PTAB

PGR2018-00089

Alnylam Pharmaceuticals Inc v. Silence Therapeutics GmbH

Key Events

Petition

petition

Title: Interfering RNA Molecules
Brief Description: The ’501 patent discloses chemically-modified, double-stranded small interfering RNA (siRNA) molecules. The claimed modifications, such as alternating 2'-O-alkyl ribonucleotides, are intended to increase stability in a biochemical environment while maintaining the ability to mediate RNA interference (RNAi) for gene silencing.

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 ’501 patent claims an enormous genus of siRNA molecules with vast potential variations in chemical modifications, strand lengths, end structures, and genetic targets. However, the specification allegedly discloses only a "narrow sliver" of structurally similar examples that are not representative of the full claimed scope. For instance, the examples are limited to 2'-O-methyl modifications that alternate only with unmodified nucleotides, have blunt ends, are 19 or 21 nucleotides in length, and target only three specific genes.
- Key Aspects: Petitioner contended this disconnect between the broad claim scope and the narrow disclosure fails to demonstrate that the inventors were in possession of the full genus, as required for written description. Further, due to the highly unpredictable nature of RNAi technology, a person of ordinary skill in the art (POSA) would require undue experimentation to determine which of the countless claimed molecules would be functional. The petition also noted that the specification discourages certain claimed embodiments (e.g., teaching that molecules with 17 ribonucleotides are "not functional"), further evidencing a lack of possession and enablement across the full claim scope.

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 asserted that because the ’501 patent is not entitled to its claimed priority date (see Section 5), Allerson qualifies as prior art. The Allerson reference allegedly discloses "duplex 8," a double-stranded siRNA molecule that anticipates claim 1 and numerous dependent claims. Petitioner mapped that duplex 8 consists of two 19-ribonucleotide strands that are blunt-ended and complementary. Crucially, each strand comprises contiguous alternating 2'-O-methyl ribonucleotides (a type of 2'-O-alkyl) and differently modified 2'-fluoro ribonucleotides, satisfying a key limitation of claim 1.
- Key Aspects: The modification pattern in duplex 8 is shifted by one nucleotide between the strands, directly reading on another element of claim 1. This single disclosed molecule was argued to contain all structural limitations of the independent claim and additional limitations of dependent claims related to strand length, blunt ends, and the specific chemical modifications used.

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: Arguing again that the ’501 patent’s effective filing date is its actual filing date, Petitioner presented Choung as anticipating prior art. Choung allegedly discloses the "Sur10058-Me-AL3" molecule, which anticipates claim 1 and several dependent claims. This molecule is a double-stranded siRNA targeting survivin mRNA. Its structure comprises two 19-ribonucleotide stretches with contiguous alternating 2'-O-methyl ribonucleotides (a 2'-O-alkyl modification) and unmodified ribonucleotides.
- Key Aspects: Unlike the molecule in Allerson, the Sur10058-Me-AL3 molecule alternates modified with unmodified nucleotides and features two-nucleotide 3' overhangs, thereby anticipating claims that require overhangs (e.g., claims 3-5 and 7). Petitioner contended this single reference disclosed every element of claim 1 as well as the specific limitations of various dependent claims related to overhangs and the use of unmodified nucleotides.
Additional Grounds: Petitioner asserted an additional anticipation challenge (Ground 5) based on Podbevsek, which disclosed a molecule with alternating 2'-O-methyl and 2'-fluoro modifications and 3' overhangs.

Term: "double-stranded siRNA molecule against a target nucleic acid"
Proposed Construction: Petitioner argued this term, which appears in the preamble but provides antecedent basis for the claim body, should be construed to require that the molecule exhibits RNA interference (RNAi) activity (i.e., interferes with gene expression).
Importance: This construction was central to Petitioner’s §112 arguments, as it would require the patent to enable a functional genus, not just a structural one. Petitioner supported this position by citing the patent’s stated purpose of providing molecules that are both "stable and active," its examples that focus exclusively on RNAi activity, and prosecution history where the Patent Owner emphasized activity to overcome prior art.

Priority Date Entitlement: A central contention underlying multiple grounds 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 series of priority applications, dating back to 2002, fail to provide adequate written description and enablement for the full, broad scope of the finally issued claims. This alleged failure to support the claims in the earlier applications breaks the priority chain, making intervening publications like Allerson (2005) and Choung (2006) valid §102 prior art against the ’501 patent.

Petitioner requested institution of Post Grant Review and cancellation of claims 1-30 of the ’501 patent as unpatentable.