PTAB

PGR2018-00089

Alnylam Pharmaceuticals, Inc. v. Silence Therapeutics GMBH

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1. Case Identification

2. Patent Overview

  • Title: Interfering RNA Molecules
  • Brief Description: The ’501 patent relates to chemically-modified, double-stranded small interfering RNA (siRNA) molecules. The technology is intended to provide molecules with improved stability and activity for use in RNA interference (RNAi) to inhibit the expression of a target gene.

3. Grounds for Unpatentability

Ground 1: Lack of Written Description and Enablement under 35 U.S.C. §112 for Claims 1-30

  • Core Argument for this Ground:
    • Prior Art Mapping: This ground does not rely on prior art but on the patent's specification itself. Petitioner argued that the patent and its priority applications fail to meet the requirements of §112. The claims cover an enormous genus of siRNA molecules with vast structural diversity, including any 2'-O-alkyl modification, various alternating patterns with unmodified or differently modified ribonucleotides, a wide range of lengths (17-30 ribonucleotides), and applicability to any target gene. However, the specification only discloses a "narrow sliver" of structurally similar examples: blunt-ended duplexes of 19 or 21 nucleotides, with a specific 2'-O-methyl modification alternating with unmodified ribonucleotides, targeting only three genes. Petitioner asserted that this disclosure of a few species from a "corner of the genus" is not representative of the full scope claimed, failing the written description requirement.
    • Key Aspects: The argument for lack of enablement runs parallel, contending that the field of chemically-modified siRNA was and remains highly unpredictable. The specification allegedly provides no principles or guidance that would allow a person of ordinary skill in the art (POSA) to practice the full scope of the claimed genus—i.e., to create and use the countless untested variations—without undue experimentation. The patent allegedly provides only a "starting point for further iterative research" rather than an enabled invention. Furthermore, the specification expressly teaches away from certain claimed embodiments, stating that molecules with 17-nucleotide stretches are "not functional."

Ground 2: Anticipation of Claims 1, 2, 9, 10, 12, 13, 16-20, 22, 24, and 25 under §102 over Allerson

  • Prior Art Relied Upon: Allerson, et al., "Fully 2'-Modified Oligonucleotide Duplexes with Improved in Vitro Potency and Stability Compared to Unmodified Small Interfering RNA" (published Jan. 20, 2005).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Allerson is valid prior art because the ’501 patent is not entitled to its claimed priority date. Allerson allegedly discloses "duplex 8," a double-stranded siRNA molecule that anticipates every limitation of independent claim 1. Specifically, duplex 8 is a 19-ribonucleotide, blunt-ended duplex targeting PTEN mRNA. It comprises contiguous alternating 2'-O-methyl ribonucleotides (a 2'-O-alkyl modification) that alternate with differently modified 2'-fluoro ribonucleotides. Petitioner asserted this structure meets the claim requirements for the alternating modification pattern, the one-nucleotide shift in pattern between strands, and the specified length. The demonstrated RNAi activity of duplex 8 was also noted. This single molecule is alleged to anticipate numerous dependent claims as well.

Ground 3: Anticipation of Claims 1, 3-5, 7, 9-11, 14, 15, 20, 21, and 23 under §102 over Choung

  • Prior Art Relied Upon: Choung, et al., "Chemical modification of siRNAs to improve serum stability without loss of efficacy" (published Feb. 20, 2006).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued Choung is valid prior art and discloses the "Sur10058-Me-AL3" molecule, which anticipates claim 1 and several dependent claims. This molecule is a double-stranded siRNA that comprises contiguous alternating 2'-O-methyl ribonucleotides with unmodified ribonucleotides, a structure falling squarely within the scope of claim 1. The molecule is 19 ribonucleotides long in its core duplex region and features a shifted modification pattern. Unlike the molecule in Allerson, Choung's molecule has two-nucleotide overhangs, which Petitioner argued anticipates dependent claims specifically requiring an overhang structure (e.g., claims 3, 4, 5, and 7).

Ground 4: Anticipation of Claims 1, 16, 19, 26, 27, and 29 under §102 over Podbevsek

  • Prior Art Relied Upon: Podbevsek, et al., "Solution-state structure of a fully alternately 2'-F/2'-OMe modified 42-nt dimeric siRNA construct" (published July 12, 2010).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued Podbevsek is valid prior art and discloses a double-stranded siRNA molecule that anticipates claim 1 and other claims. The molecule is a 19-ribonucleotide duplex targeting PTEN mRNA and comprises contiguous alternating 2'-O-methyl and 2'-fluoro ribonucleotides, with the modification pattern shifted between strands. Petitioner contended this structure meets all limitations of claim 1 and that the disclosure anticipates the claims regardless of whether they are construed to require RNAi activity. The molecule's overhangs were also cited as anticipating relevant dependent claims.

4. Key Claim Construction Positions

  • Petitioner dedicated significant argument to construing the terms "double-stranded siRNA molecule" and "double-stranded siRNA molecule against a target nucleic acid."
  • Petitioner argued these terms, read in light of the specification and prosecution history, should be construed to require that the claimed molecule is functional—that is, it must exhibit RNA interference (RNAi) activity. This construction was central to strengthening the §112 arguments, as the patent provides even fewer examples of functional molecules across the vast claimed genus than it does structural examples.

5. Key Technical Contentions (Beyond Claim Construction)

  • A central contention of the petition was that none of the challenged claims are entitled to a priority date earlier than the patent's actual filing date of May 8, 2017.
  • Petitioner argued that the entire chain of priority applications, dating back to 2002, fails to provide adequate written description and enablement for the full scope of the issued claims. This technical-legal argument was foundational to the petition, as it sought to disqualify the patent from its early priority dates, thereby establishing that the Allerson (2005), Choung (2006), and Podbevsek (2010) publications are valid §102 prior art.

6. Relief Requested

  • Petitioner requests institution of Post Grant Review (PGR) and cancellation of claims 1-30 of the ’501 patent as unpatentable.