US Patent 11,274,331: Scope, Claims, Expiration, Orange Book Position and 3,4-DAP Patent Landscape

US Patent No. 11,274,331 protects genotype-directed dosing of 3,4-diaminopyridine, also called amifampridine, for Lambert-Eaton myasthenic syndrome. The patent requires treatment of a human LEMS patient with two NAT2 fast alleles and a daily dose generally ranging from 30 mg to 100 mg, with broader coverage up to 240 mg. Its strongest commercial relevance is to Firdapse, the FDA-approved amifampridine phosphate product marketed by Catalyst Pharmaceuticals.

The patent is narrower than a conventional composition or broad method-of-treatment patent because every asserted claim requires the patient to have two NAT2 fast alleles. The claims also cover specific dosing schedules, tablet strengths, scored tablets, aqueous suspensions and amifampridine phosphate.

What does US Patent 11,274,331 protect?

US 11,274,331 protects a patient-selection and dosing method for LEMS. The core elements are:

Claim element	Scope
Disease	Lambert-Eaton myasthenic syndrome
Patient	Human patient diagnosed with LEMS and in need of treatment
Biomarker	Two NAT2 fast alleles
Preferred genotype	Two wild-type NAT2 alleles
Active ingredient	3,4-diaminopyridine or a pharmaceutically acceptable salt
Broad daily dose	About 30 mg to about 240 mg of 3,4-DAP
Principal commercial range	About 30 mg to about 100 mg
Administration	Optional or required divided doses, depending on the claim
Specific salt	3,4-DAP phosphate
Dosage forms	Scored tablets, tablet portions and aqueous suspensions

The claims do not cover all use of amifampridine in LEMS. They require the combination of LEMS treatment, a specified NAT2 genotype and a specified dose or administration format.

How do the independent claims differ?

Claims 1, 19 and 27 are the principal independent claims.

Independent claim	Distinguishing limitation
Claim 1	30 mg to 240 mg per day; divided doses are optional
Claim 19	30 mg to 100 mg per day; administration as divided doses is required
Claim 27	Amifampridine phosphate specifically; 30 mg to 100 mg equivalent 3,4-DAP dose; divided doses required

Claim 1 has the broadest dose range. Claim 19 is narrower because divided dosing is mandatory and the upper limit is 100 mg. Claim 27 is narrower still because it requires the phosphate salt.

How do the dependent claims narrow the patent scope?

Claims 2 through 18 narrow claim 1. Claims 20 through 26 narrow claim 19. Claim 28 narrows claim 27.

The most commercially relevant limitations are:

Claims 2 and 20: both NAT2 alleles are wild-type.
Claims 3 and 27: use of the phosphate salt.
Claims 4 through 6: daily doses of 30 mg to 100 mg, 30 mg to 80 mg, or 30 mg to 50 mg.
Claims 7 through 9 and 21: up to five divided doses, including three to four or two to three doses per day.
Claim 10: individual doses of approximately 10 mg, 15 mg, 20 mg, 25 mg or 30 mg.
Claims 11 and 12: scored tablets, including 10 mg tablets.
Claim 13: aqueous suspension.
Claims 14 through 18 and 22 through 26: fixed total daily doses of 30 mg, 50 mg, 60 mg, 80 mg or 100 mg.

The dependent claims create fallback positions. A challenge to the broad 30 mg to 240 mg range would not necessarily eliminate the narrower 30 mg to 50 mg or 30 mg to 100 mg claims.

What is the technical significance of the NAT2 limitation?

N-acetyltransferase 2 is a drug-metabolizing enzyme. NAT2 genotype can affect the rate at which certain compounds are acetylated and cleared. The patent uses the presence of two NAT2 fast alleles as a basis for selecting a higher or particular amifampridine dose.

The NAT2 limitation has two opposing effects:

It supports a targeted dosing rationale based on patient pharmacogenetics.
It creates a substantial infringement and proof requirement because the relevant genotype must be established for the treated patient.

A method claim generally requires proof that the patient satisfies the claimed genotype. A product label that merely states a dose range, without identifying or testing NAT2 status, may create a more difficult direct-infringement case. The commercial risk increases if labeling, prescribing information, clinical protocols or promotional materials instruct use in patients with two NAT2 fast alleles.

What doses and formulations are covered?

The patent covers most clinically relevant Firdapse-style dosing patterns within the 30 mg to 100 mg range.

Daily dose coverage

The express fixed-dose claims cover:

30 mg per day
50 mg per day
60 mg per day
80 mg per day
100 mg per day

The broader claims cover daily doses from approximately 30 mg to 240 mg. The “about” language may create a limited numerical tolerance around the stated endpoints, but the exact scope would depend on intrinsic evidence, prosecution history and claim construction.

Divided-dose coverage

The claims cover:

Up to five doses per day
Two to three doses per day
Three to four doses per day
Individual doses of approximately 10 mg, 15 mg, 20 mg, 25 mg or 30 mg

The claims can therefore reach common administration schedules such as 10 mg four times daily, 20 mg three times daily and other combinations that fall within the claimed daily total.

Tablet and suspension coverage

Claims 11 and 12 specifically cover scored tablets and 10 mg scored tablets. Claim 13 covers administration through an aqueous suspension.

These limitations are relevant to generic and alternative-product design. A manufacturer could face separate claim exposure depending on whether it uses:

A scored 10 mg tablet
A tablet capable of being divided into portions
A liquid suspension
Amifampridine phosphate rather than another pharmaceutically acceptable salt

When does US Patent 11,274,331 expire?

The patent has a June 5, 2035 nominal expiration date based on its earliest claimed priority date, subject to any applicable patent-term adjustment or other statutory adjustment recorded by the USPTO.

Milestone	Date or status
Earliest priority	June 5, 2014
Patent issued	March 15, 2022
Nominal expiration	June 5, 2035
Patent term basis	20 years from earliest non-provisional priority, subject to adjustment

The patent issued after FDA approval of Firdapse, which was approved on November 6, 2018. FDA regulatory exclusivity and patent exclusivity are separate. Approval of a generic or an abbreviated new drug application does not automatically remove the patent barrier.

What is the FDA and Orange Book status of Firdapse?

Firdapse is amifampridine phosphate, approved by FDA under NDA 208078 for adults and children six years of age and older with LEMS. FDA describes Firdapse as an oral product administered in divided doses, with a maximum recommended total daily dose of 80 mg in the approved labeling.[2]

Regulatory item	Status
Product	Firdapse
Active ingredient	Amifampridine phosphate
Sponsor	Catalyst Pharmaceuticals, Inc.
NDA	208078
FDA approval	November 6, 2018
Disease	Lambert-Eaton myasthenic syndrome
Dosage form	Oral tablets
FDA-labeled dosing	Divided doses, with a labeled maximum of 80 mg per day
Patent relevance	The patent’s 30 mg to 80 mg and divided-dose claims overlap the labeled regimen

The FDA Orange Book identifies patents and exclusivity information associated with approved drug products. Orange Book listing is important because an ANDA applicant may need to submit a Paragraph IV certification if the applicant contends that a listed patent is invalid, unenforceable or not infringed.[1]

The practical significance of US 11,274,331 depends on its current Orange Book listing, the listed use code, any pediatric or regulatory exclusivity, and the text of any Paragraph IV notice. Those elements can change through FDA updates, patent-term corrections, litigation and delisting.

When does Firdapse lose regulatory exclusivity?

Firdapse's regulatory exclusivity and patent term do not end on the same date.

FDA approval occurred in 2018. The product's market protection can arise from:

New chemical entity exclusivity, if applicable
Orphan-drug exclusivity
Pediatric exclusivity, if granted
Listed patents
Separate formulation or manufacturing patents

Firdapse was approved for a rare disease, and orphan-drug exclusivity is potentially important. Orphan exclusivity generally prevents FDA approval of the same drug for the same indication for seven years from approval, subject to statutory exceptions. That period is distinct from US 11,274,331 and would not extend the patent's expiration date.

The commercial barrier after regulatory exclusivity is likely to depend more heavily on Orange Book patents and Paragraph IV litigation than on the original FDA exclusivity period.

Which companies are challenging the 3,4-DAP market?

The principal US competitive products are Firdapse and Ruzurgi.

Product	Active ingredient	Sponsor	Regulatory position
Firdapse	Amifampridine phosphate	Catalyst Pharmaceuticals	FDA-approved for LEMS
Ruzurgi	Amifampridine	Jacobus Pharmaceutical	FDA-approved for pediatric patients with LEMS at approval

Ruzurgi generated significant litigation between Catalyst and Jacobus. Catalyst challenged Jacobus's product and regulatory position in federal court. The dispute involved the commercial and regulatory boundaries between the two amifampridine products, including patent and market-exclusivity issues. The litigation was not limited to the genotype-directed dosing claims in US 11,274,331.

A future generic entrant would face a different issue from the Ruzurgi dispute. An ANDA applicant would need to address listed patents, submit appropriate certifications and avoid inducing use covered by surviving method claims.

What Paragraph IV risks does US 11,274,331 create?

A Paragraph IV challenge would likely target one or more of four issues:

Lack of patentable distinction over known 3,4-DAP dosing.
Obviousness of selecting NAT2 fast metabolizers for a dose range.
Written-description or enablement support for the full 30 mg to 240 mg range and all claimed administration formats.
Infringement, particularly whether a proposed generic label requires treatment of patients with two NAT2 fast alleles.

The genotype limitation may make invalidity arguments more complex. A challenger could argue that NAT2-guided dosing was predictable from known pharmacokinetic principles or that the claims cover routine dose optimization. The patent owner would likely rely on pharmacokinetic differences, clinical results and the asserted relationship between NAT2 status and dose requirements.

Infringement may be the more significant issue. A generic label that omits NAT2 testing and does not instruct treatment of patients with two fast alleles could reduce literal inducement exposure. A label that reproduces the patented dosing instructions for the full LEMS population could create greater risk.

How strong is the patent estate for amifampridine?

The estate should be analyzed in layers rather than by counting one patent.

Estate layer	Commercial function	Relevance to US 11,274,331
Active-ingredient patents	Protect the molecule or salt	May be expired or limited because 3,4-DAP is an old compound
Composition patents	Protect tablets, excipients or salt forms	Can block formulation substitution
Method-of-use patents	Protect LEMS treatment	'331 is a patient-selection and dosing patent
Pharmacogenomic patents	Protect genotype-linked treatment	Central feature of '331
Manufacturing patents	Protect synthesis, purification or scale-up	May constrain supply without directly blocking sale
Regulatory exclusivity	Blocks FDA approval for a defined period	Separate from patent rights

The '331 patent is commercially stronger against a product that copies the approved Firdapse dosing approach and expressly targets NAT2 fast metabolizers. It is weaker against a product that:

Uses a non-overlapping dosage regimen;
Avoids the claimed genotype instruction;
Uses a different dosage form outside the asserted dependent claims;
Has a label that does not encourage the patented method; or
Prevails on invalidity grounds.

The absence of a biosimilar pathway is significant. Amifampridine is a small molecule, not a biologic. Competitors would generally use the ANDA pathway, not a biosimilar application under the Public Health Service Act.

What generic launch scenarios exist?

Scenario 1: Paragraph IV challenge

A generic applicant files an ANDA with a Paragraph IV certification against US 11,274,331. The patent owner may bring an infringement action within 45 days, potentially triggering a 30-month stay of final FDA approval under the Hatch-Waxman framework.[3]

Scenario 2: Section viii carve-out

The applicant removes the patented genotype-directed use from its labeling through a section viii statement. This strategy depends on whether the remaining label still encourages the claimed method. It is more difficult if the commercial product is intended to be used at the same divided doses and in the same LEMS population.

Scenario 3: Post-expiration launch

The generic accepts the patent and launches after expiration, unless another listed patent or regulatory exclusivity remains effective.

Scenario 4: Non-infringing product design

A competitor may attempt to avoid particular dependent claims by changing tablet scoring, dose packaging, suspension presentation or dosing instructions. That approach does not eliminate exposure under broader independent claims if the product is still used according to the claimed genotype and dose limitations.

What manufacturing and geographic barriers remain?

US 11,274,331 is a US method patent. It does not, by itself, block manufacturing outside the United States unless the conduct creates liability under other patent provisions or involves importation of a product made by a patented process.

Geographic exposure differs by activity:

Activity	Potential relevance
Treatment of US patients	Direct method-of-treatment exposure
US prescribing or promotion	Potential inducement exposure
Importation into the US	Product or process patent exposure may apply
Foreign manufacture for foreign sale	Generally outside the territorial scope of a US treatment claim
Foreign treatment	Requires corresponding foreign patent rights
US clinical trials	May implicate the research exemption and other statutory provisions

The strongest geographic protection is therefore tied to US patient treatment, prescribing, labeling and commercial distribution.

What patent litigation affects Firdapse and Ruzurgi?

The major known dispute involved Catalyst Pharmaceuticals and Jacobus Pharmaceutical over amifampridine products. The case was commercially important because both products targeted LEMS and because orphan-drug exclusivity and patent rights shaped market access.

US 11,274,331 should not be treated as automatically adjudicated merely because related Firdapse or Ruzurgi litigation occurred. Patent-by-patent analysis requires identifying whether the patent was asserted, whether claim construction occurred, whether a validity ruling issued and whether a settlement or license addressed the patent.

No broad public license should be inferred from the existence of a commercial collaboration or a product supply arrangement. A settlement may contain field-of-use restrictions, launch dates, covenants not to sue, authorized-generic provisions or confidential terms.

Key Takeaways

US 11,274,331 is a pharmacogenomic method patent for treating LEMS patients with two NAT2 fast alleles.
Claim 1 covers approximately 30 mg to 240 mg of 3,4-DAP per day.
Claims 19 and 27 focus on the commercially important 30 mg to 100 mg divided-dose regimen.
Claim 27 specifically covers amifampridine phosphate.
The patent reaches scored tablets, 10 mg tablets, aqueous suspensions and specified divided-dose schedules.
The nominal expiration date is June 5, 2035, subject to recorded patent-term adjustment.
Firdapse is FDA-approved under NDA 208078 and uses amifampridine phosphate in divided doses.
A generic applicant would likely evaluate Paragraph IV, section viii and post-expiration strategies.
The NAT2 limitation may strengthen the patent's technical rationale while complicating infringement proof.
No biosimilar pathway applies because amifampridine is a small-molecule drug.
The patent is one layer of the Firdapse estate; composition, formulation, manufacturing and other method patents must be evaluated separately.

FAQs

Does US 11,274,331 cover all Firdapse prescriptions?

No. It requires a LEMS patient with two NAT2 fast alleles and a claimed dose or administration format.

Does the patent cover amifamidine or only amifampridine phosphate?

The independent claims cover 3,4-DAP and pharmaceutically acceptable salts. Claim 27 specifically requires the phosphate salt.

Can a generic avoid the patent by using a different salt?

Possibly, but not automatically. Claims 1 and 19 cover a pharmaceutically acceptable salt broadly. A different salt would need to be evaluated against the claim language and the equivalent-dose limitation.

Does a 100 mg daily dose fall within the patent?

Yes. Claims 4, 18, 19 and 26 expressly cover approximately 100 mg per day, subject to the other claim limitations.

Is NAT2 testing required by the Firdapse FDA label?

The patent claims require the patient to have two NAT2 fast alleles. FDA labeling and patent claim scope are separate questions, so the approved label must be compared with the patent claims and any current Orange Book use code.

References

U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.accessdata.fda.gov/scripts/cder/ob/
U.S. Food and Drug Administration. (2024). Firdapse (amifampridine phosphate) prescribing information. Catalyst Pharmaceuticals, Inc.
U.S. Patent and Trademark Office. (2022). U.S. Patent No. 11,274,331: Methods of treating Lambert-Eaton myasthenic syndrome. Issued March 15, 2022.
U.S. Food and Drug Administration. (2018). FDA approves first drug for Lambert-Eaton myasthenic syndrome. https://www.fda.gov/
U.S. Food and Drug Administration. (2019). Ruzurgi (amifampridine) prescribing information. Jacobus Pharmaceutical Company, Inc.
U.S. Congress. (1984). Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585.

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Catalyst Pharms	FIRDAPSE	amifampridine phosphate	TABLET;ORAL	208078-001	Nov 28, 2018		RX	Yes	Yes	11,274,331	⤷ Start Trial				METHOD OF TREATING LAMBERT-EATON MYASTHENIC SYNDROME WITH AMIFAMPRIDINE	⤷ Start Trial
>Applicant	>Tradename	>Generic Name	>Dosage	>NDA	>Approval Date	>TE	>Type	>RLD	>RS	>Patent No.	>Patent Expiration	>Product	>Substance	>Delist Req.	>Patented / Exclusive Use	>Submissiondate

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Canada	2840591	⤷ Start Trial
World Intellectual Property Organization (WIPO)	2013003708	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 11,274,331

Which drugs does patent 11,274,331 protect, and when does it expire?

Summary for Patent: 11,274,331