Despite the recent advances in mRNA technology following the COVID-19 pandemic (which was the subject of the 2023 Nobel Prize), the concept of using RNA as a therapeutic has been around for many years. For example, Zamecnik et al. proposed the use of antisense oligonucleotides (ASOs) to inhibit protein synthesis as far back as 1978. Since then, the development of RNA interference (RNAi) and siRNA for controlling gene expression has led to a rapid expansion of the field of RNA therapeutics. Fast-forward to 2023, over 70% of the world’s population has received at least one dose of a COVID-19 mRNA vaccine.
In this article, we provide an overview of the various different types of RNA therapeutics and consider how the related patent landscape is evolving.
Classification of RNA therapeutics
RNA therapeutics can generally be classified into 3 categories based on their mechanism of action:
binding to a target nucleic acid by base pairing (e.g., ASOs, miRNAs, siRNAs and CRISPR);
binding to targets other than nucleic acid, such as proteins and small molecules (e.g., aptamers); and
being translated into a therapeutic protein (e.g., mRNA vaccines).
Antisense Oligonucleotides (ASOs)
Early RNA therapeutics used ASOs to inhibit Rous sarcoma virus (RSV) replication. ASO-mediated gene regulation involves the binding of a short, single stranded oligonucleotide to target RNA to modify protein expression (see below). ASOs can also be used to modulate translation of a specific protein, through binding to inhibitory or activatory components in the target mRNA or by binding to regulatory micro RNAs (miRNAs). For example, nusinerson (Spinraza®) treats spinal muscular atrophy by altering splicing of the SMN2 protein to increase production of the functional SMN protein.1
RNA Interference (RNAi)
RNAi uses short interfering RNAs (siRNAs – short double-stranded RNA molecules) or micro RNAs (miRNAs) to trigger degradation of the target mRNA and silencing expression of the target gene (see below). Conversely, RNA activation (RNAa) uses double-stranded small activating RNA molecules to target promoter sequences and upregulate gene expression, for example to upregulate tumour suppressor genes in the treatment of cancer. As an example, in 2018 patisiran (Onpattro®) was approved for medical use in the US and EU to treat hereditary transthyretin-mediated amyloidosis in adults. Patisiran uses a lipid nanoparticle (LNP) to deliver siRNA to the liver to reduce transthyretin production, reducing amyloid deposits.
Also relevant to RNA therapeutics is the widely known gene editing tool CRISPR, which uses guide RNA (gRNA) base pairing to splice or modify specific target sequences (see below). CRISPR is widely known for its significant genome-editing potential, and as a result has been the subject of several major intellectual property disputes. The CRISPR-Cas systems are derived from prokaryotic adaptive immunity systems which use a gRNA molecule bound to a Cas enzyme to cleave a target DNA molecule at a specific site. For example, Vertex Pharmaceuticals and CRISPR Therapeutics’ CRISPR-based drug exa-cel (Casgevy™) has recently been authorised by the MHRA to treat sickle cell disease and beta thalassemia, with similar FDA approval expected in the coming months.
Aptamers, often termed ‘chemical antibodies’ due to their specific structural and binding properties, are short single stranded nucleotide sequences which selectively bind to and inhibit proteins (see below). The first RNA aptamer approved for clinical use by the FDA in 2004, pegaptanib, is an anti-VEGF aptamer for use in the treatment of age-related macular degeneration.
Although mRNA is often the target of RNA therapeutics, it can be used as the therapeutic itself (see below). mRNA therapeutics can be used to treat, for example, cancer and infectious diseases. Particularly, mRNA can induce an effective immune response against a desired antigen when administered to a host and can therefore be used as a vaccine platform. mRNA vaccines have been developed for immunisation against viruses such as influenza and Sars-CoV-2.
Advantages of RNA therapeutics
Since RNA therapeutics can be used to target both translated mRNA and non-coding RNA molecules, they can theoretically be used to target the expression of any gene. This is in contrast to existing small molecule or antibody therapies, for example, which can only target the minority of the genome that is translated into a protein and are also often limited by the specific binding properties of their target. Additionally, CRISPR can target both DNA and RNA which expands the range of potential targets even further.
The specific targeting of RNA via base pairing is also advantageous because it has the potential to reduce off-target effects.
Another advantage of RNA therapeutics is the relatively fast design/manufacture and low-cost development in comparison to other biologicals (e.g., monoclonal antibodies). An RNA sequence can be readily designed to target any nucleic acid sequence or produce any target protein.
RNA therapeutics show particular promise in the treatment of rare diseases, infectious diseases and cancer, where the ability to personalise and specifically target therapeutics is extremely valuable.
Unsurprisingly, the global RNA therapeutics market is predicted to continue growing over the coming years. However, despite their potential, there are relatively few RNA therapeutics currently approved for clinical use.
Limitations of RNA therapeutics
Although, in theory, RNA-based therapeutics can be used to target any gene, in reality it is the successful delivery of the RNA which represents the biggest challenge. RNA on its own cannot easily be delivered into cells and is readily degraded by the host’s enzymes (e.g., serum nucleases). For delivery, RNA must be successfully taken up into the cell by receptor-mediated endocytosis and released from the endosome into the cytoplasm. It is therefore unsurprising that a significant proportion of research (and intellectual property) relates to RNA delivery. Popular solutions include:
incorporating the RNA-based drug into a viral or non-viral carrier; and
modifying the RNA through chemical modification or lipid conjugation to ensure the survival of the RNA in vivo.
Particularly in relation to siRNA, chemical modification has been shown to increase stability and nuclease resistance, but reduce biocompatibility, resulting in a reduction in gene silencing.
Lipid carriers show promise due to their versatility and biocompatibility which is reflected in the number of related patent filings, especially lipid nanoparticles (LNPs). Polymer carriers also show promise as delivery vectors for RNA-based drugs, due to their stability, potential for cellular uptake and ability to interact with charged RNA molecules. Lipid-polymer hybrid nanoparticles (LPNs) combine the biocompatibility of lipids with the stability of polymer carriers.
Trends in patent filings
As expected, there has been a steady increase in patent filings relating to RNA therapeutics.2,3 In particular, the increase in filings related to mRNA therapeutics exceeds the rate of increase across all fields of technology3. There has also been an increase in the number of applications relating to delivery using LNPs, particularly lipid-polymer hybrid nanoparticles.2
There also appears to be a high proportion of international patent families relating to RNA therapeutics2,3 indicating the importance of global protection.
Just 10 countries (US, Japan, China, Canada, Korea, Germany, Switzerland, UK, France and Israel) appear to be responsible for the vast majority of published patents relating to RNA therapeutics with the US being responsible for over 50% of these.2 Patent families appear to usually be filed multilaterally, apart from applicants in China, who appear to file patents in a smaller range of countries.2 The geographical distribution of patent applications has been relatively unchanged throughout the last 20 years, however a recent spike in the proportion of applications from Chinese applicants in 2020 may be the beginnings of an increase in competition for US applicants.2
Litigation may shape the future landscape of RNA therapeutics
Although mRNA vaccines have been around for some time (e.g., for influenza, Zika and rabies viruses4), the unprecedented development, authorisation and delivery of billions of COVID-19 mRNA vaccines globally brought their use to the world stage. Unsurprisingly, patentees tended not to enforce their patents during the early years of the pandemic. However, litigation in relation to mRNA vaccines is now on the rise. For example, at the time of writing, Moderna is currently pursuing competitors Pfizer and BioNTech in multiple jurisdictions for alleged infringement of patents relating to their mRNA vaccine platform. These high-profile intellectual property disputes are just some of many which have resulted from the development of the COVID mRNA vaccines. Other companies implicated in such disputes include Arbutus Biopharma, Genevant Sciences and Alnylam Pharmaceuticals.
The number of intellectual property disputes in this field is testament to the high value of the RNA therapeutics market and we expect this to increase as the market continues to grow. The prospect of litigation may, however, discourage some companies from commercialising in this field. Moreover, the outcomes of litigation relating to fundamental aspects of RNA technology, such as LNP delivery and RNA modifications, also have the potential to shape the future landscape of RNA therapeutics because such aspects can cover a wide range of potential products.
In addition to mRNA vaccines, there has also been numerous intellectual property disputes around the world in relation to CRISPR technology, most notably between the Broad Institute and the University of California, which also has the potential to shape the landscape of RNA therapeutics.
Our team has considerable experience advising clients on patent matters in relation to technologies such as mRNA vaccines, RNA interference (RNAi), antisense oligonucleotides, non-coding RNA (ASO), CRISPR-based genome editing and LNP chemistry. Our RNA experts include Andrea Hadfield, Beth Ormrod, James Cochrane, Jamie Atkins, Jessica Duncombe, Juliette Howarth, Oliver Lam, Samuel Bailey, Sarah Lau and Tom Leonard. Please get in touch if you have any related queries!
1 Dhuri, K., et al. Antisense Oligonucleotides: An Emerging Area in Drug Discovery and Development. J. Clin. Med. 2020 Jun 26;9(6):2004
2 Chen, Y., et al., Delivery of therapeutic small interfering RNA: The current patent-based landscape. Mol. Ther. Nucleic Acids. 2022 Jun 22;29:150-161
4 Pardi, N., et al., mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 2018 17;261–279