United States Patent 10,273,477: Scope, Claim Construction, Expiration and RNAi Patent Landscape

U.S. Patent No. 10,273,477 protects a chemically modified small-interfering RNA, or siRNA, architecture rather than a particular therapeutic sequence. The required combination is a conjugated sense strand with more asymmetric 2′-O-alkyl modifications than the antisense strand, together with four to 20 antisense phosphorothioate modifications. The patent is most relevant to chemically stabilized, conjugated duplex RNAs directed to human genes.

The claims do not cover every siRNA, every GalNAc-siRNA, or every RNA therapeutic. A potentially infringing product must satisfy all limitations of at least one asserted claim, including the modification counts, strand asymmetry, phosphorothioate placement or range, and sense-strand conjugation requirements.

What patent is U.S. Patent 10,273,477?

U.S. Patent 10,273,477 is titled “RNA Agents with Asymmetric Modifications.” The patent concerns RNA interference agents containing different modification patterns on the sense and antisense strands. The patent issued on April 30, 2019, from U.S. Patent Application No. 15/624,327, according to the USPTO patent record.[1]

Item	Detail
U.S. patent	10,273,477
Title	RNA Agents with Asymmetric Modifications
Issue date	April 30, 2019
Technology	Chemically modified siRNA and RNA interference agents
Claimed product	Duplex RNA agent with modified sense and antisense strands
Principal structural elements	Sense-strand 2′-O-alkyl modifications, antisense phosphorothioates, sense conjugate
Therapeutic target	A human gene sequence
Patent type	Utility patent
Regulatory category	Platform or composition patent, not inherently drug-specific

The patent should be read together with its specification, prosecution history, priority documents, continuation applications and related family members. The claim text alone establishes the enforceable limitations, but the specification and file history can affect how terms such as “asymmetrical,” “conjugate group,” “target,” and “phosphorothioate modifications” are construed.

What does claim 1 of U.S. 10,273,477 require?

Claim 1 is the only independent claim in the supplied claim set. It requires every element below:

Claim 1 limitation	Practical meaning
RNA agent	The claimed product is an RNA-based agent
Inhibits expression	The agent must be capable of suppressing expression of a target human gene
Sense and antisense sequences	The agent has two strands forming an RNAi duplex
Sense-strand 2′-O-alkyl modification	The sense strand has at least one such modification
Antisense phosphorothioates	The antisense strand has four to 20 phosphorothioate modifications
Fewer antisense 2′-O-alkyl modifications	The antisense strand has fewer asymmetric 2′-O-alkyl modifications than the sense strand
Sense conjugate	The sense strand includes a conjugate group
Human gene targeting	The antisense sequence targets a human gene sequence

The claim is cumulative. A product that has a conjugated sense strand and antisense phosphorothioates may still fall outside claim 1 if the sense strand does not have more asymmetric 2′-O-alkyl modifications than the antisense strand.

The claim also uses functional language. “For inhibiting the expression” and “targets the human gene sequence” require analysis of the product’s sequence, duplex structure and biological operation. A nonfunctional duplex may raise a separate enablement or claim-scope issue, while a demonstrated RNAi therapeutic directed to a human transcript would more readily satisfy these elements.

What chemical architecture does the patent cover?

The patent is directed to asymmetric modification patterns. The central design is:

A sense strand carrying one or more 2′-O-alkyl modifications.
An antisense strand carrying four to 20 phosphorothioate modifications.
More asymmetric 2′-O-alkyl modifications on the sense strand than on the antisense strand.
A conjugate attached to the sense strand.
An antisense strand capable of targeting a human gene.

The claims do not require a particular 2′-O-alkyl species in claim 1. Claim 2 narrows the scope by specifying at least one 2′-O-methyl, or 2′-OMe, modification. The claims also do not require GalNAc specifically. “Conjugate group” can encompass different ligand, targeting, delivery or chemical groups if supported by the specification and properly construed.

What is the significance of the asymmetric modification requirement?

The asymmetry limitation compares the number of relevant modifications on the two strands. Claim 1 requires the antisense strand to have fewer asymmetric 2′-O-alkyl modifications than the sense strand.

This limitation may exclude:

Duplexes with identical 2′-O-alkyl modification counts on both strands.
Duplexes with more 2′-O-alkyl modifications on the antisense strand.
Duplexes lacking a qualifying asymmetric 2′-O-alkyl modification on the sense strand.
Duplexes in which the claimed modifications are not present in the required strand or chemical form.

Claims 3 through 6 impose more specific sense-strand patterns. They require four to 12 2′-O-alkyl modifications, with at least four located within the terminal six or terminal four nucleotides at one end of the sense strand.

How do claims 2 through 20 narrow the patent?

Claims	Added limitation
2	At least one 2′-OMe modification
3	Four to 12 sense-strand 2′-O-alkyl modifications
4	At least four within the six terminal nucleotides of one sense-strand end
5	Same terminal requirement, plus at least one modification elsewhere
6	At least four within the four terminal nucleotides of one sense-strand end
7	At least four antisense phosphorothioates within four terminal nucleotides
8	Two sense-strand phosphorothioates within two terminal nucleotides
9	Six to 20 antisense phosphorothioate modifications
10	Fully complementary sense and antisense sequences
11	At least 21 nucleotides overall and approximately 19-nucleotide duplex
12	Approximately 19 to 21 nucleotide duplex plus one or two two-nucleotide 3′ overhangs
13-16	Additional sense-strand asymmetric modifications
17-20	Additional antisense-strand asymmetric modifications

Claims 4 through 8 are particularly dependent on positional mapping. In an infringement analysis, the exact nucleotide numbering, directionality and chemical linkage pattern would matter. A terminal modification at the 5′ end is not interchangeable with the same modification at an internal position.

Claims 13 through 20 expand the types of additional modifications that may be present. They identify 2′-5′ linkages, L sugars, modified sugars, nucleobase modifications, cationic groups, zwitterionic groups and conjugate groups. Examples include L-ribose, L-arabinose, locked nucleic acid, hexose nucleic acid and cyclohexane nucleic acid.

What products could fall within the claims?

The patent is potentially relevant to conjugated siRNA products, including ligand-conjugated RNAi agents used for targeted delivery. Candidate products would need to be analyzed at the oligonucleotide level, not merely by drug name.

Potentially relevant product categories include:

GalNAc-conjugated siRNAs.
Hepatocyte-targeted siRNAs.
Lipid- or ligand-conjugated RNAi agents.
Chemically stabilized 19- to 21-base-pair duplexes.
Duplexes with two-nucleotide 3′ overhangs.
siRNAs using 2′-OMe, 2′-fluoro or related sugar chemistry.
RNAi agents with terminal phosphorothioate linkages.

Products that may warrant review include Alnylam’s patisiran, givosiran, lumasiran, vutrisiran and zilebesiran; Novartis’ inclisiran; Novo Nordisk’s nedosiran; Arrowhead’s plozasiran and fazirsiran; Amgen’s olpasiran; and Sanofi’s fitusiran. The inclusion of a product in this list does not establish infringement. Public labels generally do not disclose every nucleotide-level modification or linkage.

How does this patent compare with GalNAc delivery patents?

A GalNAc patent generally claims a ligand structure, linker, attachment chemistry or hepatocyte-delivery configuration. U.S. 10,273,477 instead claims a combined RNA architecture involving:

Relative modification density between the two strands.
Antisense phosphorothioate count.
Sense-strand conjugation.
Optional terminal placement.
Optional duplex geometry.

A product may therefore require clearance under both a delivery patent family and an RNA-chemistry patent family. The patent does not monopolize all GalNAc-siRNA products because the claims do not require GalNAc and require a specific modification relationship.

What patent landscape surrounds U.S. 10,273,477?

The relevant landscape has five overlapping layers.

Foundational RNA interference patents

Foundational RNAi patents cover the use of double-stranded RNA to silence genes, including target-specific sequences, cellular administration and therapeutic methods. Many early RNAi patents have expired or are approaching expiration. Their practical value depends on priority dates, terminal disclaimers, PTA and claim scope.

Chemical modification patents

Chemical modification families cover 2′-O-methyl, 2′-fluoro, phosphorothioate, locked nucleic acid and related modifications. These patents can claim individual chemistries, positional patterns or combinations. U.S. 10,273,477 is most closely aligned with this layer.

Conjugate and delivery patents

These families cover GalNAc ligands, linker chemistry, lipid nanoparticles, cholesterol conjugates, peptide conjugates and other delivery systems. The commercial products of Alnylam, Novartis, Arrowhead, Dicerna and other RNAi developers often implicate this category.

Sequence and therapeutic-use patents

Separate patents may cover a particular target gene, nucleotide sequence, disease indication or dosing regimen. These patents can remain relevant even if a platform patent expires.

Manufacturing and process patents

Manufacturing patents can cover solid-phase oligonucleotide synthesis, purification, conjugation, double-stranded assembly and impurity control. They may create freedom-to-operate risk even where the product composition is outside U.S. 10,273,477.

When does U.S. Patent 10,273,477 lose exclusivity?

The ordinary U.S. patent term is generally 20 years from the earliest effective nonprovisional filing date, subject to patent-term adjustment, patent-term extension and terminal disclaimers.[2] The patent’s effective expiration therefore depends on its full continuity chain, not solely its April 30, 2019 issue date.

Based on the patent’s continuation history and underlying priority structure, the practical expiration window is expected to fall in the late 2020s, subject to the USPTO’s official patent-term calculation. The patent record and USPTO Patent Center should control the final date.[1]

Exclusivity issue	Assessment
Patent term	Determined by earliest effective nonprovisional filing
Patent-term adjustment	Must be checked in the USPTO record
Patent-term extension	No product-specific extension is established from the supplied information
Patent expiry	Expected in the late-2020s term window
Regulatory exclusivity	Separate from patent rights
Foreign expiry	Must be assessed country by country

Patent expiry does not automatically eliminate all barriers to competition. A generic or follow-on RNA product may remain exposed to later-issued sequence, formulation, conjugate, manufacturing or method-of-use patents.

What is the Orange Book status of U.S. 10,273,477?

U.S. Patent 10,273,477 is not inherently an Orange Book-listed patent. The FDA Orange Book lists patents submitted for approved drug products under the applicable NDA, subject to FDA listing rules and the sponsor’s submission.[3]

A broad RNA platform patent may not appear in the Orange Book for any individual siRNA product because:

It may not claim the approved drug as a product or approved use.
It may not be submitted by the NDA holder.
The claim may cover a platform architecture rather than the specific approved formulation.
The relevant drug may not have an NDA patent listing for that technology.

The Orange Book status must therefore be checked by approved product and NDA, not by patent number alone. Absence from the Orange Book would not eliminate ordinary patent-infringement risk outside the Hatch-Waxman listing framework.

Are there Paragraph IV challenges to this patent?

A Paragraph IV certification applies to a listed patent in connection with an abbreviated new drug application, or ANDA. It is not a general challenge mechanism for every pharmaceutical patent.[4]

For a chemically complex siRNA, an ANDA pathway may be difficult because the applicant must establish pharmaceutical equivalence and bioequivalence under FDA requirements. A competing applicant may instead pursue a different regulatory pathway, including a 505(b)(2) application or, depending on the product and agency determination, a biologics pathway.

The supplied information does not establish a public Paragraph IV case against U.S. 10,273,477. A complete assessment requires matching the patent to an Orange Book-listed NDA and reviewing FDA patent certifications and district-court docket records.

What generic-entry risks exist?

The principal entry risks are technical rather than limited to the patent’s headline expiration date.

Entry scenario	Risk under U.S. 10,273,477
Same sequence and same chemistry	High if all claim limitations are met
Same conjugate but different modification pattern	Depends on 2′-O-alkyl counts and phosphorothioate placement
Same antisense sequence with fewer antisense phosphorothioates	Potential design-around
Nonconjugated duplex	Likely outside claims requiring a sense conjugate
Conjugate on antisense rather than sense	May avoid the express sense-conjugate limitation
Different duplex length	May avoid claims 11 or 12, but not necessarily claim 1
Equal 2′-O-alkyl counts on both strands	Potentially outside the asymmetry limitation
Different target species	May avoid the human-gene limitation, subject to other claims
Same product after patent expiry	Still subject to other valid patents

Design-around strategies could include changing the strand carrying the conjugate, altering the relative 2′-O-alkyl modification counts, reducing or relocating antisense phosphorothioates, changing duplex geometry, or using a different chemical architecture. Each strategy can create new exposure under separate patent families.

How strong is the patent estate?

The patent has meaningful claim density around a defined siRNA architecture, but its scope is narrower than a generic platform patent.

Strengths

Claim 1 combines several independently measurable structural limitations.
Claims 3 through 9 add precise modification counts and terminal positions.
Claims 10 through 12 cover common RNAi duplex configurations.
Claims 13 through 20 address multiple classes of additional modifications.
The claims can reach products without requiring a particular gene, sequence or disease indication.

Weaknesses

The sense-strand conjugate requirement limits the covered architecture.
The relative 2′-O-alkyl count creates a potential design-around.
The claim requires four to 20 antisense phosphorothioate modifications, which may not match every commercial chemistry pattern.
The “human gene” limitation may limit use outside human therapeutics.
Broad claim terms may face written-description, enablement, indefiniteness or prior-art challenges depending on the prosecution record.
Later product-specific patents may provide stronger blocking rights than this platform patent.

The strongest practical claims are likely claims 1, 3, 7 and 9 when a product’s complete chemical map confirms the required counts. Claims 4 through 6 and 8 may provide narrower but more defensible positions because they specify terminal locations.

What litigation and licensing issues matter?

RNAi licensing is often distributed across multiple technology owners. A commercial product may require rights relating to:

RNAi mechanism and target suppression.
Chemical modification chemistry.
GalNAc or other conjugate structures.
Linkers and attachment methods.
Lipid nanoparticle delivery.
Therapeutic target sequences.
Manufacturing and purification.

Alnylam has historically licensed or acquired RNAi technologies and delivery rights, while other developers have built competing portfolios through acquisitions, collaborations and internal chemistry programs. The existence of a license does not establish that U.S. 10,273,477 is licensed for a particular product.

The supplied claim set does not identify a settlement agreement or litigation involving this patent. Litigation risk should be assessed against the patent family, assignee history, continuation applications and product-specific patent listings rather than this patent in isolation.

Does biosimilar law apply to this patent?

Biosimilar law generally does not apply directly to a synthetic siRNA composition. An siRNA product is typically regulated as a drug rather than a protein biologic, although regulatory classification depends on the product and FDA determination.[5]

The commercial competitor is more likely to be:

An ANDA applicant, if the product can meet generic-drug requirements.
A 505(b)(2) applicant relying partly on published or FDA-held data.
A new-drug applicant developing a differentiated siRNA.
A competing RNAi product with a different sequence, conjugate or delivery system.

The absence of a biosimilar pathway does not remove patent risk. It changes the regulatory route and may make clinical, analytical and manufacturing comparability more demanding.

What geographic coverage does the patent provide?

U.S. Patent 10,273,477 provides enforceable rights only in the United States. Equivalent protection must be evaluated through the international family, including national-stage applications and granted patents in Europe, Japan, China, Canada, Australia and other commercial markets.

The same claim set may not survive identically in every jurisdiction. Differences can arise from:

Added-matter rules.
Sufficiency and enablement standards.
Patentable-subject-matter rules.
Sequence-listing requirements.
Claim amendments during national prosecution.
Divisional and continuation practice.
Patent-term calculations.

A global freedom-to-operate opinion should map each commercial product against granted claims in each manufacturing, clinical and sales jurisdiction.

Key Takeaways

U.S. Patent 10,273,477 targets a defined chemically modified siRNA architecture.
Claim 1 requires a sense-strand conjugate, more asymmetric 2′-O-alkyl modifications on the sense strand than on the antisense strand, and four to 20 antisense phosphorothioate modifications.
Claims 3 through 9 add modification counts and terminal-position requirements.
Claims 10 through 12 cover fully complementary and conventional 19- to 21-nucleotide siRNA duplex configurations.
The patent does not cover every siRNA, GalNAc-siRNA or RNA therapeutic.
The patent’s practical term is expected to reach the late 2020s, subject to the official USPTO term calculation.
Orange Book relevance must be assessed through the approved product and NDA, not the patent number alone.
No Paragraph IV challenge, settlement or litigation outcome is established from the supplied claim information.
Commercial products require sequence-level and chemistry-level mapping before infringement conclusions can be drawn.
Later conjugate, sequence, formulation and manufacturing patents may remain relevant after this patent expires.

FAQs

Can a GalNAc-siRNA infringe U.S. Patent 10,273,477?

Yes, but only if its complete chemical structure satisfies every limitation of an asserted claim. GalNAc attachment alone is insufficient.

Does the patent cover a siRNA with phosphorothioates only on the sense strand?

Claim 1 requires four to 20 phosphorothioate modifications on the antisense strand. A product with no qualifying antisense phosphorothioates would not meet claim 1.

Can changing the number of 2′-OMe modifications avoid the patent?

Potentially. The product must still be assessed under the full claim set, because claims 1 and 2-6 apply different modification requirements.

Does expiration of U.S. 10,273,477 permit immediate generic launch?

Not necessarily. Other patents may cover the approved sequence, conjugate, formulation, use, manufacturing process or delivery system.

Is U.S. 10,273,477 a patent on a particular RNA sequence?

No. The supplied claims are architecture-based and do not identify a single target sequence. They require targeting of a human gene but do not limit the claim to one named gene.

References

United States Patent and Trademark Office. (2019). U.S. Patent No. 10,273,477, RNA agents with asymmetric modifications. https://patents.google.com/patent/US10273477B2/en
United States Patent and Trademark Office. (n.d.). Patent term adjustment. https://www.uspto.gov/patents/laws/patent-term-adjustment
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, Orange Book. https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book
U.S. Food and Drug Administration. (n.d.). Hatch-Waxman amendments and abbreviated new drug applications. https://www.fda.gov/drugs
U.S. Food and Drug Administration. (n.d.). Drug development and approval process. https://www.fda.gov/drugs/development-approval-process-drugs

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	479752	⤷ Start Trial
Australia	2004220556	⤷ Start Trial
Australia	2004227414	⤷ Start Trial
Australia	2004229519	⤷ Start Trial
Australia	2004232964	⤷ Start Trial
Australia	2004233092	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 10,273,477

Summary for Patent: 10,273,477