PTAB

PGR2018-00059

Alnylam Pharmaceuticals, Inc. v. Silence Therapeutics GMBH

Title: Interfering RNA Molecules
Brief Description: The ’423 patent describes a genus of double-stranded small interfering RNA (siRNA) molecules. The claims require specific structural modifications—where groups of nucleotides with one type of 2'-position modification are flanked by groups of nucleotides with a different 2'-position modification—and also require the molecule to possess specific functional activities, such as being capable of RNA interference (RNAi).

Prior Art Relied Upon: Not applicable (challenge is based on the patent's own specification and its priority applications).
Core Argument:
- Prior Art Mapping: Petitioner argued that the ’423 patent and its priority applications fail to provide adequate written description for the full scope of the claimed genus. The specification allegedly does not describe a single representative species that meets both the structural requirements (e.g., a strand with two different 2'-modifications) and the functional limitations (e.g., capable of RNAi, increased stability, or inhibiting a target nucleic acid). The claims cover a vast and structurally diverse genus of potentially billions of siRNA molecules, but the specification only discloses a 2'-methoxy modification and fails to provide working examples of the claimed structures possessing the claimed functions.
- Key Aspects: Petitioner contended this failure is acute for claims encompassing a double-stranded region of 17 nucleotides, as the patent’s own specification teaches that such short duplexes are "not functional," demonstrating the inventors were not in possession of this claimed subject matter.

Prior Art Relied Upon: Not applicable (challenge is based on the patent's own specification and its priority applications).
Core Argument:
- Prior Art Mapping: Petitioner asserted that, independent of written description, the patent fails to enable a person of ordinary skill in the art (POSA) to make and use the full scope of the invention without undue experimentation. The field of chemically modified siRNA was described as highly unpredictable, where minor structural changes can have drastic and unforeseen effects on function. The specification provides no guidance for a POSA to determine which of the billions of possible siRNA molecules within the claimed genus would actually exhibit the required functional activities.
- Key Aspects: The specification allegedly offers only a "starting point for research" by providing screening methods, which is insufficient for enablement. A POSA would be forced into a complicated and lengthy trial-and-error screening process to practice the invention across its full scope.

Prior Art Relied Upon: McSwiggen (International Publication No. WO 03/070918).
Core Argument:
- Prior Art Mapping: Petitioner argued that McSwiggen, published in 2003, is valid prior art because the ’423 patent is not entitled to a priority date earlier than 2015. McSwiggen allegedly discloses a specific double-stranded siRNA molecule, "30434/30430," which contains every limitation of the challenged claims. The 30434/30430 molecule has strands comprising groups of 2'-O-methyl (an alkoxy) modified nucleotides flanked by groups of 2'-fluoro modified nucleotides. The number of nucleotides in these groups (1-4) and the length of the double-stranded region (19) fall within the claimed ranges.
- Key Aspects: McSwiggen allegedly demonstrates that the 30434/30430 molecule is "capable of RNA interference" and "inhibits the expression of a target nucleic acid" (luciferase), thereby meeting the key functional limitations of the independent and dependent claims.

Prior Art Relied Upon: Allerson et al., “Fully 2’-Modified Oligonucleotide Duplexes with Improved in Vitro Potency and Stability…” (a 2005 journal publication).
Core Argument:
- Prior Art Mapping: Petitioner argued that Allerson (2005) is also valid prior art against the ’423 patent. Allerson discloses siRNA molecules "consisting entirely of 2'-O-methyl and 2'-fluoro nucleotides," including a specific molecule identified as "duplex 8." Petitioner asserted that duplex 8 meets all limitations of the challenged claims. Duplex 8 is a 19-nucleotide double-stranded molecule with alternating 2'-O-methyl (alkoxy) and 2'-fluoro modifications on both strands.
- Key Aspects: Allerson provides data showing duplex 8 is "capable of RNAi," "inhibits the expression of a target nucleic acid" (PTEN mRNA), and has "increased stability" in plasma compared to an unmodified counterpart. These disclosures allegedly satisfy all structural and functional limitations of the challenged claims, including claims 10 and 20 which explicitly require increased stability.

"capable of RNA interference": Petitioner proposed this term should be construed as a functional limitation requiring the claimed siRNA molecules to actually exhibit RNAi activity. This construction is central to the argument that the priority applications fail to describe or enable such functional molecules, and it is also used to show how the prior art meets this limitation with activity data.
"inhibits the expression of a target nucleic acid": Similarly, Petitioner argued this term is a functional limitation requiring the claimed siRNA molecule to inhibit RNA expression (preferably mRNA). This construction supports the invalidity arguments by requiring the patent to enable this function and allowing prior art with corresponding data to be anticipatory.

Effective Filing Date: A central contention of the petition is that none of the challenged claims of the ’423 patent are entitled to the early priority dates (2002-2003) asserted by the Patent Owner. Petitioner argued that because the priority applications fail the written description and enablement requirements of §112 for the invention as claimed, the claims' effective filing date can be no earlier than December 22, 2015—the filing date of the direct parent application. This argument is critical, as it seeks to establish that McSwiggen (2003) and Allerson (2005) qualify as prior art under §102.

Petitioner requests institution of Post-Grant Review (PGR) and cancellation of claims 1-25 of the ’423 patent as unpatentable.