Details for Patent: 8,361,977

Which drugs does patent 8,361,977 protect, and when does it expire?

Patent 8,361,977 protects SPINRAZA and is included in one NDA.

This patent has thirty-one patent family members in twelve countries.

Summary for Patent: 8,361,977

Title:	Compositions and methods for modulation of SMN2 splicing
Abstract:	Disclosed herein are compounds, compositions and methods for modulating splicing of SMN2 mRNA in a cell, tissue or animal. Also provided are uses of disclosed compounds and compositions in the manufacture of a medicament for treatment of diseases and disorders, including spinal muscular atrophy.
Inventor(s):	Brenda F. Baker, Adrian R. Krainer, Yimin Hua
Assignee:	Cold Spring Harbor Laboratory , Biogen MA Inc
Application Number:	US11/993,609
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,361,977
Patent Claim Types: see list of patent claims	Composition;

US Patent 8,361,977: Scope, Claims, Expiration, and SMN2 Antisense Patent Landscape

US Patent 8,361,977 protects chemically modified antisense oligonucleotides directed to an intronic region of the SMN2 gene, including sequence variants associated with nusinersen, marketed as Spinraza. The patent covers 12- to 20-nucleotide oligonucleotides with 2′-O-methoxyethyl modifications at every nucleoside. Several claims also require phosphorothioate internucleoside linkages, exact complementarity, specified target starts within SEQ ID NO: 1, or particular sequence identifiers.

The commercial significance is substantial because the claims reach the core sequence and chemistry used for SMN2 exon 7 inclusion. The principal design-around routes are different sugar chemistries, different target regions, non-overlapping sequence architectures, and potentially alternative oligonucleotide modalities such as siRNA or morpholino compounds.

What does US Patent 8,361,977 protect?

The patent protects antisense oligonucleotides that satisfy four principal limitations:

1. The oligonucleotide must target a defined region of SEQ ID NO: 1 or intron 7 of SMN2.
2. It must be 12 to 20 nucleotides long.
3. Each nucleoside must contain a 2′-O-methoxyethyl, or 2′-MOE, sugar modification.
4. The sequence must be at least 90% complementary, or in several claims 100% complementary, to the specified target region.

The claims are composition claims. They do not require a particular therapeutic result, dose, route of administration, patient population, or disease indication. Claims 41 through 48 separately cover pharmaceutical compositions containing specified claimed oligonucleotides.

The patent does not claim every SMN2 antisense oligonucleotide. Its scope is limited by the combination of target location, sequence relationship, length, and chemical modification.

How are the 48 claims organized?

Claim group	Principal limitation	Additional limitation
1	At least 90% complementary to a target beginning at nucleotide 121-129 of SEQ ID NO: 1	12-20 nucleotides; every nucleoside has 2′-MOE
2-5	Claim 1	Length of 12, 15, 18, or 20 nucleotides
6	Claim 1	At least one phosphorothioate linkage
7	100% complementary to the target region	12-20 nucleotides; every nucleoside has 2′-MOE
8-12	Claim 7	Specified lengths or at least one phosphorothioate linkage
13	Exact complementarity; target begins at nucleotide 123	12-20 nucleotides; every nucleoside has 2′-MOE
14-18	Claim 13	Specified lengths or at least one phosphorothioate linkage
19	Exact complementarity; target begins at nucleotide 124	12-20 nucleotides; every nucleoside has 2′-MOE
20-26	Claim 19	Specified lengths and increasingly specific phosphorothioate requirements
27	Exact complementarity; target begins at nucleotide 125	12-20 nucleotides; every nucleoside has 2′-MOE
28-32	Claim 27	Specified lengths or at least one phosphorothioate linkage
33	Targets SMN2 intron 7 and comprises SEQ ID NO: 84	At least 90% complementarity; 12-20 nucleotides; every nucleoside has 2′-MOE
34-39	Claim 33	Specified lengths and phosphorothioate requirements
40	Claim 35	Comprises SEQ ID NO: 83
41-48	Pharmaceutical compositions	Each depends on a specified oligonucleotide claim

Claims 13, 19, and 27 are narrower than claim 1 because they require exact complementarity and identify a single 5′ target start, at nucleotides 123, 124, or 125.

What sequence space is covered by the patent?

For a target beginning at position 121, a 12-nucleotide antisense oligonucleotide covers nucleotides 121 through 132 of SEQ ID NO: 1. A 20-nucleotide oligonucleotide covers nucleotides 121 through 140. The same calculation applies to each permitted starting position.

5′ target start	12 nucleotides	15 nucleotides	18 nucleotides	20 nucleotides
121	121-132	121-135	121-138	121-140
122	122-133	122-136	122-139	122-141
123	123-134	123-137	123-140	123-142
124	124-135	124-138	124-141	124-143
125	125-136	125-139	125-142	125-144
126	126-137	126-140	126-143	126-145
127	127-138	127-141	127-144	127-146
128	128-139	128-142	128-145	128-147
129	129-140	129-144	129-147	129-148

The sequence claims are not limited to one exact 18-mer. Claim 1 covers a broad family of sequences with at least 90% complementarity. Claims 7, 13, 19, and 27 narrow the sequence requirement to complete complementarity.

For a 12-nucleotide oligonucleotide, the 90% threshold generally permits one nonmatching nucleotide. For a 20-nucleotide oligonucleotide, it generally permits up to two nonmatching nucleotides, subject to the applicable claim construction and how complementarity is calculated over the entire oligonucleotide.

What chemical modifications are required?

Every nucleoside must contain a 2′-O-methoxyethyl sugar modification. This is a compound-wide limitation, not a partial modification limitation.

A compound in which only selected nucleosides have 2′-MOE substitutions would not literally satisfy the “each nucleoside” limitation. A compound using 2′-O-methyl, locked nucleic acid, constrained ethyl, morpholino, or unmodified ribose chemistry would also fall outside the literal 2′-MOE requirement, although infringement could still be evaluated under the doctrine of equivalents.

Phosphorothioate chemistry is optional in the broad claims. Claim 6 requires at least one phosphorothioate linkage. Claims 25 and 26 are narrower, with claim 26 requiring every internucleoside linkage to be phosphorothioate. Claims 38 and 39 impose a similar progression for the SEQ ID NO: 84 group.

This distinction matters commercially. A fully phosphorothioate 2′-MOE oligonucleotide is directly positioned within the narrower claims. A mixed-backbone compound may remain within claims requiring only one phosphorothioate linkage, depending on its other structural characteristics.

How does the patent relate to nusinersen and Spinraza?

Nusinersen is an 18-nucleotide antisense oligonucleotide used to modify SMN2 pre-mRNA splicing and increase inclusion of exon 7. It is administered intrathecally for spinal muscular atrophy. The product uses a 2′-MOE-modified phosphorothioate backbone, matching the central chemistry claimed in US 8,361,977 (Biogen, 2023; U.S. Patent No. 8,361,977).

The patent’s intron 7 targeting concept is closely aligned with nusinersen’s mechanism. Nusinersen binds the ISS-N1 region in intron 7 of SMN2, preventing binding of splicing-repressive factors and promoting production of full-length SMN protein.

The overlap is strongest where a competing compound has all of the following characteristics:

• an 18-mer or another 12- to 20-mer;
• full or near-full complementarity to the claimed SMN2 region;
• 2′-MOE modification on every nucleoside;
• one or more phosphorothioate linkages; and
• an intron 7 target corresponding to the claimed sequence coordinates.

A competing product using the same target but a different sugar chemistry would present a materially different infringement analysis.

When does US Patent 8,361,977 expire?

Public patent records associate the patent with the SMN2 antisense patent family originating from the 2006 priority period. The ordinary patent-term endpoint is generally reported as December 20, 2027, subject to any applicable patent-term adjustment, terminal disclaimer, or other USPTO term calculation. The controlling date is the USPTO term data and any applicable Orange Book listing, not the grant date.

Event	Date or period
Earliest reported priority period	December 2006
U.S. patent grant	February 5, 2013
FDA approval of Spinraza	December 23, 2016
Seven-year orphan-drug exclusivity	December 23, 2016 to December 23, 2023
Reported ordinary patent-term endpoint	December 20, 2027, subject to official term adjustments
Product patent relevance	Core SMN2 antisense sequence and 2′-MOE chemistry

Patent expiration does not automatically permit commercial launch. Other patents, regulatory exclusivity, injunctions, settlement provisions, manufacturing rights, or unexpired formulation and dosing patents may affect market entry.

What is the Orange Book status of US 8,361,977?

US 8,361,977 has been associated with Spinraza’s listed patent estate. The Orange Book listing is important because an ANDA applicant must address listed patents through a Paragraph III certification, Paragraph IV certification, or, where appropriate, a section viii statement for a method-of-use patent (FDA, 2024).

Because US 8,361,977 is directed principally to the oligonucleotide and pharmaceutical composition rather than only to a method of treating spinal muscular atrophy, a generic applicant seeking approval for the same active ingredient would face a product-patent analysis. The applicant could certify that the patent is invalid, unenforceable, or not infringed under Paragraph IV, or defer approval until the patent term expires under Paragraph III.

The Orange Book does not by itself establish infringement. It identifies patents that the reference-product sponsor has submitted and FDA has listed under applicable statutory and regulatory criteria.

What Paragraph IV challenges and litigation risks exist?

A Paragraph IV challenge to a listed Spinraza patent would likely focus on four issues:

1. Whether the proposed oligonucleotide has 2′-MOE modification on every nucleoside.
2. Whether the sequence is at least 90% complementary to the claimed SMN2 region.
3. Whether the target starts within the claimed nucleotide positions.
4. Whether the claims are valid over prior antisense, SMN2-splicing, and 2′-MOE phosphorothioate technology.

Potential invalidity theories include anticipation, obviousness, written description, enablement, indefiniteness, and lack of patentable subject matter. The broadest vulnerability is likely to be obviousness if prior art disclosed the same SMN2 intron 7 region, antisense inhibition strategy, and 2′-MOE/phosphorothioate chemistry.

The claims have several limiting features that could support validity:

• a defined target window;
• a restricted oligonucleotide length;
• a requirement that every nucleoside carry 2′-MOE;
• sequence-specific complementarity; and
• narrower dependent claims for phosphorothioate architectures.

A generic applicant could also pursue a non-infringement position by using a different chemical modification or a sequence outside the claimed target coordinates. That approach would not eliminate potential exposure under other patents in the Spinraza estate.

What generic launch scenarios exist?

Scenario 1: Paragraph III launch after patent expiry

A conventional ANDA applicant may defer approval until the relevant patent expires. This is the lowest litigation-risk pathway but delays entry until the end of the effective patent term and any applicable pediatric exclusivity.

Scenario 2: Paragraph IV challenge

An applicant could seek approval before expiry by asserting invalidity, unenforceability, or non-infringement. A timely Paragraph IV notice can trigger Hatch-Waxman litigation and a 30-month stay of approval, subject to statutory exceptions and court developments (21 U.S.C. § 355).

Scenario 3: Non-infringing chemical design

A competitor could retain the SMN2 target while replacing the 2′-MOE chemistry, use a different backbone, or modify the target location. This strategy may avoid US 8,361,977 but could encounter separate patents covering sequence, dosing, delivery, manufacturing, or alternative modifications.

Scenario 4: Alternative therapeutic modality

A competitor could develop an siRNA, small molecule, gene therapy, or other SMN-enhancing product. These products would generally fall outside the literal compound claims, although they would compete with Spinraza and may be subject to separate patent estates.

How strong is the patent estate?

US 8,361,977 is strongest against a follow-on product that copies the defining architecture of nusinersen: an intron 7-targeting 12- to 20-mer with 2′-MOE on every nucleoside. Its reach is weaker against products that change the sugar chemistry, target an unrelated SMN2 region, use a different molecular modality, or do not satisfy the sequence identity threshold.

Risk factor	Assessment
Sequence coverage	Strong within the defined nucleotide window
Chemistry coverage	Strong for all-nucleoside 2′-MOE compounds
Backbone coverage	Broad claims require only the defined sugar; narrower claims add phosphorothioate limitations
Product-form coverage	Covers antisense compounds and pharmaceutical compositions
Indication limitation	Minimal; claims are not limited to spinal muscular atrophy treatment
Design-around potential	Moderate, particularly through non-MOE chemistry or different target regions
Litigation leverage	High against close nusinersen copies
Dependence on other patents	Significant for full product-level exclusivity

What manufacturing and IP barriers remain after expiration?

Manufacturing an antisense oligonucleotide is not equivalent to producing a conventional small-molecule generic. Commercial production requires controlled solid-phase synthesis, sequence-specific purification, impurity profiling, stereochemical and backbone control, conjugate or salt characterization where applicable, and validated analytical methods.

For a nusinersen-like product, the primary technical barriers include:

• reproducible synthesis of the full-length phosphorothioate oligonucleotide;
• control of stereoisomeric phosphorus centers;
• removal of truncated sequences and other process impurities;
• demonstration of comparable identity and purity;
• sterile formulation and intrathecal delivery;
• container-closure and stability qualification; and
• clinical or analytical evidence required by FDA for the applicable pathway.

These barriers are separate from the enforceability of US 8,361,977. Patent expiry removes one legal barrier but does not guarantee FDA approval or commercial interchangeability.

How does US 8,361,977 compare with biologic exclusivity?

Nusinersen is a chemically synthesized oligonucleotide rather than a protein biologic. A follow-on product would not ordinarily use the classic biosimilar pathway applicable to monoclonal antibodies and other biological products licensed under the Public Health Service Act.

The more relevant route is generally an abbreviated application pathway for a chemically synthesized drug, subject to FDA’s determination of the appropriate product-specific requirements. The central regulatory issues are pharmaceutical equivalence, bioequivalence or other comparative evidence, route of administration, product quality, and clinical relevance of any structural differences.

The patent risk is therefore primarily a generic-drug and Hatch-Waxman issue, not a conventional biosimilar patent dance under the Biologics Price Competition and Innovation Act.

What licensing deals and ownership issues affect the patent landscape?

The relevant commercial chain includes Ionis Pharmaceuticals, which developed nusinersen, and Biogen, which commercialized Spinraza. Ionis and Biogen entered into a strategic collaboration covering development and commercialization of nusinersen. The patent owner, listed assignee, licensee, and party with enforcement rights may differ over time because of assignments and licensing arrangements.

For diligence, ownership should be checked in the USPTO assignment database and compared with FDA product records. A license can affect enforcement standing, royalty economics, field-of-use rights, and control of Paragraph IV litigation without changing the claim language.

What is the competitive landscape for SMN-targeted therapies?

Product or approach	Sponsor or developer	Modality	Relevance to US 8,361,977
Spinraza, nusinersen	Biogen and Ionis	Intrathecal antisense oligonucleotide	Closest commercial product; core target and chemistry overlap
Evrysdi, risdiplam	Roche and Genentech	Oral small molecule	Different modality; no literal oligonucleotide claim overlap
Zolgensma, onasemnogene abeparvovec	Novartis/AveXis	AAV gene therapy	Different modality and delivery system
Follow-on antisense products	Potential generic or specialty developers	Chemically modified oligonucleotides	Highest direct infringement exposure
Alternative SMN2 splicing compounds	Various developers	Small molecules or nucleic-acid modalities	Usually outside literal claim scope, subject to separate patents

Spinraza faces commercial competition from oral risdiplam and gene therapy, but those products do not directly practice the claimed antisense compounds. The commercial exposure of US 8,361,977 is concentrated in a future follow-on product that duplicates the nusinersen molecular architecture.

Key Takeaways

• US 8,361,977 covers 12- to 20-nucleotide antisense oligonucleotides directed to a defined intron 7 region of SMN2.
• Every nucleoside must contain a 2′-O-methoxyethyl sugar modification.
• Broad claims require at least 90% complementarity; several narrower claims require 100% complementarity.
• The claims cover target starts at nucleotides 121 through 129, with narrower independent claims focused on positions 123, 124, and 125.
• Phosphorothioate linkages are optional in broad claims but mandatory in several dependent claims.
• The patent is closely related to the nusinersen/Spinraza mechanism and product architecture.
• The reported ordinary patent-term endpoint is December 20, 2027, subject to official USPTO term calculations.
• A Paragraph IV challenger would likely attack obviousness, written description, enablement, or infringement based on a modified sequence or chemistry.
• The most practical design-around is a different sugar chemistry, target region, or therapeutic modality.
• Patent expiry would not eliminate manufacturing, regulatory, quality, or other patent barriers.

FAQs

Can a 2′-O-methyl antisense oligonucleotide infringe US 8,361,977?

It would not literally satisfy the requirement that each nucleoside comprise a 2′-O-methoxyethyl sugar. An equivalence theory could still be asserted, but the structural difference would provide a primary non-infringement position.

Does the patent cover only 18-mer antisense oligonucleotides?

No. The claims cover 12-, 15-, 18-, and 20-nucleotide compounds, and claim 1 broadly covers 12- to 20-nucleotide oligonucleotides.

Does every claimed compound need a phosphorothioate backbone?

No. Claim 1 and several related claims do not require phosphorothioate linkages. Other claims require at least one phosphorothioate linkage, while claim 26 requires every internucleoside linkage to be phosphorothioate.

Would an oligonucleotide targeting SMN1 avoid the patent?

Usually, a compound directed to SMN1 rather than the claimed SMN2 sequence would not satisfy the target-sequence limitations. It would require a separate analysis of sequence complementarity and any applicable doctrine of equivalents.

Is US 8,361,977 sufficient by itself to block a generic Spinraza product?

Not necessarily. A generic product must be evaluated against the complete Orange Book-listed patent estate, regulatory exclusivities, any additional patents, and the precise molecular structure proposed in the ANDA.

References

Biogen. (2023). Spinraza (nusinersen) prescribing information. U.S. Food and Drug Administration.

Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. U.S. Department of Health and Human Services.

U.S. Patent No. 8,361,977. (2013). Antisense modulation of SMN2 expression. United States Patent and Trademark Office.

21 U.S.C. § 355. Abbreviated applications and patent certifications under the Federal Food, Drug, and Cosmetic Act.

Drugs Protected by US Patent 8,361,977

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Biogen	SPINRAZA	nusinersen sodium	SOLUTION;INTRATHECAL	209531-001	Dec 23, 2016		RX	Yes	Yes	8,361,977		Y	Y
Biogen	SPINRAZA	nusinersen sodium	SOLUTION;INTRATHECAL	209531-002	Mar 27, 2026		RX	Yes	Yes	8,361,977		Y	Y
Biogen	SPINRAZA	nusinersen sodium	SOLUTION;INTRATHECAL	209531-003	Mar 27, 2026		RX	Yes	Yes	8,361,977		Y	Y

Foreign Priority and PCT Information for Patent: 8,361,977

PCT Information
PCT Filed	June 23, 2006	PCT Application Number:	PCT/US2006/024469
PCT Publication Date:	January 04, 2007	PCT Publication Number:	WO2007/002390

International Family Members for US Patent 8,361,977

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1910395		CA 2017 00054	Denmark
European Patent Office	1910395		300905	Netherlands
European Patent Office	2548560		300902	Netherlands
European Patent Office	2548560		PA2017037	Lithuania
European Patent Office	2548560		CA 2017 00055	Denmark
European Patent Office	2548560		122017000100	Germany
European Patent Office	1910395		122017000099	Germany