RNAi Patent Success in China: Overcoming “Comprising” Claim Challenges

An Update on Sufficiency and Inventiveness of RNAi Patents in China

RNAi is a fast-developing technology that has gained traction in the pharmaceutical industry as a promising therapeutic agent. It is important to follow closely RNAi patent proceedings to learn how different examination boards and courts understand and handle these new technologies.

The first-ever invalidation decision in China for an RNAi patent¹ was rendered in 2022 by the Patent Re-examination Board (the “Board”). We previously wrote about this case, which discussed the standards for post-filing data, sufficiency, and inventive step, particularly for RNAi inventions. Since then, two newer cases involving RNAi have also been upheld by the Board after facing similar challenges against support and inventiveness. These cases provide further insight into the Board’s standards on examining RNAi patent invalidations.

Quick Recap on the First RNAi Invalidation Decision in China

The invalidation decision concerned a patent claiming Hepatitis B Virus (HBV) RNAi compositions². The following is a brief recap on the key issues examined in the decision:

Key Issues Examined:

1. Sufficiency: The petitioner argued that the open-ended term “comprising” in the claims allowed for any nucleotide additions, making the claim scope unclear. The Board dismissed this and emphasized that as long as the primary sequence was intact, a person having ordinary skill in the art (PHOSITA) would understand how to selectively add nucleotides to the primary sequence without compromising the sequence’s main function of silencing the HBV gene.
   
2. Inventiveness: The petitioner claimed the patented sequences were minor modifications of known HBV RNAi sequences. The Board disagreed, noting that due to the unpredictability in the RNAi field, a PHOSITA would recognise that even minor modifications to the primary sequence could significantly impact the resulting siRNA characteristics.
   

Ultimately, the Board upheld the patent’s validity, concluding that identifying the primary sequence was inventive due to the difficulty in predicting which sequence(s) would have activity. However, once the primary sequence was identified, minor modifications that maintained the integrity of the primary sequence intact were expected to also solve the technical problem. For a detailed analysis of this case, please refer to our previous article here: First ever Invalidation decision on an RNAi Invention patent in China

Later Invalidation Decisions related to RNAi

So what’s happened since then? In China’s 2023 Summaries of 50 Typical Patent Invalidation Cases, two newer cases also involving RNAi were also upheld³ by the Board after facing similar challenges against support and inventiveness. These cases provide further insight into the Board’s standards on examining RNAi patent invalidations.

Background

The patents involve inclisiran, a PSCK9-inhibiting RNAi composition for reducing LDL cholesterol in adult HeFH⁴ and ASCVD⁵ patients. The parent patent primarily focuses on claiming the double-stranded RNAi agent, with specific sequences, modifications and conjugations; while the divisional patent has a broader claim scope, covering variations in the RNAi design.

Sufficiency

In both patents, support for claims relating to the RNAi composition conjugated to at least one ligand (parent patent) and conjugated to GalNAc- ligands (divisional patent) were challenged.

The petitioner argued that the specifications only provided data support for the RNAi composition linked to one GalNAc ligand, L96, but did not provide any data to support technical effects of the claimed RNAi composition linked to other ligands.

The Board reinstated that the amount of support needed in a patent specification should be considered in combination with a skilled person’s expectations. Specifically, 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, such that it is possible to combine varying known ligands with the RNAi component (and still expect successful delivery of the RNAi composition).

The Board believed that a PHOSITA could anticipate the components needed to independently achieve the separate parts of the completed product’s technical solution, such that the complete product could still to solve the presented technical problem. Hence, the Board concluded that the technical solution presented was supported by the specification.

Inventiveness

Regarding the divisional patent, the requester contended that the closest prior art, CN 102458366A^6[6], already disclosed highly effective nucleotide regions that could inhibit PCSK9 expression. Therefore, it would be obvious for a PHOSITA to add modifications and ligands to the sequence and design RNAi compositions targeting the PCSK9 gene.

The Board examined the differences between the closest prior art and the claimed invention and highlighted the following differences:

1. The targeted regions in the unmodified antisense strand sequences are different
   
2. The present invention claims modifications for all nucleotides in the RNAi composition, while the closest prior art only claims modifications for some nucleotides
   
3. The closest prior art does not include the phosphorothioate modifications in the claimed invention.
   
4. The claimed invention depends solely on ligands to deliver the RNAi composition, while the closest prior art uses a lipid formulation, and only in some embodiments in combination with ligands

Moreover, the cited prior art previously “taught away” from the claimed invention, teaching that additional modifications in (2) were not particularly beneficial. The claimed invention also showed higher silencing effect for compositions of the selected primary sequence in combination with specific phosphorothioate modifications of (3). Lastly, the Board indicated that, while use of ligands was disclosed in an examplary embodiment of the closest prior art, the main technical solution of the closest prior art to aid delivery was still the lipid transfection reagent in the composition, and not ligands covalently-linked to the dsRNAi structure.

The Board concluded that, based on the disclosurse in the closest prior art, a PHOSITA would not be motivated to add modifications and ligands to the claimed invention, nor make alterations to the target region sequence. Moreover, the Board affirmed that the technical solution provided was to “provide a RNAi composition of different target sequence, modification and delivery method”, which was different from that of the cloest prior art.

EIP Thoughts

Consistent with the previous case, the conclusions made by the Board were based on the reasonable anticipation of a PHOSITA, which is done by examining the state of the art and the technical problem presented.

Sufficiency

In both cases, the Board upheld claims directed towards a “general” ligand, despite the specification only providing experimental data on one specific ligand L96. These current decisions illustrate the extent to which a broader, more “general” claim scope is possible.

In this instance, the Board reaffirmed that the siRNA and its covalently-linked ligand address different technical problems and are relatively functionally independent. Given that there is a variety of known-in-the-art ligands for directing RNAi delivery, a PHOSITA should be able to “mix-and-match” suitable ligands, and still expect a similar technical effect. Similar to the first invalidation case, the broader claim scope was upheld, based on the notion that the current disclosure is sufficient for a PHOSITA to combine a different ligand to the claimed siRNA, and expect no major compromise on its gene silencing effect.

Inventiveness

The Board’s inventiveness determination consisted of:

1. identifying the differences in technical effect between the closest prior art and the claimed invention
   
2. determining whether the changes applied to achieve those technical effects are obvious or not

Regarding obviousness, it comes down to whether there is motivation for a PHOSITA to make such changes. This is very case-specific and depends on whether teachings of the prior art would cause a PHOSITA to “readily recognize” how a (minor) change could solve the problem.

In this case, the technical differences were examined in detail, with reference to what teachings are available in the prior art. The Board was able to confirm that, in view of the closest prior art, a PHOSITA would not be motivated to add alterations in the primary sequence, make nucleotide modifications and change methods of delivery.

Generally, the RNAi field is considered unpredictable, as it is difficult to predict how a certain composition will react within a living organism.

Can We Get Broader Sequence Claims Now?

Although these cases seem to imply applicants can obtain broader claim scopes without providing as much supporting data (e.g., being able to use “comprising” language), our experience with the CNIPA is not consistent with this decision. In a majority of our prosecution cases, Examiners are still very, very reluctant to grant “comprising” language for sequence listings when there is no data support.

Having said that, these cases were published in the annual list of “50 typical cases”, highlighting representative patent invalidation cases decided by the Board in 2023. Importantly, the Board has affirmed that there is indeed “room” to obtain a generic scope around RNAi inventions that only disclose a handful of species. The cases provide helpful guidance by highlighting the importance of considering the PHOSITA, and how much information (whether prior art knowledge or data in the specification) is needed for a PHOSITA to be “convinced” and “readily recognize” that a different (closely related) species within a generic scope would also work.

We hope examiners and judges alike will refer to these cases when handling RNAi related patent proceedings. In particular, these two cases go into the specifics of RNAi technology, examining technical features beyond just the primary sequence, such as investigating the different modifications to the nucleotides and ligands. As RNAi compositions get more sophisticated and complex, the predictability of each feature behaving a certain way may diminish. This unpredictability could ultimately impact a PHOSITA’s ability to be convinced (without data) that a particular feature works throughout the entire scope of a large genus.

These invalidation proceedings emphasize the importance of considering the specific problem being addressed and the unpredictable nature of certain fields when assessing inventiveness and sufficient disclosure.

This article is for general informational purposes only and should not be considered legal advice or a legal opinion on a specific set of facts.

 About the Authors

1. No. 58530

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2. Chinese patent CN108064294 claims Hepatitis B Virus (HBV) iRNA compositions, including a double-stranded RNAi with sense and antisense strands each comprising a specific sequence. Assignee of this patent is Alnylam Pharmaceuticals Inc.

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3. Chinese patents CN104854242A (parent, case no. 4W115308) and CN108220295A (divisional, case no. 4W115598) were concerned. The parent patent was fully upheld, where the divisional patent had claims amended upon the invalidation request and the amended claim set was upheld.

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4. Heterozygous Familial Hypercholesterolemia

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5. Atherosclerotic cardiovascular disease

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6. The closest prioir art CN102458366A, also assigned to Alnylam Pharmaceuticals Inc, claimed compositions of lipid formulated dsRNA that are used to suppress PCSK9 gene expression.

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