Freedom to operate for therapeutic nucleic acids: looking beyond the lead sequence

Therapeutic nucleic acids are no longer a niche technology. Antisense oligonucleotides (ASOs), siRNAs and related RNA-based medicines now form a commercially important class of therapeutics, with expanding clinical pipelines and a growing number of approved products. However, as the field becomes more crowded and competitive, so too does the patent landscape making freedom-to-operate more complex. A company may develop an entirely novel ASO yet still face significant patent risks arising from other aspects of its product. Effective FTO therefore requires a comprehensive assessment extending well beyond the sequence of the therapeutic nucleic acid.

Start with what is fixed: the drug

The obvious starting point is the sequence of the therapeutic nucleic acid itself. Patent searches should assess whether the candidate oligonucleotide, closely related sequences, overlapping target regions or conserved motifs have already been claimed. However, it is important to consider how these sequences can be claimed. For example, the sequence could be claimed as a nucleic acid of defined length (e.g., 20-30 nucleotides) of which at least a select number (e.g., 15) are complementary to a specific region of a DNA or RNA sequence. Clearly, this brings in a lot of variables to be considered when considering relevance to a therapeutic nucleic acid. However, sequence analysis represents only one component of a broader FTO assessment.

Despite the length of time therapeutic nucleic acids have been known, there are still granted platform patents in force defining nucleic acids having a specific mechanism of action. This is more likely for therapeutic nucleic acids that have activities such as upregulating expression or translation of a protein than the older nucleic acids that downregulate expression.

How is the drug going to be used?

Method of treatment claims represent another important consideration. Existing patents may claim treatment of particular diseases, patient populations, dosing schedules, routes of administration or combination therapies. These claims can be granted in much broader form than claims to a therapeutic nucleic acid per se and can affect commercialisation even where the active nucleic acid itself is not patented. For example, ongoing litigation in the US between Ionis and Arrowhead in case Ionis Pharmaceuticals Inc v Arrowhead Pharmaceuticals Inc, Case No. 2:25-cv-08609 is in relation to a patent claiming a “method of treating or ameliorating lipoprotein lipase deficiency (LPLD) in an animal comprising administering a therapeutically effective amount of a compound comprising an ApoCIII specific inhibitor to the animal, wherein administering the compound reduces a triglyceride level by at least 10%, thereby treating or ameliorating LPLD” with another claim defining the inhibitor as “a nucleic acid capable of inhibiting the expression or activity of ApoCIII”.

Chemistry

Chemical modifications of the nucleic acid are also often subject of patent protection. Oligonucleotide-based therapeutics comprise modified backbones or nucleosides for various reasons, including to improve stability or half-life or specificity. Numerous patent families claim specific backbone chemistries, sugar modifications, stereochemical configurations, gapmer architectures and conjugation technologies. While many of the modifications have been known for many years, some are newer and patents also exist claiming specific arrangements or positions of modified bases within a therapeutic nucleic acid. Even where the nucleotide sequence is novel, the selected chemistry may fall within the scope of existing patents owned by platform technology companies.

Delivery

Delivery technologies require separate consideration. Conjugation to carbohydrates, peptides or antibodies, lipid nanoparticles and other targeted delivery systems are often protected by extensive patent portfolios that can sit independent of the therapeutic sequence. This means a separate search, separate to that of the therapeutic molecule may be required. Similar considerations apply to linker chemistry and methods used to attach targeting ligands.

Manufacturing

Manufacturing processes may also present infringement risks. Commercial-scale synthesis, purification, deprotection, conjugation to delivery agents, analytical characterisation and formulation methods are patented. Although process patents are sometimes overlooked during early development, they can become critical as programmes move towards commercial manufacture. Again these patents are often independent of a claim to the specific therapeutic nucleic acid and may require an independent search.

Global considerations

Territorial differences further complicate FTO. Patent scope, claim interpretation, patent expiry dates and available exemptions differ significantly between jurisdictions. An FTO opinion prepared solely for the United States may not accurately reflect risks in Europe, Japan, Australia or other key markets. Additionally, therapeutic nucleic acids have not faced the same level of scrutiny by the courts as other molecules, such as antibodies and small molecules. Accordingly, the law as to allowable scope is not yet settled in many jurisdictions.

Importantly, FTO is not a one-time exercise. Patent landscapes evolve continuously through new filings, patent grants, divisional applications, continuations, oppositions and litigation. Programmes that appear to have clear FTO during lead optimisation may encounter new obstacles before clinical development or launch.

Conclusion

Assessment of FTO for therapeutic nucleic acids can be complex. An effective strategy is to integrate FTO into product development from the earliest stages and start with what is fixed, usually the molecule and the indication(s) of interest. Early identification of third-party rights as projects develop allows informed decisions regarding sequence selection, chemistry, delivery platform, licensing opportunities and design-around strategies before significant development costs are incurred. A comprehensive, regularly updated FTO assessment can therefore reduce legal risk while preserving flexibility throughout the product lifecycle.