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:
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binding to a target nucleic acid by base pairing (e.g., ASOs, miRNAs, siRNAs and CRISPR);
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binding to targets other than nucleic acid, such as proteins and small molecules (e.g., aptamers); and
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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
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)
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.
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)
CRISPR
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
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.
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)
mRNA therapeutics
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.
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)
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:
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incorporating the RNA-based drug into a viral or non-viral carrier; and
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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
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3 https://link.epo.org/web/business/patent-insight-reports/mrna_technologies_2023_EN.pdf
4 Pardi, N., et al., mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 2018 17;261–279