China's Patent Re-examination Board has delivered significant victories for RNAi therapeutic patent holders, upholding multiple patents despite challenges to their broad claim language and sufficiency of experimental support. The decisions, featured in China's 2023 Summaries of 50 Typical Patent Invalidation Cases, provide crucial guidance for the rapidly expanding RNAi pharmaceutical sector.
Landmark Inclisiran Patent Decisions
The Board upheld patents covering inclisiran, a PCSK9-inhibiting RNAi composition designed to reduce LDL cholesterol in adult patients with heterozygous familial hypercholesterolemia (HeFH) and atherosclerotic cardiovascular disease (ASCVD). The patents faced invalidation challenges on grounds of insufficient disclosure and lack of inventiveness, but the Board rejected these arguments after detailed technical analysis.
The parent patent primarily claims the double-stranded RNAi agent with specific sequences, modifications and conjugations, while the divisional patent covers broader variations in RNAi design. Both patents successfully defended against challenges to their claim scope covering RNAi compositions conjugated to various ligands.
Sufficiency Standards for Broad Claims
Petitioners argued that the patent specifications only provided experimental data for RNAi compositions linked to one specific GalNAc ligand, L96, but lacked support for compositions linked to other ligands. The Board rejected this challenge, establishing that the amount of support needed should be considered alongside a skilled person's reasonable expectations.
The Board determined that ligand-mediated delivery and gene silencing represent relatively independent technical solutions. Since various ligands for directing RNAi delivery are known in the art, a person having ordinary skill in the art (PHOSITA) could reasonably "mix-and-match" suitable ligands with the claimed siRNA while expecting similar technical effects.
"The technical solution provided by the ligand is directed delivery of the RNAi composition, which is provided relatively independently from the gene-silencing solution of the effective RNAi sequence," the Board stated, concluding that skilled practitioners could anticipate combining different components to solve the presented technical problem.
Inventiveness Analysis Considers Field Unpredictability
For the divisional patent, challengers contended that prior art CN 102458366A already disclosed highly effective nucleotide regions inhibiting PCSK9 expression, making it obvious to add modifications and ligands to create similar RNAi compositions.
The Board identified several key differences between the prior art and claimed invention:
- Different targeted regions in unmodified antisense strand sequences
- Complete nucleotide modifications throughout the RNAi composition versus partial modifications in prior art
- Novel phosphorothioate modifications not disclosed in prior art
- Sole reliance on ligands for delivery versus lipid formulation-based delivery systems
Critically, the Board noted that the cited prior art "taught away" from the claimed invention by suggesting that additional modifications were not particularly beneficial. The claimed invention demonstrated superior silencing effects through specific combinations of sequence selection and phosphorothioate modifications.
Implications for RNAi Patent Strategy
These decisions build upon China's first RNAi patent invalidation case from 2022, which involved Hepatitis B Virus RNAi compositions. That landmark case established that identifying effective primary sequences represents inventive activity due to the field's unpredictability, while minor modifications maintaining sequence integrity could be expected to solve similar technical problems.
The Board consistently emphasized that RNAi represents an unpredictable field where minor sequence modifications can significantly impact siRNA characteristics. This unpredictability supports broader patent protection when applicants can demonstrate that skilled practitioners would recognize the inventive nature of their technical solutions.
Examination Practice Remains Restrictive
Despite these favorable invalidation decisions, patent prosecution experience suggests that China National Intellectual Property Administration (CNIPA) examiners remain reluctant to grant broad "comprising" language for sequence listings without extensive data support. The Board's recognition of broader claim scope possibilities may not immediately translate to more permissive examination practices.
However, these cases provide important precedent by affirming that generic scope around RNAi inventions disclosing limited species can be obtained when specifications provide sufficient information for skilled practitioners to recognize that related species would function similarly.
Technical Complexity Drives Patent Strategy
As RNAi compositions become increasingly sophisticated, incorporating complex modifications to nucleotides and delivery ligands, the predictability of individual features may diminish. This growing complexity could impact the ability of skilled practitioners to confidently predict functionality across broad patent claims without supporting data.
The invalidation proceedings underscore the importance of addressing specific technical problems while acknowledging the unpredictable nature of RNAi technology when assessing both inventiveness and sufficient disclosure requirements. These principles will likely influence future RNAi patent examination and litigation strategies in China's expanding biotechnology market.
