United States Patent 10,266,822: SMN2 Exon 7 Inclusion Claims, Scope and Patent Landscape

U.S. Patent No. 10,266,822 covers methods that increase inclusion of exon 7 in SMN2 messenger RNA using antisense oligonucleotides directed to an intron 7 regulatory sequence. Its broadest claims are functional method claims rather than composition claims. The estate can reach antisense products used to promote full-length SMN protein production, including oligonucleotides directed to the ISS-N1 region targeted by nusinersen, depending on claim construction, sequence identity, prosecution history and the specific marketed product.

The patent does not claim an antisense oligonucleotide as a standalone composition. Infringement therefore generally requires performance of the claimed method, or inducement or contributory infringement based on supplying an oligonucleotide for the claimed use.

What does U.S. Patent 10,266,822 claim?

The patent has three principal claim groups:

Claim group	Claims	Core subject matter
Cell and cell-extract methods	1-9, 17-19	Increasing exon 7-containing SMN2 mRNA in cells
Organism-level methods	10-13	Administering an oligonucleotide to an organism, mammal or human
Therapeutic methods	14-16	Treating SMA or subjects needing increased neuronal SMN2 exon 7 inclusion

The central technical requirement is that the oligonucleotide:

Is sufficiently complementary to intron 7 of SMN2;
In claims 1, 10, 14, 15 and 18, is complementary over its entire length to the specified intron 7 region;
In claims 1, 10, 14 and 15, is sufficiently complementary to the 15-nucleotide sequence CCAGCAUUAUGAAAG, identified as SEQ ID NO:3; and
Increases the level of exon 7-containing SMN2 mRNA.

The claims are directed to splice correction. SMN2 normally produces a substantial proportion of transcripts lacking exon 7. Increasing exon 7 inclusion raises production of full-length SMN protein, which is the therapeutic objective in spinal muscular atrophy.

How broad is claim 1 of U.S. Patent 10,266,822?

Claim 1 is broad because it does not limit the oligonucleotide to a particular sequence length, chemical backbone, sugar modification, delivery vehicle, dose, route of administration or commercial product.

It requires a method of contacting a cell or cell extract with an oligonucleotide that is sufficiently complementary to the specified intron 7 sequence and produces the claimed increase in exon 7-containing SMN2 mRNA.

Functional limitation

The phrase “such that the level of exon 7-containing SMN2 mRNA in the cell is increased” is a material limitation. A candidate oligonucleotide that binds the relevant region but does not increase exon 7 inclusion would not satisfy the claim.

The claim also does not expressly require:

Increased SMN protein;
Improved motor function;
Treatment of SMA;
A particular percentage increase in exon 7 inclusion;
A particular assay;
Administration to a living patient; or
Clinical benefit.

This makes the claim potentially broad at the molecular assay level. The required increase must still be demonstrated under the relevant infringement theory.

“Sufficiently complementary”

“Sufficiently complementary” permits some sequence mismatch, depending on how the term is interpreted in light of the specification, prosecution record and applicable claim-construction principles. The claim does not require perfect Watson-Crick complementarity to every nucleotide.

A competitor’s risk therefore cannot be assessed solely by comparing whether its oligonucleotide is identical to a disclosed antisense sequence. The analysis must consider:

The entire oligonucleotide sequence;
Mismatch location;
Length;
Target accessibility;
Whether the oligonucleotide overlaps the specified 15-nucleotide region;
The functional effect on exon 7 inclusion; and
Any limiting statements made during prosecution.

What oligonucleotide lengths are protected?

Claim 2 covers oligonucleotides of approximately 5 to 50 nucleotides. Claim 19 narrows the range to approximately 8 to 19 nucleotides or approximately 8 to 14 nucleotides.

Claim	Length range
Claim 1	No express length limit
Claim 2	About 5 to about 50 nucleotides
Claim 19	About 8 to about 19 nucleotides
Claim 19 alternative	About 8 to about 14 nucleotides

The length limitations are dependent claims and do not restrict claim 1 unless a court or prosecution history supplies a separate limitation. The broad independent claim could therefore reach qualifying oligonucleotides outside the dependent ranges.

An 18-nucleotide antisense oligonucleotide falls within claim 2 and the first alternative in claim 19. This is commercially important because nusinersen is an 18-mer antisense oligonucleotide directed to the SMN2 intron 7 splicing silencer region.

What chemical modifications are protected?

Claims 3 through 7 cover chemical modifications intended to enhance in vivo stability. The listed modifications include:

Sugar-modified nucleotides;
Nucleobase-modified nucleotides;
2'-deoxyribonucleotides;
2'-O-methyl ribonucleotides;
2'-fluoro nucleotides;
2'-amino nucleotides;
2'-thio modifications;
Halogenated uridines and cytidines;
5-methyl-cytidine;
Locked nucleic acids;
Backbone-modified nucleotides; and
Phosphorothioate-containing backbones.

Claim 7 specifically covers a backbone-modified nucleotide containing a phosphorothioate group.

The claims are drafted as alternatives. A qualifying oligonucleotide does not need to contain every listed modification. It needs to include a modification within the applicable dependent-claim category and retain the required targeting and exon 7-inclusion function.

Relationship to nusinersen chemistry

Nusinersen is an 18-mer antisense oligonucleotide with 2'-O-(2-methoxyethyl) modifications and a phosphorothioate backbone. The claim text supplied does not expressly identify 2'-MOE as a listed modification, although it may fall within broader sugar-modification or backbone-modification language depending on the asserted claim and construction.

The commercial relevance is therefore strongest for:

The target sequence;
The 18-nucleotide length;
The phosphorothioate backbone;
The therapeutic use in SMA; and
The resulting increase in exon 7-containing SMN2 transcripts.

The patent’s claims should not be treated as a direct composition claim to nusinersen. The most relevant question is whether administration or use of nusinersen practices a claimed method.

What sequences are covered by claims 17 and 18?

Claim 17 expands the target set by referring to SEQ ID NO:3 and SEQ ID NOs:40-66. It covers methods using an oligonucleotide sufficiently complementary to one of those listed sequences, provided exon 7-containing SMN2 mRNA increases.

Claim 18 uses a different sequence requirement. It requires an oligonucleotide complementary to intron 7 over its entire length and complementary to nucleotides 1 and 6 of SEQ ID NO:3.

These claims create two separate infringement pathways:

Claim	Sequence architecture
Claims 1, 10, 14, 15	Complementarity to intron 7 and to SEQ ID NO:3
Claim 17	Complementarity to SEQ ID NO:3 or SEQ ID NOs:40-66
Claim 18	Full-length intron 7 complementarity plus complementarity to positions 1 and 6 of SEQ ID NO:3

Claim 17 is particularly important for sequence-screening analyses because it may capture variants that are not identical to a single commercial antisense sequence but fall within the listed sequence set.

Does the patent cover SMA treatment?

Yes. Claim 14 specifically covers treating SMA by administering a qualifying oligonucleotide at a dose effective to increase exon 7-containing SMN2 mRNA.

Claim 13 is broader at the organism level because it requires only that the human have SMA. Claim 14 adds the treatment limitation. Claim 15 covers subjects who would benefit from increased neuronal SMN2 exon 7 mRNA, and claim 16 identifies ALS as one example.

The SMA claims do not specify:

Infantile-onset or later-onset SMA;
SMN1 genotype;
Disease severity;
Intrathecal or systemic administration;
Loading dose;
Maintenance dose;
Treatment duration; or
Combination therapy.

The absence of a route and dosing limitation increases the potential breadth of the therapeutic claims.

Which commercial products are most relevant?

Spinraza and nusinersen

Spinraza is the closest commercial product because nusinersen is designed to bind the SMN2 intron 7 splicing silencer region and promote exon 7 inclusion. Its mechanism aligns directly with the biological result required by the patent claims.

Potentially relevant claims include claims 1, 2, 3, 7, 10, 12, 13, 14 and 19. The exact analysis depends on the marketed sequence, chemical structure, use instructions and the patent’s enforceable scope.

Evrysdi and risdiplam

Risdiplam is a small-molecule SMN2 splicing modifier, not an antisense oligonucleotide. It does not appear to fall within the oligonucleotide limitations in the supplied claims.

The patent therefore has limited direct relevance to risdiplam as a product. Risdiplam remains a commercial competitor because it addresses the same SMN-restoration market through a different modality.

Zolgensma and onasemnogene abeparvovec

Onasemnogene abeparvovec is an AAV-based gene-replacement therapy. It does not satisfy the oligonucleotide limitations in the supplied claims. Its relevance is competitive rather than claim-overlap based.

How strong is the patent estate?

The patent is strongest against antisense products that satisfy all of the following characteristics:

Target SMN2 intron 7;
Overlap the SEQ ID NO:3 region or one of the listed sequence variants;
Increase exon 7-containing SMN2 mRNA;
Are approximately 5 to 50 nucleotides long;
Are administered to a human with SMA; and
Use stability-enhancing chemical modifications.

The estate is weaker against:

Small-molecule splicing modifiers;
Gene-replacement therapies;
Antisense compounds targeting unrelated SMN2 regions;
Products that do not increase exon 7-containing mRNA;
Research tools used only in noninfringing assay systems; and
Products that target SMN1 rather than SMN2.

The patent’s functional language creates potential enablement, written-description and indefiniteness issues that would be evaluated claim by claim. The breadth of “sufficiently complementary” and “increased” is commercially valuable but can also create litigation exposure if the asserted scope exceeds the technical disclosure or lacks a reproducible boundary.

What is the Orange Book relevance?

The claims are method-of-use claims and do not themselves establish Orange Book listing status. FDA listing depends on whether the patent holder submitted the patent for the approved drug and whether FDA accepted it under the applicable Orange Book rules.

For Spinraza, the relevant regulatory analysis should separate:

FDA-approved use;
Listed patents;
Patent use codes;
Patent expiration and pediatric exclusivity;
Paragraph IV certifications; and
Any litigation under the Hatch-Waxman framework.

A patent may be technically relevant to nusinersen without being listed in the Orange Book. Conversely, an Orange Book-listed patent may protect a use or formulation narrower than the full technical disclosure.

What generic entry risks exist?

A generic or follow-on nusinersen applicant could challenge the patent through a Paragraph IV certification if the patent is listed and the applicant asserts that the patent is invalid, unenforceable or not infringed.

The principal design-around strategies would include:

Targeting a different SMN2 intron 7 sequence;
Using a different mechanism for exon 7 inclusion;
Altering the sequence so it does not satisfy the relevant “sufficiently complementary” limitation;
Avoiding a claimed length range where practical;
Demonstrating that the product does not increase exon 7-containing SMN2 mRNA under the asserted test conditions; or
Relying on a non-oligonucleotide modality.

A sequence-only design-around may be difficult if claim 1 is construed broadly and claim 17 covers multiple sequence variants. A modality change to risdiplam-like small molecules or AAV gene replacement is more structurally distinct.

What licensing deals affect the landscape?

The commercial development of nusinersen involved Ionis Pharmaceuticals and Biogen, while the underlying SMN2 splicing technology has been associated with research originating at Cold Spring Harbor Laboratory and academic collaborators. The commercial rights, patent ownership, prosecution history and enforcement rights should be analyzed separately because the patent owner, exclusive licensee and product sponsor may be different entities.

This distinction matters in litigation. Standing, sublicensing rights, royalty interests, prosecution control and the right to seek injunctive relief can depend on the specific license agreements.

What is the likely exclusivity timeline?

The patent issued in 2019 and belongs to an earlier SMN2 antisense patent family. Its remaining term is determined by the earliest effective nonprovisional filing date, applicable patent-term adjustment, any terminal disclaimer and any patent-term extension. The issue date does not determine expiration.

The commercial exclusivity timeline must therefore be modeled separately for:

Exclusivity layer	Relevance
Patent term	Determines enforceable patent rights
FDA orphan-drug exclusivity	Can restrict approval of the same drug and indication
Pediatric exclusivity	May add six months to qualifying FDA exclusivity and listed patent terms
Regulatory exclusivity	Depends on the approval pathway and product status
Trade secrets and manufacturing know-how	May delay practical competition even after patent expiry

Patent expiry alone does not guarantee immediate generic entry. An ANDA applicant may face additional listed patents, regulatory exclusivity, manufacturing complexity and supply-chain barriers.

Key Takeaways

U.S. Patent 10,266,822 is directed to increasing SMN2 exon 7 inclusion with antisense oligonucleotides.
The broadest claims are functional method claims, not composition claims.
The central target is the SMN2 intron 7 sequence containing CCAGCAUUAUGAAAG.
Claims 2 and 19 cover commercially relevant oligonucleotide lengths, including 18-mers.
Claims 3-7 cover multiple stability-enhancing nucleotide and backbone modifications.
Claim 14 specifically covers SMA treatment.
Nusinersen is the principal commercial product implicated by the claim strategy.
Risdiplam and onasemnogene are competing modalities but do not appear to satisfy the oligonucleotide limitations.
Claim 17 broadens the sequence landscape through SEQ ID NOs:40-66.
Current Orange Book status, Paragraph IV challenges, litigation and exact patent expiry require review of the current FDA and USPTO records rather than the claim text alone.

Frequently Asked Questions

Does U.S. Patent 10,266,822 claim nusinersen itself?

No. The supplied claims do not claim an antisense oligonucleotide as a composition. They claim methods using qualifying oligonucleotides. Nusinersen may be relevant to infringement analysis because its target and biological effect align with the claimed SMN2 splicing mechanism.

Can a small-molecule SMN2 splicing modifier infringe this patent?

The supplied claims require an oligonucleotide. A small-molecule product such as risdiplam would not ordinarily satisfy that limitation.

Does the patent cover systemic administration of an SMN2 antisense oligonucleotide?

The organism and treatment claims do not specify a route of administration. They can therefore reach administration methods that satisfy the sequence, oligonucleotide and biological-effect limitations, subject to claim construction and validity.

Are phosphorothioate oligonucleotides covered?

Yes. Claim 7 expressly recites a backbone-modified nucleotide containing a phosphorothioate group, provided the parent claim limitations are also satisfied.

Does patent expiration eliminate all barriers to generic nusinersen entry?

No. Generic entry may remain subject to other patents, FDA exclusivity, pediatric exclusivity, manufacturing requirements, regulatory review and litigation outcomes.

References

U.S. Patent No. 10,266,822. (2019). Methods of increasing exon 7-containing SMN2 mRNA and treating spinal muscular atrophy. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (2024). Spinraza (nusinersen) prescribing information. FDA.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.
Biogen Inc. (2024). Annual report for the fiscal year ended December 31, 2023. U.S. Securities and Exchange Commission.
Hua, Y., Vickers, T. A., Okunola, H. L., Bennett, C. F., & Krainer, A. R. (2008). Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice. American Journal of Human Genetics, 82(3), 834-848.

Details for Patent: 10,266,822

Summary for Patent: 10,266,822