US Patent 10,421,966: Scope, Claim Construction, and Exon 53 Antisense Patent Landscape

US Patent 10,421,966 claims a narrowly defined PEG-conjugated morpholino antisense oligonucleotide designed to induce exon 53 skipping in human dystrophin pre-mRNA. The patent does not claim every exon 53-skipping oligonucleotide. Its principal limitations are the 25-base length, the defined exon 53 target region, morpholino chemistry, covalent polyethylene glycol linkage, and exon-skipping function.

The PEG-conjugation requirement is commercially significant. FDA-approved exon 53 products, including golodirsen and viltolarsen, are morpholino antisense drugs but are not generally described as PEG-conjugated products in their approved labeling. A product lacking the claimed PEG chain should not literally fall within claim 1 or claim 2, even if it has the same target region and induces exon 53 skipping.

What does US Patent 10,421,966 cover?

The patent covers two principal categories:

A composition-of-matter claim directed to a specific class of 25-base antisense oligonucleotides.
A pharmaceutical-composition claim directed to that oligonucleotide combined with a pharmaceutically acceptable carrier.

The relevant claim elements are cumulative:

Claim limitation	Requirement
Molecular class	Antisense oligonucleotide
Length	Exactly 25 bases
Target	Consecutive bases in exon 53 of human dystrophin pre-mRNA
Sequence relationship	100% complementary to the target region
Sequence limitation	At least 12 consecutive bases corresponding to the disclosed SEQ ID NO: 195 region
Base convention	Uracil treated as thymine
Chemistry	Morpholino antisense oligonucleotide
Conjugation	Chemically linked to a polyethylene glycol chain
Function	Induces exon 53 skipping
Claim 2 formulation	Includes a pharmaceutically acceptable carrier

A molecule missing any one of these limitations may avoid literal infringement, subject to claim-construction principles and the doctrine of equivalents.

How should the 25-base sequence limitation be interpreted?

SEQ ID NO: 195 is stated as:

CUG AAG GUG UUC UUG UAC UUC AUC C

With uracil converted to thymine, the corresponding disclosed RNA-style region is:

CTG AAG GTG TTC TTG TAC TTC ATC C

The sequence contains 25 bases. The claimed antisense oligonucleotide must be 100% complementary to a consecutive target segment of exon 53 and must include at least 12 consecutive bases from the disclosed region, subject to the claim’s uracil/thymine language.

The claim is therefore broader than one single 25-mer, but narrower than a generic exon 53-skipping claim. Potentially covered molecules can vary in their exact 25-base sequence if they remain fully complementary to an eligible consecutive target region and retain at least 12 consecutive bases from the specified sequence.

Key sequence-scope consequences

A 25-mer with a single mismatch is outside the literal “100% complementary” limitation.
A 24-mer or 26-mer is outside the literal length limitation.
A sequence targeting a different exon 53 region may be outside the claim.
A molecule containing fewer than 12 consecutive bases from the specified sequence is outside the express sequence limitation.
A morpholino without a covalently attached PEG chain is outside the literal claim.
A PEG-linked antisense molecule using a different backbone, such as a 2'-O-methyl phosphorothioate backbone, is outside the morpholino limitation.
A PEG mixture or noncovalently associated PEG may not satisfy the “chemically linked” requirement.

Does the patent claim golodirsen or viltolarsen?

Not automatically. The approved exon 53 drugs must be evaluated against every limitation.

Product	Sponsor	Exon target	Broad chemistry	PEG limitation apparent from approved product description?	Literal risk under US 10,421,966
Golodirsen, Vyondys 53	Sarepta Therapeutics	Exon 53	PMO antisense oligonucleotide	No	Likely limited unless the marketed or accused molecule has the claimed PEG linkage and sequence
Viltolarsen, Viltepso	Nippon Shinyaku and NS Pharma	Exon 53	PMO antisense oligonucleotide	No	Likely limited unless the accused molecule satisfies the PEG and sequence limitations
PEG-conjugated exon 53 PMO	Any developer	Exon 53	Morpholino PMO	Yes	Highest relevance
Peptide-conjugated PMO	Any developer	Variable	PMO	No PEG limitation	Outside literal scope unless PEG is also chemically linked
Non-PMO exon 53 antisense	Any developer	Exon 53	Alternative oligonucleotide chemistry	No morpholino limitation	Outside literal scope

FDA describes golodirsen and viltolarsen as phosphorodiamidate morpholino oligomers designed to bind exon 53 of dystrophin pre-mRNA and induce exon skipping.[1,2] Those product descriptions do not, by themselves, establish infringement of a claim requiring a PEG chain.

What is the strongest infringement issue?

The PEG-conjugation limitation is the central commercial boundary.

A potential accused product would need to show:

A morpholino backbone.
A covalent chemical bond to PEG.
A PEG chain meeting the claim construction adopted by the court.
A 25-base antisense sequence.
Full complementarity to the relevant exon 53 target region.
At least 12 consecutive bases from the claimed sequence region.
Exon 53-skipping activity.

The functional limitation, “induces exon 53 skipping,” may be established through RNA analysis, RT-PCR, sequencing, or other biological testing. It is not merely a statement of intended use if the claim is construed to require that the molecule have the stated biological property.

The phrase “pharmaceutically acceptable salt thereof” extends claim 1 to qualifying salt forms. It does not remove the sequence, morpholino, PEG, length, or exon-skipping limitations.

How broad is claim 1 compared with claim 2?

Claim 1 is a product claim. Claim 2 is a pharmaceutical-composition claim.

Issue	Claim 1	Claim 2
Claimed subject	Antisense oligonucleotide	Pharmaceutical composition
Required carrier	No	Yes
PEG-linked morpholino required	Yes	Yes
Exon 53 skipping required	Yes	Yes
Salt alternative	Yes	Yes
Infringement theory	Making, using, selling, or importing the claimed oligonucleotide	Making, using, selling, or distributing a composition containing the claimed oligonucleotide

Claim 2 does not materially broaden the oligonucleotide itself. It adds a pharmaceutically acceptable carrier. A composition containing a non-PEG morpholino would not satisfy claim 2 merely because it is formulated for injection.

What formulations are protected by US 10,421,966?

Claim 2 covers a formulation containing the claimed PEG-linked, 25-base morpholino and a pharmaceutically acceptable carrier. The claim does not specify:

A particular carrier;
A concentration;
A buffer;
A pH;
A dosage;
A route of administration;
A vial configuration;
A dosing schedule;
A particular PEG molecular weight;
A particular PEG architecture.

The carrier can therefore potentially include conventional aqueous pharmaceutical excipients, buffers, tonicity agents, stabilizers, and related formulation components, provided the composition contains the claimed oligonucleotide.

The claim does not expressly protect:

A lyophilized formulation as such;
A specific injectable concentration;
A particular prefilled syringe;
A specific dosing regimen;
A particular PEG size;
A formulation containing only an unconjugated PMO.

Those subjects may be covered by separate formulation or method-of-use claims in the patent family or related patent families, but they are not independently recited in the provided claims.

What method-of-use protection does the patent provide?

The provided claims do not contain a conventional patient-treatment method claim. They require that the oligonucleotide induce exon 53 skipping, but they do not expressly recite:

Treating Duchenne muscular dystrophy;
Treating a patient with a dystrophin mutation;
Administering a specified dose;
Administering at a specified interval;
Treating a defined amenable mutation;
Improving dystrophin expression;
Improving ambulation or muscle function.

This distinction matters in litigation and regulatory analysis. A product claim can be infringed by manufacture or sale without proof of a particular treatment protocol. Conversely, the absence of an express treatment step limits the patent’s direct method-of-use reach based on the provided claims.

When does US Patent 10,421,966 lose exclusivity?

The patent’s enforceable term cannot be calculated reliably from the patent number and claim text alone. The controlling date depends on the earliest effective nonprovisional or international priority date, terminal disclaimers, patent-term adjustment, and any patent-term extension.

The relevant term analysis is:

Term factor	Relevance
Earliest effective filing date	Establishes the baseline 20-year term
PCT history	May affect the effective US filing date
Continuation or divisional status	Can preserve disclosure while changing term analysis
Patent-term adjustment	May extend the ordinary term
Terminal disclaimer	Can shorten the enforceable term
Patent-term extension	May extend the term for qualifying regulatory delay
Patent-term disclaimer	Can eliminate otherwise available extension

The USPTO Patent Center record and the face of the issued patent control the precise expiration calculation.[3] FDA regulatory exclusivity is separate from patent term. Drug approval does not establish that this patent is listed in the Orange Book or that it covers the approved commercial product.

What is the Orange Book status of US 10,421,966?

A patent number is not an Orange Book patent merely because it claims an active pharmaceutical ingredient or an antisense drug.

Orange Book listing depends on FDA submission by the NDA holder and on whether the patent qualifies under FDA listing rules. Relevant categories include patents claiming:

The drug substance;
The drug product or formulation;
An approved method of use.

The provided claims could potentially be characterized as drug-substance and drug-product claims. They do not, however, establish that the patent was submitted for listing against any NDA.

For golodirsen and viltolarsen, Orange Book status must be checked against the current FDA Approved Drug Products with Therapeutic Equivalence Evaluations database and the applicable NDA patent-listing submissions.[4] A patent directed to a PEG-linked version may have limited Orange Book significance if the approved product is an unconjugated PMO.

Which companies are challenging the patent?

No Paragraph IV challenger, ANDA litigation event, or settlement can be established from the claims alone. The patent’s commercial vulnerability is also affected by its product fit.

A conventional ANDA pathway is unlikely to be the primary route for a complex PMO product. Generic developers would need to address:

Structural identity of the oligonucleotide;
Sequence identity;
Morpholino chemistry;
PEG conjugation;
Purity and impurity profile;
Molecular weight distribution;
Bioactivity;
Exon-skipping performance;
Manufacturing comparability.

For an approved exon 53 PMO, an applicant could pursue a noninfringement position by arguing that the proposed product lacks the claimed PEG linkage, does not use the claimed 25-base sequence, or does not include at least 12 consecutive bases from the recited region.

A Paragraph IV notice would be relevant only if an ANDA applicant certifies that a listed patent is invalid, unenforceable, or not infringed. The patent number alone does not establish that a Paragraph IV dispute exists.

How does this patent compare with the broader exon 53 patent landscape?

The exon 53 landscape generally divides into four layers:

Patent layer	Typical subject matter	Relevance to US 10,421,966
Sequence patents	Specific antisense sequences targeting exon 53	Direct overlap risk if the claimed sequence is used
Chemistry patents	PMO, peptide-PMO, conjugated oligonucleotide, or delivery chemistry	Overlap depends on backbone and conjugate
Formulation patents	Concentration, buffer, stability, dosage form, or delivery system	Claim 2 has only broad carrier language
Method patents	Treating DMD, mutation-specific use, dosing, or clinical response	Not present in the provided claims

Golodirsen and viltolarsen create the principal approved-product comparison. Both target exon 53, but product-level patent risk depends on their exact sequences, chemical structures, commercial formulations, and listed patent estates. Exon 53 targeting alone is insufficient to establish overlap.

What manufacturing and IP barriers does the patent create?

The patent’s manufacturing relevance is concentrated in PEG-conjugated PMO development. A competing developer would need to control:

Solid-phase morpholino synthesis;
Sequence-specific coupling chemistry;
Site-selective PEG attachment;
Removal of unconjugated and over-conjugated species;
Control of molecular weight distribution;
Residual reagent clearance;
Identity and potency assays;
Scale-up and batch consistency.

The patent does not, based on the provided claims, claim a manufacturing process. It can still create a product-level barrier if a commercially attractive PEG-linked PMO necessarily satisfies the claimed structural and functional limitations.

A design-around strategy could focus on:

An unconjugated PMO;
A different conjugate;
A different target sequence;
A different oligonucleotide length;
A non-morpholino backbone;
A sequence retaining exon 53 activity while avoiding the specified 12-base segment.

Each design-around must be tested against the doctrine of equivalents and related patent-family claims.

How strong is the patent estate for a competing exon 53 product?

The claims are technically narrow but potentially valuable if PEG conjugation improves tissue distribution, exposure, dosing interval, or muscle delivery. Their strength depends on whether the commercial development path requires the claimed conjugate.

Strengths

Covers a defined therapeutic target, exon 53.
Requires a specific antisense chemistry associated with DMD development.
Includes a covalent PEG limitation that may capture a differentiated delivery platform.
Contains both product and composition claims.
Includes a biological activity requirement tied to exon skipping.

Limitations

Exact 25-base length narrows coverage.
Full complementarity narrows sequence coverage.
At least 12 consecutive bases creates a defined sequence dependency.
PEG linkage excludes conventional unconjugated PMOs.
The provided claims do not expressly cover treatment, dosing, or manufacturing.
The claims do not establish coverage of approved exon 53 products without product-specific structural analysis.

Key Takeaways

US Patent 10,421,966 is a narrow composition and formulation patent for a 25-base, PEG-linked morpholino antisense oligonucleotide targeting exon 53 of dystrophin pre-mRNA.
Literal infringement requires all major limitations, especially the morpholino backbone, covalent PEG linkage, exact 25-base length, sequence relationship, and exon-skipping activity.
Golodirsen and viltolarsen are relevant exon 53 comparators, but exon 53 activity and PMO chemistry alone do not establish infringement.
The patent does not, based on the provided claims, expressly claim a DMD treatment method, dosing regimen, or manufacturing process.
Orange Book listing and Paragraph IV exposure cannot be inferred from the patent number or claim text.
The principal design-around opportunities are non-PEG chemistry, alternative sequence selection, alternative length, and non-morpholino backbones.
The decisive commercial question is whether the competing product uses a PEG-conjugated PMO within the claimed sequence window.

FAQs

Does a PEG-free morpholino infringe US Patent 10,421,966?

Not literally under the provided claims, because each claim requires that the morpholino antisense oligonucleotide be chemically linked to a polyethylene glycol chain.

Does a 25-base exon 53 oligonucleotide infringe if it has a different sequence?

Not necessarily. It must be 100% complementary to a qualifying exon 53 target region and contain at least 12 consecutive bases from the specified sequence region.

Is viltolarsen automatically blocked by this patent?

No. Viltolarsen would require a product-specific comparison of its exact sequence, backbone, conjugation structure, and formulation against every claim limitation.

Can a company avoid claim 2 by selling the antisense oligonucleotide as a drug substance?

Potentially, if the drug substance does not satisfy claim 1 or if the product lacks the required PEG-linked morpholino structure. Claim 2 is directed to a pharmaceutical composition and adds a pharmaceutically acceptable carrier.

Does this patent protect a treatment regimen for Duchenne muscular dystrophy?

The provided claims do not expressly recite a patient, DMD treatment, dose, frequency, or clinical outcome. They claim the oligonucleotide and a composition containing it.

References

U.S. Food and Drug Administration. (2019). Vyondys 53 (golodirsen) prescribing information.
U.S. Food and Drug Administration. (2020). Viltepso (viltolarsen) prescribing information.
United States Patent and Trademark Office. (n.d.). Patent Center: U.S. Patent No. 10,421,966.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, Orange Book.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Australia	2004903474	Jun 28, 2004

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	E498685	⤷ Start Trial
Cyprus	1111447	⤷ Start Trial
Cyprus	1117475	⤷ Start Trial
Germany	602005026386	⤷ Start Trial
Denmark	1766010	⤷ Start Trial
Denmark	2206781	⤷ Start Trial
European Patent Office	1766010	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 10,421,966

Summary for Patent: 10,421,966