U.S. Patent 9,994,851: Claim Scope, Golodirsen Coverage, Exclusivity and Exon 53 Patent Landscape

U.S. Patent 9,994,851 protects a narrowly defined class of morpholino antisense oligonucleotides that induce skipping of exon 53 in the human dystrophin transcript. The claims are limited by oligonucleotide length, target location, sequence complementarity, morpholino chemistry and exon-skipping activity. The patent is directed to the technical basis of Sarepta Therapeutics' Vyondys 53, or golodirsen, although marketed-product coverage must be confirmed by exact sequence mapping and Orange Book listing.

The patent has an estimated ordinary expiration date of June 12, 2036, based on its priority framework, subject to any patent-term adjustment or patent-term extension. Golodirsen received FDA accelerated approval on December 12, 2019, and has orphan-drug exclusivity through December 12, 2026. Patent protection extends materially beyond the regulatory exclusivity period.[1-4]

What does U.S. Patent 9,994,851 protect?

Patent 9,994,851 protects antisense oligonucleotides meeting all of the following conditions:

Limitation	Requirement
Molecule type	Antisense oligonucleotide
Length	20 to 31 bases
Chemistry	Morpholino antisense oligonucleotide
Target	Human dystrophin pre-mRNA exon 53
Complementarity	100% complementary to consecutive target bases
Target position	Within the specified H53A annealing-site region
Sequence motif	At least 12 consecutive bases corresponding to SEQ ID NO: 195
Biological activity	Induces exon 53 skipping
Salt form	Pharmaceutically acceptable salts are included

Claim 1 is a composition-of-matter claim. It does not require a particular dose, route of administration, disease indication, carrier or formulation excipient. A morpholino meeting the structural and functional limitations can fall within the claim even if it is administered in a different formulation from the reference product.

Claim 2 is a pharmaceutical-composition claim. It requires the claimed antisense oligonucleotide plus a pharmaceutically acceptable carrier. Because claim 2 incorporates the full limitations of claim 1, adding a carrier does not broaden the claim. It creates a separate composition category that can support product, formulation and regulatory enforcement theories.

How should the SEQ ID NO: 195 limitation be interpreted?

The cited RNA sequence is:

CUG AAG GUG UUC UUG UAC UUC AUC C

The claim states that uracil bases are thymine bases for purposes of the antisense oligonucleotide. The relevant DNA representation of the claimed target motif is therefore:

CTG AAG GTG TTC TTG TAC TTC ATC C

The antisense molecule must contain at least 12 consecutive bases complementary to a consecutive segment of that sequence. The claim does not require the entire 27-base sequence to be present in the antisense molecule. It permits a 20- to 31-base morpholino containing a qualifying 12-base contiguous motif, provided the molecule also satisfies the claimed target-location and exon-skipping requirements.

This creates several layers of scope:

The claimed oligonucleotide must be 20 to 31 bases long.
Its relevant sequence must be fully complementary to the selected exon 53 target.
The target must fall within the identified H53A annealing-site boundaries.
The oligonucleotide must include at least a 12-base contiguous sequence from the specified motif.
The molecule must induce exon 53 skipping.

A sequence with only partial complementarity, a discontinuous match, or a mismatch within the relevant target region may avoid literal infringement. A sequence outside the claimed H53A target region may also avoid literal infringement even if it induces exon 53 skipping.

What is the scope of the H53A(+23+47) and H53A(+39+69) limitations?

The claim identifies two annealing-site designations:

H53A(+23+47)
H53A(+39+69)

These designations define the relevant exon 53 target space. The claim is not a broad genus covering every exon 53-skipping oligonucleotide. It is tied to a defined segment or overlapping set of segments within exon 53.

The practical effect is that the patent covers a sequence-design window rather than the entire exon. Competing exon 53-skipping PMOs directed to other portions of exon 53 may fall outside the literal scope, even where they use the same morpholino backbone and produce the same pharmacological result.

The target-location limitation is important in validity and enforcement analysis. A challenger could argue that a particular marketed or proposed PMO does not hybridize within the claimed annealing-site coordinates. The patent holder would likely respond with sequence alignment, transcript numbering and experimental data showing that the accused molecule lies within the claimed region.

Does Patent 9,994,851 cover golodirsen?

The patent is closely associated with the exon 53-skipping product category occupied by golodirsen. FDA approved golodirsen under NDA 211970 for Duchenne muscular dystrophy patients with a confirmed mutation amenable to exon 53 skipping.[1]

Patent coverage of a marketed PMO should be tested against the actual drug substance sequence, not only the brand name or therapeutic indication. The relevant analysis requires:

The exact golodirsen base sequence.
The sequence orientation used in the patent.
The transcript reference and exon numbering.
The location of the PMO's annealing site.
Whether the molecule contains at least 12 consecutive bases corresponding to SEQ ID NO: 195.
Whether the approved product is a morpholino meeting the 20- to 31-base limitation.
Whether the product's biological activity satisfies the exon-skipping limitation.

The label confirms the pharmacological objective, but the label alone does not establish every sequence limitation in claim 1. Patent and regulatory records should be read together.

What is the Orange Book status of U.S. Patent 9,994,851?

The patent is associated with the U.S. regulatory estate for Vyondys 53. Orange Book listing is commercially important because it can trigger a statutory notice and litigation process if an abbreviated new drug application, or ANDA, challenges the listed patent with a Paragraph IV certification.[2,3]

Regulatory item	Status
Product	Vyondys 53
Active ingredient	Golodirsen
Sponsor	Sarepta Therapeutics
NDA	211970
FDA approval	December 12, 2019
Approval pathway	Accelerated approval
Molecular class	Phosphorodiamidate morpholino oligomer
Exon target	Exon 53
Relevant patent	U.S. 9,994,851
Estimated patent expiration	June 12, 2036, subject to adjustment or extension
Orphan exclusivity	Through December 12, 2026

The Orange Book should be checked for the current listing code, expiration date, pediatric-extension status and any later patent additions. Listed-patent status can change through FDA administrative updates even when the underlying patent remains in force.

When does golodirsen lose regulatory and patent exclusivity?

Golodirsen has separate regulatory and patent timelines.

Regulatory exclusivity

Golodirsen received orphan-drug designation and approval for a genetically defined DMD population. Orphan-drug exclusivity generally prevents FDA approval of the same drug for the same disease or condition for seven years, subject to statutory exceptions. The expected orphan-exclusivity endpoint is December 12, 2026.[1,4]

The product was approved under the accelerated-approval pathway. That approval does not itself create market exclusivity equivalent to a patent. FDA can require postmarketing confirmatory evidence, and failure of required evidence can create regulatory consequences independent of patent expiry.

Patent exclusivity

The ordinary patent term is expected to extend to June 12, 2036, based on the patent's priority framework. The actual enforceable date depends on:

Patent-term adjustment listed on the patent certificate.
Any patent-term extension under 35 U.S.C. § 156.
Terminal disclaimers, if any.
Post-grant proceedings or claim cancellation.
Claim validity and enforceability.
Orange Book listing status.

A patent-term extension is not automatic. FDA approval date, regulatory review periods and statutory eligibility determine whether an extension is available. The patent therefore creates a longer potential barrier than orphan exclusivity, but the exact terminal date must be taken from the USPTO patent record and any applicable extension certificate.[2,5]

What generic entry risks exist for Vyondys 53?

The principal near-term challenge is not a conventional small-molecule generic. Golodirsen is a complex synthetic oligonucleotide, and an abbreviated pathway would require the applicant to address active-ingredient identity, sequence, stereochemical or chemical attributes, purity, impurities, analytical comparability and clinical pharmacology.

A potential ANDA or 505(b)(2) applicant would face several barriers:

Barrier	Commercial effect
Sequence identity	Limits design-around options
Morpholino chemistry	Narrows acceptable substitute structures
Exon-skipping activity	Requires biological comparability
Defined target region	Creates infringement risk for close sequence variants
Manufacturing controls	Requires specialized oligomer synthesis and purification
FDA pathway uncertainty	May require more than a conventional bioequivalence package
Orange Book patents	Creates Paragraph IV litigation exposure
Small patient population	Reduces expected return on a challenge

A nonidentical exon 53 PMO could attempt to avoid the patent by targeting a different region, using a different length or adopting chemistry outside the morpholino limitation. That strategy would not eliminate regulatory hurdles and could create separate patent exposure under other exon 53 patents.

Which companies compete with golodirsen in exon-skipping therapy?

The relevant commercial competitors are other exon-skipping products, not direct substitutes with identical target sequences.

Product	Active ingredient	Target exon	Sponsor	Chemistry
Vyondys 53	Golodirsen	53	Sarepta Therapeutics	PMO
Viltepso	Viltolarsen	53	NS Pharma/Nippon Shinyaku	PMO
Exondys 51	Eteplirsen	51	Sarepta Therapeutics	PMO
Amondys 45	Casimersen	45	Sarepta Therapeutics	PMO

Golodirsen and viltolarsen are the direct exon 53 competitors. Their shared target exon does not mean that one product automatically infringes the other's patents. The relevant comparison is sequence, target coordinates, chemical structure, formulation, manufacturing process and claim language.

Nippon Shinyaku's involvement in viltolarsen also makes the exon 53 landscape strategically concentrated. A competitor seeking to launch another exon 53 PMO would need to evaluate both Sarepta-related rights and Nippon Shinyaku-related rights.

What formulation patents protect Vyondys 53?

Claim 2 of Patent 9,994,851 protects a broad pharmaceutical composition consisting of the claimed morpholino antisense oligonucleotide and a pharmaceutically acceptable carrier. It does not recite a specific buffer, pH range, concentration, excipient, container or injection device.

The claim therefore has broad structural coverage but limited formulation detail. More narrowly drafted patents could separately protect:

Specific aqueous formulations.
Concentration and pH ranges.
Stabilizers or tonicity agents.
Subcutaneous or intravenous administration systems.
Manufacturing and purification processes.
Dosing regimens.
Combination treatment with corticosteroids or other DMD therapies.

A generic or follow-on applicant could avoid claim 2 only if its product does not contain a claim 1 oligonucleotide or does not satisfy the composition limitations. Changing the carrier alone would usually not avoid claim 2 if the underlying PMO remains within claim 1.

Are method-of-use claims included in Patent 9,994,851?

The two claims supplied are not method-of-treatment claims. They claim:

The antisense oligonucleotide itself.
A pharmaceutical composition containing that oligonucleotide.

They do not expressly require:

Treating Duchenne muscular dystrophy.
A patient with a particular mutation.
A dose or dosing interval.
Intravenous infusion.
Restoration of dystrophin protein.
A specific clinical endpoint.

Separate patents may cover exon 53 skipping methods, dosing schedules, patient selection or treatment combinations. Those rights must be analyzed independently. Patent 9,994,851 is strongest as a product and composition patent, rather than as a dosing or treatment-method patent.

How strong is the patent estate for exon 53 PMOs?

Patent 9,994,851 has meaningful blocking value because claim 1 combines a defined target region, a sequence motif, morpholino chemistry and biological function. The combination reduces the number of literal design-around paths while avoiding an attempt to claim every exon 53-skipping oligonucleotide.

Its main vulnerabilities are technical and claim-construction issues:

Whether the accused molecule fits the H53A coordinates.
Whether the 12-base motif is present in the required orientation.
Whether the molecule is within the 20- to 31-base range.
Whether the accused chemistry qualifies as a morpholino antisense oligonucleotide.
Whether exon 53 skipping is a claim limitation requiring experimental proof.
Whether the patent specification provides adequate written description and enablement across the claimed genus.
Whether prior art disclosed overlapping exon 53 target sequences or morpholino designs.

The claim is narrower than a full exon 53 platform patent but potentially stronger against close substitutes that use the same target window and chemistry.

Has Patent 9,994,851 faced Paragraph IV litigation or a settlement?

No publicly established Paragraph IV challenge or settlement affecting this patent should be inferred from the patent's existence or from competitive exon 53 development. A Paragraph IV case would require an ANDA filing, notice to the NDA holder, a patent-holder lawsuit and a court docket or settlement record.

As of the available record, the principal commercial risk remains prospective rather than an identified generic launch. The absence of a known challenge does not eliminate future risk, particularly after orphan exclusivity ends in December 2026.

What manufacturing and geographic rights matter?

The patent is a U.S. patent and directly controls U.S. manufacture, importation, offer for sale and sale of products falling within an enforceable claim. It does not, by itself, establish equivalent protection in Europe, Japan, China or other markets.

International risk depends on corresponding national-phase patents and local prosecution outcomes. A manufacturing site outside the United States can still create U.S. exposure if the resulting product is imported or sold in the United States.

Morpholino manufacturing also creates practical barriers independent of patent rights. Commercial production requires controlled oligomer synthesis, impurity management, analytical characterization and reproducible drug-product manufacture. A design-around that avoids literal patent infringement may still face substantial CMC development costs.

Key Takeaways

U.S. Patent 9,994,851 is a product and composition patent for exon 53-skipping morpholino antisense oligonucleotides.
Claim 1 requires a 20- to 31-base morpholino, 100% complementarity to the claimed exon 53 target region, at least 12 consecutive bases from SEQ ID NO: 195 and exon 53-skipping activity.
Claim 2 adds a pharmaceutically acceptable carrier and does not require a specific formulation.
The patent is closely relevant to golodirsen and Vyondys 53, but exact product coverage requires sequence-level mapping.
Golodirsen's orphan exclusivity is expected to end December 12, 2026.
The patent's estimated ordinary expiration is June 12, 2036, subject to patent-term adjustment or extension.
Viltolarsen is the principal competing exon 53 product, but its separate sequence and patent estate require independent analysis.
The main design-around options are a different target region, non-morpholino chemistry, a sequence outside the claimed length range or a molecule lacking the claimed motif.
Manufacturing, regulatory pathway and sequence-specific patent barriers make near-term generic entry difficult.

FAQs

Can a 32-base exon 53 PMO infringe Patent 9,994,851?

Literal infringement of claim 1 is less likely because the claim expressly limits the antisense oligonucleotide to 20 to 31 bases. Other patents or the doctrine of equivalents could remain relevant.

Does every exon 53-skipping morpholino infringe this patent?

No. The molecule must satisfy the claimed length, target-region, sequence-motif, complementarity, morpholino and functional limitations.

Does changing the carrier avoid claim 2?

No, not necessarily. Claim 2 covers a composition containing the claimed antisense oligonucleotide and a pharmaceutically acceptable carrier. Changing only the carrier may leave the claim intact.

Can viltolarsen be assumed to infringe because it also targets exon 53?

No. Exon identity alone is insufficient. Infringement requires comparison of sequence, target coordinates, chemistry, length and the other claim limitations.

Can an ANDA applicant challenge the patent after orphan exclusivity ends?

Yes. Expiration of orphan exclusivity does not end patent rights. An ANDA applicant would still need to address any listed patent through the applicable certification process and could face patent litigation.

Sources:

U.S. Food and Drug Administration. (2019). FDA approves targeted treatment for Duchenne muscular dystrophy.
U.S. Patent and Trademark Office. (2018). U.S. Patent No. 9,994,851: Antisense oligonucleotide for inducing exon skipping in dystrophin gene.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
U.S. Food and Drug Administration. (2024). Drugs@FDA: Vyondys 53, NDA 211970.
United States Code, 35 U.S.C. §§ 154, 156.

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
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 9,994,851

Summary for Patent: 9,994,851