siRNA science journey as reflected by the patent literature Alison Gallafent, Patent Director, HGF
• 1990 Napoli / Lemieux / Jorgensen - RNAi first discovered siRNA Timeline, how it began: trying to create purple flowers • 1998 Fire and Mello – identified RNAi as a distinct form of post translational gene silencing in C elegans • 2000 / 2001 Elbashir / Tuschl – siRNA design rules and 3’ overhang • February 2002 Ribozyme / Sirna / McSwiggen group – further teaching on purine / pyrimidine chemical modification • August 2002 Atugen - further teaching of chemical modification and relative positioning of such modification
Tuschl / 2001: Patent landscape: Stability and manufacturing considerations Why the overhang? To protect against exonuclease activity? Ease of synthesis?
2002, availability of starting materials Patent landscape: Manufacturing considerations For example, Ribozyme’s WO 03/070895, modifications described: Pyrimidine bases = Sugars fluoro modified Purine bases = Sugars H or Me modified Modifications linked to underlying base type, initially linked to specific target down regulation
Fast forward to 2012: Patent landscape: Manufacturing resulting in rule patent A later US patent US 8202979 derived from this family granted with the following claim in 2012, no longer target limited: Remember the possibility of continuations and the need to constantly monitor – speak to your Patent Attorney
Atugen: Relative positioning of modifications / blunt ended: Patent landscape: Modifications: Relative positioning, and blunt ended EP 1857547B: Modified group of nucleotides of the first strand corresponds to the unmodified group of nucleotides of the second strand, or modified group of nucleotides of the first strand corresponds to differently modified nucleotides of the second strand US 7893245: 2′ -O-methyl modified ribonucleotides alternate with unmodified or modified ribonucleotides and the 2′ -O-methyl modified ribonucleotides of said first strand are shifted by one ribonucleotide relative to the 2′ -O-methyl modified ribonucleotides of the second strand US 8933215: Nucleic acid molecule is blunt ended on at least one end
Atugen: Modifications: Relative positioning, and blunt ended Moved away from previous modification based on underlying base cf. Ribozyme, and overhang cf. Tuschl • Relative positioning / blunt ended now key
Inventive step: Inventive step An invention is considered as involving an inventive step if, having regard to what was previously known, it is not obvious to a person skilled in the art • Who is the person skilled in the art? • Person skilled in the art: For Europe, an experienced practitioner who has average knowledge and abilities and is aware of what was common general knowledge (cgk) in the relevant art
Arguments in support of inventive step: For example Inventive step: Atugen: • Prior art taught in the opposite direction to what the inventors did • Elbashir / Tuschl – siRNA design rules taught against extensive modification on both strands that was achieved by Atugen • No pointer to relative positioning • Blunt ended structure provided by Atugen went against the previous requirement for 3’ overhang • Good arguments for inventive step?
Detailed dialogue between inventor / Patent Attorney is key: Inventive Step: • Explain to Patent Attorney “leap” from the prior art • Explain to Patent Attorney problem solved by the invention and advantages provided by invention • Work together to identify data to support inventive step through “broad” claim scope • For example, Atugen data supported modified / unmodified pattern, but did not include data on modified / differently modified pattern • Work together to identify data to support advantage over closest prior art
Sufficiency: Sufficiency: Europe: The European patent application shall disclose the invention in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art • Would the disclosure of the patent have worked in the hands of the skilled team at the priority date – again the concept of the “skilled team” is key, can be supplemented by cgk • Based on disclosure, a skilled worker should be able to work through scope of claims • If there are significant embodiments within a claim that do not work, then monopoly exceeds technical contribution, and there are grounds for insufficiency • What might this mean for the Ribozyme / Tuschl / Atugen claims that define broad principles of application? Vulnerable?
Sufficiency and different jurisdictions: Sufficiency: • UK courts – Tough audience for acknowledging sufficiency • UK courts – Technical contribution / invention story needs to “fit” with sufficiency • EPO – Product claims, can the products be made? Sufficient? • Benefit of the doubt usually goes to Patentee at EPO
Later Rule Patents: Alnylam US Patent: siRNA Timeline, how it moved on: US 9290760: An iRNA duplex agent capable of silencing a target gene in vivo, comprising: (a) a sense strand with an alternating motif with at least 2 different chemically modified nucleotides; and one or more carbohydrate ligand; and (b) an antisense strand with the alternating motif the alternating motif is within the duplex region Embodiments:
Later Rule Patents: Alnylam US Patent: siRNA Timeline, how it moved on: US 8828956:
Specific sequence / linker claims: siRNA Timeline, how it moved on: A double stranded RNAi agent, sense strand is UfgGfgAfuUfuCfAfUfgUfaacCfaAfgAfL96 and the antisense strand is uCfuUfgGfUfUfaCgaugAfaAfuCfcCfasUfsc ….. Lower case = 2Me, Nf = 2F, s = phosphorothioate linkage, L96 = Sequence, modification, bonds, linker specific – less vulnerable to attack for claim scope?
Specific sequence / activity claim: siRNA Timeline, how it moved on: A pharmaceutical composition comprising dsRNA for inhibiting expression of TTR, where the antisense strand comprises SEQ 1D No 450 and the sense strand is complementary to the antisense strand, wherein the dsRNA comprises at least one chemically modified nucleotide and administration of 10nM of the dsRNA to a HepG2 cell results in at least 80% inhibition of TTR mRNA expression as measured by a real time PCR assay Again sequence specific – less vulnerable to attack for claim scope? Data to support advantage / difference over prior art?
Beginning with general rule applications: siRNA Patent Journey: Advantages: broad scope, good for infringement; early in the science, good for inventive step Challenges: broad claim scope brings more sufficiency challenges, especially in certain jurisdictions Moving on to more specific rule applications: Advantages: still relatively broad claim scope, good for infringement Challenges: more prior art, inventive step becoming more difficult; sufficiency continues to be challenging Specific sequence / linker applications: Advantages: protect specific products, less vulnerable to claim scope attack Disadvantages: no longer provide broad platform protection and as such less like to catch third party products
Thank you! Thank you for your attention! Contact details: Alison Gallafent: • Email: agallafent@hgf.com • Mobile: 00447387134290 • http://www.hgf.com/
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