were never applied in a rejection. Petitioner argued the Examiner overlooked Popplewell’s key teaching that the 25-mer PMO-A was a "viable alternative" and instead focused on a 30-mer, and failed to consider the detailed synthesis teachings of Reeves. Petitioner contended these new references and arguments demonstrated that the Office erred in allowing the claims.

6. Relief Requested

  • Petitioner requested institution of an inter partes review (IPR) and cancellation of claims 1-10 of Patent 10,683,322 as unpatentable under 35 U.S.C. §103.