BioTech IP Review

Circular RNA (circRNA) therapeutics are rapidly emerging as a next-generation platform in RNA medicine. Unlike conventional linear mRNA, circRNAs form covalently closed loops, which confer resistance to exonucleases, enhanced stability, and prolonged protein expression in cells. By exploiting these features, researchers are developing circRNA-based vaccines, protein replacement therapies, and cell engineering tools. For attorneys, circRNA therapeutics raise unique questions regarding patentable subject matter, claim scope, and enablement, particularly given the intersection of chemical modification, sequence design, and delivery technologies.

Biological and Technical Foundations of circRNA

Circular RNAs are generated either naturally through back-splicing of pre-mRNA or synthetically using in vitro transcription followed by enzymatic ligation or ribozyme-mediated self-cyclization. Their covalently closed structure eliminates free 5’ and 3’ ends, which are vulnerable to exonuclease degradation in linear RNA molecules. This stability enhances intracellular half-life and allows sustained translation when engineered with appropriate internal ribosome entry sites (IRES) or N6-methyladenosine (m6A)-mediated translation initiation.

Key design considerations include:

1. Coding sequence optimization for desired protein expression.
2. Circularization method, including enzymatic ligation or self-splicing ribozymes.
3. Regulatory elements, such as IRES, cap-independent translation enhancers, and stabilizing motifs.
4. Chemical modifications to improve immunogenicity, folding, or translational efficiency.

By combining these features, circRNAs can be tailored to achieve controlled protein expression in vitro and in vivo, positioning them as a versatile therapeutic modality.

Therapeutic and Cell Engineering Applications

CircRNA therapeutics have several emerging applications:

• Vaccines: CircRNAs encoding viral antigens induce sustained antigen expression, potentially enhancing immunogenicity and durability of immune responses.
• Protein replacement therapy: CircRNAs can deliver therapeutic proteins for genetic disorders with transient but prolonged expression.
• Cell engineering: CircRNAs can transiently express transcription factors, genome editors, or synthetic regulators to reprogram cells without integrating vectors, minimizing genomic disruption.
• Multi-functional expression platforms: CircRNAs can encode multiple proteins or regulatory RNAs from a single transcript using strategies such as self-cleaving peptides.

These features make circRNA a promising alternative to linear mRNA in both ex vivo and in vivo therapeutic applications.

Patentable Subject Matter

CircRNA inventions may be claimed across several domains:

• Synthetic circRNA molecules: Defined by sequence, circularization strategy, or functional motifs.
• Circularization methods: Enzymatic ligation, ribozyme-mediated self-cyclization, or chemical strategies.
• Delivery systems: Lipid nanoparticles, polymeric carriers, or conjugates designed for efficient cellular uptake.
• Applications: Therapeutic use, vaccination, or cellular reprogramming.
• Platform claims: Modular circRNA systems capable of expressing multiple proteins or regulatory RNAs in a controlled manner.

Because the circular form is not typically present in natural human transcripts at the same efficiency or with engineered regulatory elements, circRNAs are more clearly human-made than unmodified linear mRNAs, supporting patent eligibility.

Enablement and Written Description Considerations

CircRNA stability and translation efficiency are highly context-dependent. Factors such as IRES selection, sequence context, and cell type influence protein expression. Broad claims to “any circular RNA encoding protein X” require experimental evidence demonstrating functional expression across multiple designs or cell types.

Patent applicants are generally advised to provide representative sequences, circularization methods, and expression data to satisfy §112 enablement and written description requirements. Claims solely directed to sequence without guidance on folding, circularization, or translation may face rejection.

Obviousness and Prior Art Challenges

CircRNAs are conceptually derived from natural RNA molecules and linear mRNA therapeutics. Obviousness rejections may arise if claimed sequences or circularization methods are viewed as predictable modifications of known mRNA platforms.

Applicants may overcome §103 challenges by emphasizing:

• Non-intuitive circularization methods, such as engineered ribozymes or optimized ligation strategies.
• Unique stabilizing elements or motifs enhancing translation or reducing immunogenicity.
• Delivery combinations or multi-gene expression strategies not previously disclosed.

AI-assisted circRNA design may also impact nonobviousness, particularly where sequence optimization or structural prediction produces unexpected functional outcomes.

Regulatory and Commercial Context

Regulators classify circRNAs as biologics, with evaluation focused on safety, immunogenicity, and functional expression. Their enhanced stability may reduce dosing frequency or improve therapeutic window, but off-target effects or immune activation remain critical considerations.

Commercially, circRNA platforms are often positioned as modular systems capable of producing diverse protein products. Intellectual property protection therefore emphasizes platform claims, synthetic circularization methods, and functional embodiments.

Intersection with Cell Engineering

CircRNAs are particularly valuable for ex vivo cell engineering. Transient circRNA expression allows delivery of transcription factors, genome editors, or synthetic regulators to reprogram cells without genomic integration. This approach minimizes insertional mutagenesis and allows rapid iterative testing in cell therapy pipelines.

From an IP perspective, claims may encompass the circRNA sequence, delivery strategy, or resultant engineered cell phenotype, providing layered protection for both composition and method of use.

Conclusion

Circular RNA therapeutics represent a next-generation RNA platform, combining molecular stability, programmable translation, and modularity for diverse applications in vaccination, protein replacement, and cell engineering. By exploiting their closed-loop structure and engineered regulatory elements, circRNAs overcome key limitations of linear RNA therapeutics. circRNA inventions present distinct challenges in claim drafting, enablement, and nonobviousness. Protectable subject matter spans the synthetic molecule, circularization methods, delivery systems, and functional applications. Drafting strategies must balance platform claims with detailed experimental evidence to withstand scrutiny. As circRNA therapeutics expand, they offer a compelling example of how engineering RNA structure, rather than DNA sequence, can create patentable, functional innovations in medicine and synthetic biology.