Protecting therapeutic nucleic acids: patent strategies beyond sequence claims

The number of therapeutic nucleic acids such as antisense oligonucleotides (ASOs), RNAi and siRNA in development is expanding with one study estimating a 2.4 fold increase in clinical trials for siRNAs in the period 2017-2024 compared to the eight years before.^1. This increasing development has resulted in an increasing number of patent filings to nucleic acid-based therapies. A review of the patents listed in the FDA’s Orange Book shows that for the most part the primary protection is based on claims to the ASO/siRNA itself (defined at the genus level or the specific sequence of the molecule) or methods for treating a specific condition. However, there are more opportunities to protect these drugs, which may provide additional protection against competition in the future.

The golden ticket: patenting the drug

As the patent landscape for therapeutic nucleic acids becomes more crowded, it is becoming more difficult to obtain composition of matter claims. Where ASO/siRNAs against a target are known, some patent offices are alleging that all ASOs/siRNAs against that target are obvious. However, what is becoming clearer is that there are hostpots in a target to provide a therapeutic effect and these regions can provide a patentable position. Additionally, even single nucleotide changes in a therapeutic nucleic acid can have substantial effects not only on therapeutic effect but also other important measures such as toxicity or off-target effects. Such effects also provide a good argument for patentability of a narrow claim to a therapeutic lead and similar sequences. However, there are more opportunities to protect these drugs, which may provide additional protection against generic competition in the future.

Methods of treatment

Method of treatment claims provide an important level of protection and need not be limited to entirely new conditions to be treated. These claims may encompass particular patient populations, dosing regimens, routes of administration, effects on biomarkers of efficacy, or combination therapies that emerge during clinical development. As clinical evidence accumulates, new therapeutic applications or improved dosing strategies can provide valuable opportunities for additional patent filings with later expiry dates. For example, extended periods of therapeutic effect can provide for reduced dosage frequency which provides a commercial advantage and may provide a patentable position.

Formulations

Formulation patents likewise continue to grow in importance. While ASO and siRNA formulations are generally quite simple not all formulations perform at the same level of these differences in performance can provide a patentable position. For example, an ASO may be very stable in one formulation but unstable or less stable in other buffer systems. Buffer systems, excipient combinations, lyophilised products, ready-to-use liquid formulations and stability-enhancing compositions can extend protection beyond the active oligonucleotide itself while addressing real commercial challenges.

Delivery

Delivery technologies also remain fertile areas for patenting. Newer therapeutic nucleic acids either recently approved or in development are conjugated to ligands such as carbohydrates, peptides or antibodies to enhance delivery to a cell type of interest. Some of these ligands additionally include components to enhance therapeutic effect of the conjugated nucleic acid, e.g., PEG molecules or antibody Fc regions to enhance half-file. The ligand itself as well as the conjugation chemistry and the complete conjugate can all provide patentable positions.

Regulatory requirements

FDA guidance for approval of generic versions of nucleic acid-based drugs identify additional patenting opportunities for these drugs. For example, the FDA has indicated it will look to product or process related impurity levels, potency based on a specific assay, counter-ion effect and dosage units. Traditional small molecule and biologic drugs has many examples of where such characteristics have provided the basis for successful patent filings.

Conclusion

Successful ASO or siRNA portfolios rarely depend upon a single patent family. Instead, they comprise coordinated protection spanning the molecule, chemistry platform, manufacturing, formulations, methods of treatment and regulatory requirements. Such layered portfolios not only increase barriers to entry but also provide flexibility for lifecycle management as clinical development progresses.