siRNA drugs have become one of the fastest-growing innovative therapies in the biopharmaceutical field in recent years.

The biggest difference between them and traditional drugs is: traditional chemical drugs are single molecules, and patents only protect one structure; However, siRNA drugs are a “combination system” composed of multiple modules such as sequences, modifications, delivery vectors, formulation processes, and clinical applications. Each module has different functions and can be bypassed by competitors. If only one module is protected, competitors only need to modify the other modules to circumvent patents.

Looking at the entire lifecycle of drug development, the relationship among these five layers can be understood as follows:

• The core sequence is the “foundation,” which determines which gene the drug targets;
• Chemical modification acts as the “wall,” determining whether drugs can survive in the body;
• The delivery system acts as the “door and window,” determining whether the drug can reach the lesion;
• Formulations and processes are the “internal components,” determining whether a drug can be made into a stable product;

Usage and administration regimen are “peripheral support,” determining how to use the drug for best effect.

All five layers are indispensable, together forming a complete patent protection system.

The following will describe each one in detail:

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1. Core sequences and structural motifs

The core sequence of siRNA is the molecular design of this double-stranded RNA itself, covering six dimensions: sequence, length, terminal structure, mismatch design, derived structure, and structural motif.

(1) Double-stranded siRNA
consists of two RNA strands: the sense strand and the antisense strand. The antisense chain is the truly effective “effector chain”—after entering the cell, it binds to the Ago2 protein, guiding the RISC complex to cleave the target gene’s mRNA. Sequence patents protect the base sequence of these two chains.
Once the target gene is identified, the number of effective sequences that can be designed is quite limited—siRNA must be completely complementary to the target gene’s mRNA to effectively silence it. After the first entrant patents all valid sequences, newcomers have almost no room to circumvent.
(2) Strand length

: The classic length is 19-25 nucleotides, but the range of strand length may be wider in different patents (e.g., 16-30 NT). Strand length directly affects the efficiency of siRNA entering the RISC complex, silencing activity, and off-target effect. Chains that are too long may activate interferon responses, while chains too short cannot effectively silence them. 21nt has the best activity, and 19nt has a lower off-target rate—this length design is itself a patented technical parameter.
(3) Terminal structure

: The bilateral structure of siRNA directly affects its efficiency and stability in entering the RISC complex. The classic design features two nucleotides protruding at each end of the 3′ end—this “3′ protrusion” structure helps siRNA bind correctly with the Ago2 protein. If made flat (without protrusion), the efficiency of entering RISC will decrease. Cap structures (such as phosphorylation at the 5′ end) affect stability, in vivo distribution, and pharmacokinetics.
(4) Base Mismatch Design

Mismatch is not an error but a deliberate design strategy. Fully complementary siRNAs may simultaneously silence multiple non-target genes, known as the “off-target effect.” Introducing 1-2 mismatches at non-critical locations can reduce off-target effects without affecting target gene silencing efficiency. Mismatching at certain positions, how many, and which base is mismatched are all patentable technical solutions.
(5) Derived Structures

: Besides the classic double-stranded linear siRNA, there are two other derivative structures worth noting:
hairpin structure (shRNA), which connects the sense strand and antisense strand through a circular sequence to form a single-stranded hairpin. After entering the cell, it is cleaved into double-stranded by Dicer enzyme to exert its function. The length and sequence composition of the ring can be patented.
Polymer structure: By linking multiple siRNAs together, it can simultaneously silence multiple target genes or improve in vivo stability. The connection method, chemical structure of the connecting arm, and arrangement sequence can all be patented.
(6) Structural Motifs
Structural motifs refer to the position, quantity, and distribution patterns of specific structural units on the molecule, specifically including three dimensions in siRNA:

• Modification sites: at which nucleotide sites are chemical modifications are made. For example, modifications are limited to the antisense strand seed region (positions 2-8, key regions for identifying target genes), or only at the 3′ end of the justice strand to reduce interference with antisense strand activity.
• Number of modifications: how many modifications are applied on a chain. Full-chain modification is highly stable but may have reduced activity, while local modification has high activity but insufficient stability. Finding the “optimal modification ratio” is itself a patentable technical solution.
• Chain distribution rules: Justice chains and antisense chains use different modifiers. For example, the full-chain justice chain is modified by 2′-OMe, while the antisense chain only has partial 2′-F modification; this differentiated pattern is called the structural motif. Conversely, the results vary.

The structural motif is important because it determines the boundaries of patent protection. Take core patents as an example: they often not only protect sequences but also protect combinations of “sequence + specific modification positions + specific modification counts + specific chain distribution rules.” If competitors want to bypass it, they must simultaneously change the sequence, the position of the modification, the number of modifications, and the chain distribution—doing this across multiple dimensions at once is extremely difficult.
The core logic of this layer: sequences determine “what is targeted,” structure determines “how to design,” and motifs determine “how to modify.” The combination of these three forms the most fundamental patent protection for siRNA drugs. When initiating a research and development project, a comprehensive search of patent sequences for the target target must be conducted—if all valid sequences have already been patented by a certain company, that target is basically unsuitable for further entry.

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2. Chemical Modification System

: Naked siRNA is degraded by enzymes within minutes after entering the body, so chemical modification is necessary, essentially putting a “bulletproof vest” on RNA. Chemical modification directly determines the stability, efficacy, and immunogenicity of the drug. Modification patents protect specific schemes about “where to use, which chemical groups to use, how much modification to make, and how to distribute them across two chains.”

Skeleton modification: refers to the chemical modification of phosphodiester bonds between nucleotides. The most common is thiophosphate (PS) modification, which replaces unbridged oxygen atoms in the phosphate framework with sulfur atoms, effectively resisting nuclease degradation. In addition, there are dithiophosphate (PS2) and methylphosphonate (MP), among others. Most basic patents for skeleton modification have expired, but combination modification, positional restrictions, and proportional limitations can still be redeployed. For example, introducing PS modifications in the antisense strand seed region (positions 2-8) can reduce off-target effects, and this specific localization alone can be patented.
Ribose modification: Ribose is the “pentaccharide” of nucleotides, and chemical modification of the 2′ position of ribose is the most common method.
Common types:

• 2′-O-methyl (2′-OMe): Replace the 2′ hydroxyl group with a methoxy group
• 2′-Fluorine (2′-F): Replacing the hydroxyl group at the 2′ position with a fluorine atom
• Lock in nucleic acids (LNA): Lock in ribose through methylene bridges, enhancing binding affinity

Base modification: refers to chemical modification of the four bases of RNA (A, U, G, C). Naturally occurring base modifications (such as N6-methyladenosine m6A, 5-methylcytidine m5C) carry lower patent risks due to limited inventiveness. Non-natural base modifications (such as 2,4-difluorotoluene ribonucleoside rF) may involve patent protection. The patent layout in the terminal modification field (fluorescent labeling, biotin, end-end groups, etc.) is relatively blank, providing innovation space for newcomers.
Develop new ribose/skeleton/base-modified monomers, apply for basic compound patents, and establish independent intellectual property rights from the source. At the same time, multiple modification collaborative systems can be deployed, limiting the complete scheme of “modification type + position + quantity + effect,” supporting creativity with data such as stability and low immunogenicity. Domestic companies can focus on introducing PS modifications in antisense strand seed regions to reduce off-target effects.

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3. Delivery System

siRNA cannot enter cells on its own and must rely on delivery carriers to “get in”—delivery systems are key to clinical translation of siRNA drugs and have the highest patent barriers.
(1) GalNAc Binding System (Hepatic Targeting Mainstream)

GalNAc (N-acetylgalactosamine) is a sugar molecule that conjugates siRNA and GalNAc together, allowing it to enter liver cells via receptors on the liver cell surface (ASGPR).
The GalNAc system consists of three core components:

• Target: Responsible for recognizing receptors on the surface of liver cells
• Linker: connects the target to siRNA
• Joints: determine the connection site and release mechanism

Breakthrough directions include: developing univalent or bivalent GalNAc (which alters target valence states), non-classical linker arms (such as degradable linkers, linkers containing ribose rings), site isomerism (changing the binding position), and heterozygous targets (GalNAc combined with peptides or lipids).
(2) LNP lipid nanoparticles:
siRNA is encapsulated in lipid nanoparticles and delivered into the body via intravenous injection. LNPs consist of cationic lipids (or ionizable lipids), auxiliary lipids, cholesterol, and PEG lipids in specific proportions.
Currently, the breakthrough directions for LNP patents are focused on the following areas:

• Developing novel ionizable lipids
• Develop naturally sourced lipids and biodegradable lipids
• Particle size/surface charge differentiation
• Freeze-dried prescription LNP (solving cold chain transportation issues)

(3) Novel delivery

peptide carriers, polymer nanoparticles, exosomes, lipopeptides, as well as extrahepatic targeted delivery (muscle, heart, kidney, lung, central nervous system). There is a significant global patent gap, making it suitable for domestic companies to differentiate their positioning.

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4. Formulations and Preparation Processes

Formulations and processes are a layer of siRNA drug patents that are often overlooked but are crucial, serving as a “moat” within the entire patent system.

• At the formulation level, parameters include dosage form selection (injections, lyophilized preparations, sustained-release microspheres, in situ gels, topical/inhalation preparations), excipient combinations (buffer fluid systems, stabilizers, anti-agglomerants), pH value, osmotic pressure, and other parameters.
• At the process level, it includes synthesis processes (solid-phase synthesis, liquid-phase synthesis), purification processes (chromatography, ultrafiltration, precipitation), scale-up production processes (process adaptation from laboratory to industrial production), and quality control methods (purity testing, impurity control standards), etc.

Although siRNA formulations often appear simple, their performance varies significantly, and these differences represent patent opportunities.
Buffer systems, excipient combinations, lyophilized products, ready-to-use liquid formulations, and stability-enhancing compositions can extend protection beyond the active oligonucleotides themselves, while addressing practical commercial challenges. More importantly, patents for sequence, modification, and delivery all have expiration dates, but formulation and process patents often last longer. Even if the previous layers of patents have expired, formulation and process patents can still protect products from being counterfeited. In addition, process patents are essential IP credentials for CDMO collaboration, commercial production, export, and other commercial activities.
In determining inventiveness in formulation patents, conventional excipient selection and dosage form design usually lack inventiveness. Without unexpected technical effects, simply routinely replacing the type or amount of auxiliary materials is hard to recognize. Applicants must provide experimental data demonstrating significant improvements in the formulation’s stability (e.g., no loss of activity at 25°C for 6 months), ease of administration (e.g., prefilled syringes), and patient compliance (e.g., reduced injection volume).

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5. Pharmaceutical uses, dosing regimens, and combination therapy

are the latest to mature and are closely linked to clinical development. As clinical trials advance, new indications, dosing regimens, and combination therapies are constantly emerging, providing a continuous increase in patents to extend product lifecycles.

New indications: The same siRNA drug has expanded into indications not covered by leading companies, such as rare diseases, chronic diseases, oncology, autoimmune diseases, and infections. Such patents are presented in the form of claims for “use of drug preparation method,” such as “use of substance X in the preparation of a drug for treating disease Y.” The value of new indication patents lies in the fact that even when core sequence and delivery patents expire, new indication patents can still protect specific therapeutic scenarios and extend product lifecycles.

Administration regimen: including dosing frequency, dose gradient, route of administration (subcutaneous/intravenous/topical/intrathecal), and long-cycle dosing regimen. Drug delivery protocol patents are important statutory and authorizable topics in countries like the United States, and overseas innovative pharmaceutical companies often use them to build a follow-up line of defense throughout the product lifecycle. For example, a long-acting siRNA drug administered every six months, or a maintenance regimen administered subcutaneously once a month, can both be patented. Such claims may cover specific patient populations, administration regimens, routes of administration, efficacy biomarker effects, and combination therapies arising during clinical development.

Combination drugs: Combinations of siRNA with small molecules, monoclonal antibodies, immune checkpoint inhibitors, chemotherapy drugs, or other nucleic acid drugs. The claims require specifying factors such as combination ratio, dosing sequence, and synergistic efficacy. For example, when siRNA targets PCSK9 in combination with statins, synergistic lipid-lowering data must be provided to demonstrate that the combined effect is superior to either single agent.

Avoid core indications and standard dosages of the original research, focusing on differentiated approaches such as low-dose long-acting, intermittent dosing, and local dosing. Combination drug patents must provide experimental data on synergistic effects, attenuation, or overcoming resistance, to avoid being recognized as conventional combinations. As clinical evidence accumulates, new therapeutic applications or improved delivery strategies may offer additional application opportunities and later expiration dates.
In determining the inventiveness of a patent for use, the disease treatment method itself is an unlicensed topic, but the drug preparation method can be licensed for use. If only dosage or frequency is changed without unexpected technical effects, creativity is often hard to recognize. Applicants must provide preclinical or clinical data demonstrating the unique technical advantages brought by the specific dosing regimen.

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Conclusion:
The core logic of siRNA drug patent layout can be summarized in one sentence: the delivery system forms the highest barrier, the sequence is the foundation, and modification determines the difference. All three are indispensable, but the difficulty of breaking through is different—serial patents are relatively easy to circumvent, modification patents require differentiated design, and submitting patents is the real “deep waters.”

For domestic companies, the most pragmatic strategy is to avoid direct competition with original researchers on mature targets and classic delivery routes, and instead focus on blank areas such as extrahepatic targeted delivery, novel biodegradable carriers, and innovative modification systems. They should first build independent core patents, then expand peripheral strategies around these cores. On this basis, a three-dimensional layout centered on core sequences, modification combinations, delivery carriers, formulation processes, and application plans can form effective intellectual property barriers.

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