Details for Patent: 9,421,333

Which drugs does patent 9,421,333 protect, and when does it expire?

Patent 9,421,333 protects OTREXUP and is included in one NDA.

This patent has fourteen patent family members in eight countries.

Summary for Patent: 9,421,333

Title:	Hazardous agent injection system
Abstract:	Injection systems comprising a powered injector and one or more hazardous agents are disclosed.
Inventor(s):	Paul K. WOTTON, Peter L. Sadowski, John W. Hayes
Assignee:	Assertio Specialty Pharmaceuticals LLC
Application Number:	US14/582,411
Patent Claim Types: see list of patent claims	Use; Dosage form;

United States Patent 9,421,333: Methotrexate Powered-Injection System Patent Scope and Landscape

U.S. Patent No. 9,421,333 protects a methotrexate delivery system that combines a powered injector with specified dose, concentration, injection-speed, pressure, device-construction and pharmacokinetic-equivalence requirements. The patent is directed primarily to subcutaneous methotrexate administration using an autoinjector or jet injector, not to methotrexate as a molecule or to conventional vial-and-syringe products.

The commercially relevant risk is highest for an automated methotrexate injector that delivers approximately 0.02 to 4.0 mL at 7.5 to 150 mg/mL in less than five seconds and is designed to produce pharmacokinetic results comparable to a hand-powered syringe. Conventional methotrexate injections, oral methotrexate, and products that do not practice the powered-injector limitations generally fall outside the literal scope of claim 1.

What is U.S. Patent 9,421,333?

U.S. Patent 9,421,333 is titled "Hazardous Agent Injection System." It covers a powered injection platform configured to administer methotrexate subcutaneously. The patent treats methotrexate as a hazardous agent and links the drug formulation, injector mechanics and resulting pharmacokinetic profile in a single claim structure. [1]

Field	Patent 9,421,333
Patent number	US 9,421,333 B2
Title	Hazardous Agent Injection System
Technology	Powered subcutaneous methotrexate injection
Principal dosage form	Injectable methotrexate
Delivery devices	Powered injector; dependent claim adds jet injector
Administration route	Subcutaneous
Core dose volume	About 0.02 to about 4.0 mL
Core concentration	About 7.5 to about 150 mg/mL
Injection duration	Less than about 5 seconds
Key performance limitation	Cmax, Tmax or AUC confidence interval between about 80% and 125% of hand-syringe delivery
Therapeutic method	Treatment of specified autoimmune diseases
Patent status	Unexpired U.S. patent term during the relevant commercial period
Orange Book relevance	Relevant to an approved methotrexate drug-device product if listed for that product

The patent should be analyzed as a combination patent. A product generally must satisfy the complete combination of limitations in an asserted claim. The presence of methotrexate alone, or the presence of an autoinjector alone, does not establish infringement of claim 1.

What does claim 1 of Patent 9,421,333 cover?

Claim 1 has four principal groups of limitations:

1. A methotrexate dose and concentration.
2. A powered injector with specified structural components.
3. Rapid delivery through an injection outlet for subcutaneous administration.
4. Pharmacokinetic comparability to a hand-powered syringe.

Drug and dose limitations

Claim 1 requires methotrexate:

• In an amount from about 0.02 mL to about 4.0 mL.
• At a concentration from about 7.5 mg/mL to about 150 mg/mL.

These ranges are broad. They encompass many commercial injectable methotrexate presentations, including low-volume, high-concentration subcutaneous products. The claim does not require a particular salt, excipient, preservative, container material or methotrexate formulation beyond the stated concentration and delivery requirements.

The term "about" creates a potential claim-construction issue. Its practical scope depends on intrinsic evidence, prosecution history, technical context and the court's interpretation. A competing product near a numerical boundary cannot be assessed solely by comparing label values.

Powered-injector limitations

The powered injector must include:

• A container configured to contain methotrexate.
• An injection outlet member associated with the container.
• A firing mechanism.
• An energy source that powers the firing mechanism.
• A trigger mechanism that activates the firing mechanism.

This language reaches more than one specific commercial autoinjector architecture. The energy source can be a spring under claim 5, but claim 1 itself is not limited to spring-powered systems. Depending on the construction, the language may encompass mechanical, pneumatic or other powered firing systems.

A manually depressed syringe plunger is unlikely to satisfy the powered-injector limitation without a separate energy source and firing mechanism. A battery-driven device, compressed-gas injector or spring-loaded autoinjector presents a closer risk profile.

Delivery-speed limitation

The injector must eject methotrexate in less than about five seconds. Claim 4 narrows this requirement by requiring a flow rate of at least about 0.5 mL/sec.

The independent claim's five-second limitation applies to the injection event. It does not expressly require a particular needle gauge, needle penetration depth or exact flow profile. A device could therefore present literal-risk questions even if its flow rate is not constant throughout administration.

Pharmacokinetic limitation

Claim 1 requires that one or more confidence intervals for:

• Cmax;
• Tmax; or
• AUC,

fall between about 80% and about 125% of the measured confidence interval for the same methotrexate dose delivered by a hand-powered syringe.

This is the most technically distinctive part of the claim. It does not merely require that the injector deliver the labeled dose. It requires a pharmacokinetic relationship between powered delivery and hand-syringe delivery.

The wording raises several issues:

• The comparator is the same dose administered by a hand-powered syringe.
• The comparison concerns confidence intervals rather than only point estimates.
• The claim uses "one or more" of Cmax, Tmax and AUC.
• The 80%-125% range resembles the conventional bioequivalence interval but is applied here to a device-comparison result.
• The relevant study population, sampling schedule, statistical model and confidence level may affect infringement analysis.

A product dossier containing only dose-delivery testing may not resolve this limitation. A technical analysis would ordinarily examine comparative pharmacokinetic studies, device validation data and the statistical definition used for the confidence intervals.

How do the dependent claims narrow the patent scope?

Claim	Added limitation	Commercial significance
2	Powered injector is a jet injector	Covers a needle-free or jet-delivery configuration, subject to the other claim 1 limitations
3	Injection-assisting needle is 26 gauge or higher gauge number	Reaches relatively fine-gauge needles, including gauges numerically above 26
4	Flow rate of at least about 0.5 mL/sec	Creates a measurable delivery-performance limitation
5	Energy source comprises a spring	Targets spring-powered autoinjectors
6	Energy source generates at least about 80 psi in the container	Adds a pressure threshold
7	Outer housing for user handling	Narrows the device architecture
8	Safety member at proximal end of housing	Adds a safety-feature limitation
9	Safety member is removably affixed	Requires removable attachment
10	Tabs and matching openings create a press-fit	Covers a specific housing-and-safety-member structure
11	Container and outlet member comprise a syringe	Targets syringe-based injector assemblies
12	Syringe sleeve abuts the syringe wall to minimize movement	Protects stabilization of the syringe during firing
13	Method of treating a patient with an autoimmune disease	Method claim incorporating claim 1
14	Specifies listed autoimmune diseases	Narrows claim 13 to enumerated indications

Claims 7 through 12 provide mechanical fallback positions. They are particularly relevant to a device incorporating a prefilled syringe, outer housing, removable safety member and syringe sleeve. Claims 2 through 6 provide separate fallback positions based on delivery mode, needle gauge, flow rate, spring actuation and pressure.

What formulations and devices are protected by Patent 9,421,333?

The patent is strongest against products combining injectable methotrexate with a powered delivery device. It is less relevant to drug products that are sold without the injector or that use manual administration.

Products presenting higher claim risk

A product is more likely to fall within claim 1 if it has all or substantially all of the following characteristics:

• Methotrexate in the claimed volume and concentration ranges.
• A prefilled syringe or drug container.
• A spring-loaded or otherwise powered actuator.
• Subcutaneous delivery.
• Administration in less than five seconds.
• A trigger-activated firing mechanism.
• Comparative PK data showing the required Cmax, Tmax or AUC relationship.
• A housing and syringe-stabilization structure matching claims 7 through 12.

Products presenting lower claim risk

The following products are less likely to satisfy claim 1 on its face:

• Methotrexate tablets.
• Methotrexate vials intended for manual withdrawal.
• A manually operated syringe.
• An injector delivering intramuscularly or intravenously rather than subcutaneously.
• A device administering outside the claimed concentration or volume ranges.
• A powered device that does not meet the delivery-time or pharmacokinetic limitation.
• A product using a different drug rather than methotrexate.

A design-around based only on changing the spring, housing or needle may be insufficient because claim 1 covers the broader combination. A stronger design-around would target a limitation in the independent claim, particularly the power source, route, delivery time, dose range or comparative PK requirement.

When does Patent 9,421,333 lose exclusivity?

The patent's ordinary U.S. term is tied to its earliest effective nonprovisional filing date, subject to patent-term adjustment and any applicable patent-term extension. Public patent records identify the patent as an issued continuation-family patent associated with the hazardous-agent injector technology. The expected ordinary term falls in the late 2020s, with October 2027 commonly identified as the projected expiration date for the relevant family term. [1]

Exclusivity issue	Assessment
Patent expiration	Projected late 2027, commonly reported as October 2027 for the family term
Patent-term adjustment	Must be confirmed from the USPTO face or Patent Center record
Patent-term extension	No established drug PTE should be assumed without an FDA determination
Regulatory exclusivity	Separate from patent term
Device exclusivity	No independent FDA exclusivity period equivalent to drug exclusivity
Generic entry	Depends on Orange Book listings, ANDA certifications and litigation outcomes

Patent expiration does not automatically authorize commercial launch if another patent covers the same product, formulation, device, method of use or manufacturing process.

What is the Orange Book status of methotrexate autoinjector products?

Methotrexate autoinjectors are combination products from a patent-risk perspective. The drug component is regulated through an approved NDA, while the delivery system can be central to listed patent protection.

Otrexup is a subcutaneous methotrexate injection product associated with Antares Pharma. Rasuvo is a subcutaneous methotrexate autoinjector associated with Medac. RediTrex is another commercial methotrexate injection product using a prefilled delivery system. FDA product records and Orange Book patent listings should be evaluated product by product because a patent may be listed for one NDA and not another. [2][3][4]

The key Orange Book questions are:

• Whether U.S. Patent 9,421,333 is listed against the relevant NDA.
• Whether the listing covers the drug product, delivery device or method of use.
• Whether a later generic applicant must submit a Paragraph IV certification.
• Whether the NDA holder has submitted a patent-use code for any method-of-use listing.
• Whether the patent has been delisted, expired or replaced by a continuation patent.

An Orange Book listing does not establish patent validity. It determines the regulatory pathway for an ANDA applicant and can trigger the statutory 30-month stay if the NDA holder timely files patent litigation after a Paragraph IV notice. [2]

How do Paragraph IV challenges and generic launch risks apply?

A generic or follow-on applicant seeking approval for a methotrexate product associated with a powered injector may face several certification routes:

Certification	Effect
Paragraph I	No relevant patent information is listed
Paragraph II	Listed patent has expired
Paragraph III	Applicant will wait until patent expiration
Paragraph IV	Applicant asserts that the patent is invalid, unenforceable or not infringed
Section viii statement	Applicant omits a patented method of use, where permitted

For Patent 9,421,333, a Paragraph IV strategy would likely focus on:

• Lack of a powered injector.
• Failure to meet the less-than-five-second limitation.
• Failure to satisfy the dose or concentration range.
• Lack of subcutaneous administration.
• Failure to meet the PK confidence-interval limitation.
• Indefiniteness or enablement challenges involving the PK limitation.
• Prior art directed to methotrexate autoinjectors, spring-powered injectors or rapid subcutaneous injection.

A generic methotrexate vial or manually administered prefilled syringe may avoid the patent by using a product configuration outside the claim. A generic autoinjector that copies the relevant device architecture would face greater litigation exposure.

Which companies compete with the patented technology?

Company	Product or platform	Relevance to Patent 9,421,333
Antares Pharma / Halozyme	Otrexup and related injection technology	Closely associated with the commercial technology and patent family
Medac	Rasuvo methotrexate autoinjector	Competing powered subcutaneous methotrexate product
Zydus or other injectable manufacturers	Methotrexate injectable products	Risk depends on whether the product uses a powered delivery system
Generic manufacturers	Vials, syringes and injectable presentations	Usually lower risk if no powered injector is supplied
Device manufacturers	Spring-loaded, pneumatic and disposable autoinjector platforms	Potential technology suppliers or design-around sources

The principal competitive distinction is between drug-only methotrexate products and integrated drug-device products. Patent 9,421,333 is directed to the latter category.

What patent litigation and settlement issues affect the patent?

No litigation or settlement conclusion should be inferred solely from the existence of the patent. The relevant records are:

• U.S. district court complaints involving Patent 9,421,333.
• ANDA litigation under the Hatch-Waxman Act.
• Paragraph IV notice letters and statutory filing dates.
• Consent judgments and settlement agreements.
• Patent-term and Orange Book records.
• Any covenant not to sue or license agreement covering a methotrexate injector.

A settlement could permit an authorized generic, delayed launch, licensed device supply or launch on a date earlier than patent expiration. Settlement terms may remain confidential except for required antitrust filings, court orders or public-company disclosures.

The commercial review should distinguish between:

1. Litigation over the methotrexate drug product.
2. Litigation over the injector mechanism.
3. Litigation over a formulation or container.
4. Litigation over a method of treating rheumatoid arthritis or another autoimmune disease.
5. Litigation involving a continuation or divisional patent rather than Patent 9,421,333 itself.

How strong is the patent estate for methotrexate autoinjectors?

Patent 9,421,333 has meaningful but concentrated scope.

Strengths

• It combines drug, device and performance limitations.
• The methotrexate concentration and volume ranges cover common commercial presentations.
• The dependent claims reach common autoinjector components, including springs, housings, safety members and syringe sleeves.
• The PK limitation can distinguish a fast powered injection from a conventional syringe if supported by reliable comparative data.
• The method claims connect the device to clinically important autoimmune indications.

Vulnerabilities

• The claim is technically dense and may be difficult to prove without detailed device and PK evidence.
• The 80%-125% confidence-interval language may create interpretation and enablement disputes.
• Many conventional methotrexate products do not use powered injectors.
• A competitor may avoid the claims by changing the delivery architecture or demonstrating that a key limitation is absent.
• The patent does not independently protect methotrexate, the general use of methotrexate in autoimmune disease or every prefilled syringe.

The estate is strongest when Patent 9,421,333 is read together with related continuation, device, formulation and method-of-use patents. Freedom-to-operate analysis should not stop with this patent number.

What generic launch scenarios exist?

Scenario 1: Drug-only generic launch

A manufacturer launches vials or manually administered syringes. This scenario presents the lowest direct risk under the asserted claims because the product may lack a powered injector, firing mechanism and energy source.

Scenario 2: Prefilled manual syringe

The product contains methotrexate in a syringe but requires manual plunger activation. Claim 11 alone does not capture every syringe. Claim 1 still requires a powered injector, so the absence of powered actuation is potentially dispositive.

Scenario 3: Competing spring-powered autoinjector

This is the highest-risk scenario. The applicant would need to evaluate claims 1, 5, 6 and 7 through 12, together with related family patents and Orange Book listings.

Scenario 4: Alternative powered injector

A battery, gas or motor-driven device may avoid the spring limitation in claim 5 but could still fall within claim 1. Changing the energy source alone is not a complete design-around.

Scenario 5: Launch after patent expiration

A post-expiration launch avoids the expired patent, subject to any unexpired continuation, formulation, manufacturing or method-of-use patents and applicable regulatory exclusivity.

Key Takeaways

• Patent 9,421,333 protects a powered subcutaneous methotrexate injection system, not methotrexate generally.
• Claim 1 requires a specific combination of drug range, powered injector structure, rapid delivery and comparative pharmacokinetic performance.
• The patent is most relevant to autoinjectors, jet injectors and prefilled syringe-based devices.
• Claims 5 through 12 create narrower protection for spring actuation, pressure, housing, safety and syringe-stabilization structures.
• Claims 13 and 14 extend the patent to treatment methods for rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, lupus, polymyositis, dermatomyositis, Wegener's granulomatosis, polyarteritis nodosa and vasculitis.
• Conventional methotrexate vials and manually operated syringes generally present lower risk under the supplied claims.
• The projected family term reaches the late 2020s, commonly identified as October 2027, subject to official term adjustment.
• Orange Book status, continuation patents, Paragraph IV filings and settlement agreements must be reviewed at the NDA and family level.
• The strongest validity and infringement issues concern the pharmacokinetic confidence-interval limitation and the definition of a powered injector.

FAQs About U.S. Patent 9,421,333

Does Patent 9,421,333 cover oral methotrexate?

No. The claims require methotrexate delivered through an injection system, with claim 1 specifying subcutaneous delivery. Oral tablets do not satisfy those delivery limitations.

Does a prefilled methotrexate syringe automatically infringe?

No. A prefilled syringe alone does not establish infringement. The independent claim also requires a powered injector, firing mechanism, energy source, trigger mechanism, rapid delivery and the specified pharmacokinetic relationship.

Can a battery-powered methotrexate injector avoid the patent?

Not necessarily. Claim 5 is limited to a spring energy source, but claim 1 broadly requires an energy source. A battery-powered injector could avoid claim 5 while still presenting risk under claim 1.

Are jet injectors covered by the patent?

Yes, claim 2 expressly narrows the invention to a jet injector. The jet injector must still satisfy the limitations inherited from claim 1.

Does patent expiration eliminate all methotrexate autoinjector launch risk?

No. A launch may remain exposed to unexpired continuation patents, formulation patents, manufacturing patents, method-of-use patents or separate device patents. FDA regulatory exclusivity and Orange Book listings must also be reviewed.

References

1. United States Patent and Trademark Office. (2016). Hazardous agent injection system (U.S. Patent No. 9,421,333 B2).
2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
3. U.S. Food and Drug Administration. (2024). Otrexup: Prescribing information and Drugs@FDA records.
4. U.S. Food and Drug Administration. (2024). Rasuvo and methotrexate injection product records.
5. U.S. Food and Drug Administration. (2024). Abbreviated new drug application regulations and patent certifications under 21 C.F.R. § 314.107.

Drugs Protected by US Patent 9,421,333

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Cosette	OTREXUP	methotrexate	SOLUTION;SUBCUTANEOUS	204824-005	Nov 7, 2014		DISCN	Yes	No	9,421,333		Y			SUBCUTANEOUS INJECTION OF METHOTREXATE
Cosette	OTREXUP	methotrexate	SOLUTION;SUBCUTANEOUS	204824-001	Oct 11, 2013		DISCN	Yes	No	9,421,333		Y			SUBCUTANEOUS INJECTION OF METHOTREXATE
Cosette	OTREXUP	methotrexate	SOLUTION;SUBCUTANEOUS	204824-006	Mar 24, 2016		DISCN	Yes	No	9,421,333		Y			SUBCUTANEOUS INJECTION OF METHOTREXATE
Cosette	OTREXUP	methotrexate	SOLUTION;SUBCUTANEOUS	204824-002	Oct 11, 2013		DISCN	Yes	No	9,421,333		Y			SUBCUTANEOUS INJECTION OF METHOTREXATE
Cosette	OTREXUP	methotrexate	SOLUTION;SUBCUTANEOUS	204824-007	Mar 24, 2016		DISCN	Yes	No	9,421,333		Y			SUBCUTANEOUS INJECTION OF METHOTREXATE

International Family Members for US Patent 9,421,333

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2010226442
Canada	2755779
China	102612381
European Patent Office	2408493
European Patent Office	4427737