US Patent 9,855,215: Methotrexate Oral Solution Claims, Scope, Expiration, and Patent Landscape

U.S. Patent No. 9,855,215 protects a liquid oral methotrexate formulation centered on four technical elements: a pharmaceutically acceptable methotrexate salt, purified water, a pH-adjusting buffer system maintaining pH 6.0 to 7.0, and at least one preservative, flavoring agent, or sweetener. The patent is directed to a finished oral solution rather than methotrexate as an active pharmaceutical ingredient.

The strongest commercial embodiment is a methotrexate disodium oral solution buffered near pH 6.25 and containing a preservative and flavor or sweetener. The patent does not broadly cover every oral methotrexate product. A competing product must satisfy the limitations of at least one claim, either literally or under the doctrine of equivalents.

What does U.S. Patent 9,855,215 protect?

The independent claim protects a composition that contains:

Required element	Claim 1 requirement
Active ingredient	A pharmaceutically acceptable salt of methotrexate
Dosage form	Composition for oral administration
Vehicle	Purified water
pH control	One or more buffer agents
pH range	pH 6.0 to 7.0
Additional excipient	At least one preservative, flavoring compound, or sweetening agent
Claim format	“Consisting of”

The claim is composition-focused. It does not require a particular indication, dosing schedule, patient population, manufacturing process, container, or administration device.

The claim also excludes several common alternatives from its literal scope. A formulation using methotrexate in a form that is not a pharmaceutically acceptable salt may fall outside the claim. A formulation outside pH 6.0 to 7.0 may also avoid literal infringement, although pH measurement, manufacturing tolerances, and equivalents would matter in litigation.

How do the dependent claims narrow the patent scope?

Claims 2 through 12 create progressively narrower protection.

Methotrexate salt limitation

Claim 2 limits the active ingredient to methotrexate disodium. This is commercially important because methotrexate disodium is the likely active form in the covered oral liquid formulation.

A product using methotrexate disodium would satisfy this limitation if all limitations of claim 1 are also met. Claim 2 does not independently protect methotrexate disodium in every formulation. It remains dependent on the oral, aqueous, buffered, pH-controlled composition in claim 1.

pH limitations

The pH hierarchy is:

Claim	pH range
Claim 1	6.0 to 7.0
Claim 3	6.1 to 6.5
Claim 4	6.10 to 6.40, based on 6.25 ± 0.15

Claim 4 is the narrowest pH claim and is likely directed to the preferred formulation window. A formulation at pH 6.25 would fall within claims 1, 3, and 4, assuming the remaining limitations are met.

A product at pH 6.05 could fall within claim 1 but outside claims 3 and 4. A product at pH 6.50 could fall within claim 3 depending on claim construction and measurement convention, but it would generally be outside the literal range of claim 4 if the upper endpoint is treated as 6.40.

Buffer limitations

Claim 5 lists individual buffer agents, including:

Citric acid
Citric acid monohydrate
Sodium citrate
Sodium dihydrogen phosphate
Disodium hydrogen phosphate
Trometamol, also known as Tris
Hydrochloric acid
Ascorbic acid
Sodium ascorbate
Corresponding potassium salts

Claim 6 requires two or more buffer agents forming a buffer system. Claim 7 specifies buffer combinations, including citrate, phosphate, Tris, and ascorbate systems. Claim 8 narrows the combination to citric acid monohydrate and disodium hydrogen phosphate.

The buffer claims create several design-around paths. A formulation may attempt to use a different pH-adjusting system, no buffer within the claimed meaning, or a pH-control excipient not included in the listed combinations. The strength of such a design-around depends on whether claim 1 is construed broadly enough to cover the alternative buffer and whether a dependent claim is asserted.

Buffer strength

Claim 9 requires a buffer strength of 2 to 200 millimolar, with an optional narrower range of 2 to 20 millimolar.

The “optionally” language may create a claim-construction issue. The 2 to 200 millimolar range is the principal limitation. The 2 to 20 millimolar range is narrower and may be treated as an additional disclosed embodiment rather than a mandatory limitation of every claim 9 formulation.

Preservatives

Claim 10 lists:

Sodium methyl hydroxybenzoate
Sodium ethyl hydroxybenzoate
Sodium propyl hydroxybenzoate
Sodium benzoate
Potassium sorbate

These excipients are relevant to multidose oral liquids because microbial preservation is a central formulation requirement. A product using a different preservative could avoid claim 10 but could still fall within claim 1 if it uses a preservative not listed in claim 10.

Flavoring and sweetening agents

Claim 11 lists sucralose, acesulfame potassium, other water-soluble sweeteners, and Raspberry Flavour 545742E.

The phrase “any other water soluble sweetener” materially expands the practical scope of claim 11 beyond the named compounds. It may also create an indefiniteness or written-description issue if the patent specification does not adequately support the full class.

Strength and dose limitations

Claim 12 covers:

2.5 mg per 5 mL, equivalent to 0.5 mg/mL
5 mg per 5 mL, equivalent to 1 mg/mL
10 mg per 5 mL, equivalent to 2 mg/mL
A broader range of 0.05 mg/mL to 20 mg/mL

The broad concentration range covers many possible oral methotrexate solutions. It also covers the three express concentrations. A product containing 2 mg/mL methotrexate would fall within claim 12 if it satisfies the composition and pH requirements of claim 1.

What are the principal claim-construction issues?

What does “consisting of” mean in the patent?

Claim 1 uses “consisting of,” which generally closes the claimed composition to additional ingredients that materially alter the basic and novel characteristics of the formulation. Incidental components, impurities, residual solvents, and excipients that do not materially alter the claimed characteristics may not necessarily avoid infringement.

The closed transitional language is significant. A competing product with an additional active ingredient, a different functional excipient, or a materially different formulation architecture may argue that it does not meet the claim.

Does pH need to be measured in the finished product?

The claim refers to the pH “of the composition.” The relevant value would ordinarily be measured in the finished aqueous formulation using an accepted analytical method. A product manufactured within the claimed range but released outside the range could raise separate infringement and product-quality questions.

Are the listed buffers exhaustive?

For claim 5 and the specific dependent claims, the listed buffer agents and combinations are important. Claim 1, however, refers more generally to “one or more buffer agents.” A formulation could therefore infringe claim 1 while avoiding a particular dependent claim by using a buffer not named in claim 5 or claim 7.

What is the patent’s expected expiration date?

The patent has a reported priority framework associated with a 2012 priority filing and a resulting patent term that extends into 2033. The expected U.S. expiration date is July 4, 2033, subject to confirmation of the patent’s terminal disclaimer, patent-term adjustment, patent-term extension, and any post-grant status in USPTO records.[1]

The patent issued on January 2, 2018. The issue date does not determine expiration for a modern utility patent. The relevant term is generally 20 years from the earliest effective nonprovisional or international filing date, subject to statutory adjustments under 35 U.S.C. §§ 154 and 156.

Event	Date or status
Earliest reported priority	July 4, 2012
U.S. patent	9,855,215
Issue date	January 2, 2018
Expected expiration	July 4, 2033
Patent type	Formulation composition patent
Patent-term extension	No extension is identified in the cited public FDA materials

What is the FDA and Orange Book status of the patent?

The patent is associated with the regulatory category of oral methotrexate solution products, including Jylamvo, a methotrexate oral solution product approved by the FDA.[2] FDA product labeling identifies methotrexate oral solution as a prescription product for conditions including rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, and certain neoplastic diseases, depending on the specific product label.[3]

The Orange Book is the principal FDA source for patents submitted for approved drug products. Patent listing status can change through sponsor submissions, FDA review, delisting, expiration, or corrections. U.S. Patent 9,855,215 should therefore be reviewed against the current Orange Book entry for the applicable methotrexate oral solution NDA rather than assumed to cover every methotrexate product.[4]

The patent’s composition claims are more relevant to an oral solution NDA than to methotrexate tablets, injectable products, or extemporaneously compounded formulations.

Does the patent create Paragraph IV risk for generic methotrexate oral solutions?

A generic applicant seeking approval of a product that references an NDA with a listed patent may address the patent through a Paragraph IV certification under the Hatch-Waxman Act. The applicant would assert that the patent is invalid, unenforceable, or not infringed.

The principal Paragraph IV positions would likely include:

The proposed formulation does not contain the claimed methotrexate salt.
The finished product has a pH outside the claimed range.
The product uses a nonclaimed buffer system.
The product does not contain a claimed preservative, flavoring compound, or sweetener.
The product includes additional ingredients inconsistent with the “consisting of” limitation.
The patent claims are obvious over prior methotrexate oral solutions and conventional pharmaceutical buffer systems.
Broad terms such as “any other water soluble sweetener” lack adequate written-description support or are indefinite.
The asserted claims are not infringed because the applicant’s formulation falls outside the relevant pH or concentration range.

A formulation applicant may also seek a Paragraph III certification and defer launch until patent expiration. The commercial choice depends on the estimated litigation cost, the strength of the noninfringement position, the value of an early launch, and the scope of the reference product’s regulatory exclusivity.

What patent litigation or settlement agreements affect U.S. Patent 9,855,215?

The materials provided do not establish a reported federal patent case, Paragraph IV litigation, or settlement agreement specifically involving U.S. Patent 9,855,215. FDA Orange Book records generally do not provide a complete litigation history, and an absence from an Orange Book entry is not proof that no dispute has occurred.

No biosimilar pathway applies. Methotrexate is a chemically synthesized small molecule, so competing products would generally proceed through an ANDA, 505(b)(2) application, or an independent NDA rather than the biologics license application and biosimilar framework.

How strong is the patent estate for methotrexate oral solution products?

The patent has meaningful protection against a close copy of the covered formulation, particularly a product with the following profile:

Methotrexate disodium
Purified water
pH approximately 6.25
Citric acid monohydrate and disodium hydrogen phosphate
A listed preservative
Raspberry flavor or a water-soluble sweetener
Methotrexate concentration within the claim 12 range

Its strength is lower against a product designed around different technical parameters. The patent does not claim every methotrexate oral formulation, every methotrexate dosage form, or every method of treating rheumatoid arthritis or cancer with methotrexate.

The broadest vulnerability is claim 1. Its pH range and general buffer requirement provide meaningful breadth, but the “consisting of” language and the requirement for a preservative, flavoring compound, or sweetener narrow the formulation universe. Claims 4, 8, 10, and 11 are narrower and easier to avoid, but they may provide stronger protection against a product matching the preferred formulation.

How does U.S. Patent 9,855,215 compare with competing methotrexate products?

Product category	Typical regulatory route	Relevance to Patent 9,855,215
Methotrexate tablets	ANDA or NDA	Generally outside the liquid composition claims
Injectable methotrexate	ANDA or NDA	Outside the oral aqueous composition claims
Methotrexate oral solution	NDA, ANDA, or 505(b)(2)	Principal infringement and Paragraph IV risk
Compounded oral liquid	State and federal compounding framework	Commercial and enforcement analysis depends on formulation and use
Jylamvo	Approved oral solution product	Closely aligned with the claimed formulation category
Xatmep	Approved oral solution product	Competing oral solution; patent relevance depends on formulation composition and NDA listings

Jylamvo and Xatmep are competing oral methotrexate solutions, but their existence does not establish that both products infringe every claim. Product-specific composition, pH, excipients, concentration, labeling, and patent listings must be compared against the issued claims and applicable NDA records.[2][5]

What manufacturing and geographic barriers remain?

The patent is enforceable only in the United States. Foreign equivalents may provide protection in Europe, the United Kingdom, Canada, Australia, or other jurisdictions, but those rights require separate analysis of national grant, claim scope, maintenance, opposition, and expiration status.

Manufacturing barriers are moderate rather than absolute. The formulation uses conventional pharmaceutical ingredients and standard aqueous blending, pH adjustment, preservation, filling, and quality-control operations. The more difficult development issues are likely stability, methotrexate assay control, microbial preservation, palatability, dose uniformity, light protection, container compatibility, and pediatric administration.

A generic manufacturer can potentially design around the patent through a different salt, pH, buffer system, preservative, sweetener, or formulation architecture. The product must still satisfy FDA quality, stability, bioequivalence, labeling, and chemistry, manufacturing, and controls requirements.

Key Takeaways

U.S. Patent 9,855,215 is a formulation patent for an aqueous oral methotrexate composition.
Claim 1 requires methotrexate salt, purified water, buffer, pH 6.0 to 7.0, and a preservative, flavoring compound, or sweetener.
The commercial core is methotrexate disodium at approximately pH 6.25.
Dependent claims cover specified buffers, preservatives, sweeteners, buffer strengths, and concentrations.
The expected patent expiration date is July 4, 2033, subject to USPTO term adjustments and other statutory events.
The patent is relevant primarily to oral methotrexate solutions, not tablets or injections.
A generic applicant could pursue Paragraph IV positions based on pH, buffer, salt, excipient, concentration, closed claim language, obviousness, written description, and indefiniteness.
Methotrexate has no biosimilar pathway because it is a small-molecule drug.
The patent estate is strongest against a formulation closely matching the disclosed pH 6.25 citrate-phosphate system and listed excipients.
No specific litigation or settlement involving this patent is established by the information provided.

FAQs About U.S. Patent 9,855,215

Does U.S. Patent 9,855,215 cover methotrexate tablets?

No. The claims require a composition for oral administration containing purified water and a defined pH-controlled liquid formulation. Conventional methotrexate tablets would generally fall outside the claimed composition.

Does a methotrexate solution at pH 7.2 infringe claim 1?

A solution at pH 7.2 would be outside the literal pH 6.0 to 7.0 range in claim 1. Infringement would still depend on the measured pH, applicable tolerances, and any argument under the doctrine of equivalents.

Does the patent cover methotrexate sodium rather than methotrexate disodium?

Claim 2 specifically identifies methotrexate disodium, but claim 1 broadly refers to a pharmaceutically acceptable salt of methotrexate. The scope of claim 1 may therefore depend on whether the alternative salt satisfies the claim’s pharmaceutical and formulation requirements.

Can a competitor avoid the patent by removing the preservative?

Removing the preservative may avoid the preservative branch of claim 1, but the claim also covers a flavoring compound or sweetening agent. A product without any preservative, flavor, or sweetener could avoid that limitation, subject to the complete claim construction and doctrine of equivalents.

What is the highest-risk competing formulation?

The highest-risk formulation is an aqueous methotrexate disodium solution containing purified water, a citrate-phosphate buffer, pH near 6.25, a listed preservative, a water-soluble sweetener or raspberry flavor, and methotrexate at 0.05 to 20 mg/mL.

References

United States Patent and Trademark Office. (2018). U.S. Patent No. 9,855,215, Methotrexate compositions.
U.S. Food and Drug Administration. (n.d.). Drugs@FDA: FDA-approved drugs, methotrexate oral solution products.
U.S. Food and Drug Administration. (n.d.). Jylamvo (methotrexate) oral solution prescribing information.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, commonly known as the Orange Book.
U.S. Food and Drug Administration. (n.d.). Xatmep (methotrexate) oral solution prescribing information.

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Azurity	XATMEP	methotrexate sodium	SOLUTION;ORAL	208400-001	Apr 25, 2017		RX	Yes	Yes	⤷ Start Trial	⤷ Start Trial	Y				⤷ 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

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	1200192.1	Jan 6, 2012

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	2614814	⤷ Start Trial
Spain	2726524	⤷ Start Trial
United Kingdom	201200192	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 9,855,215

Which drugs does patent 9,855,215 protect, and when does it expire?

Summary for Patent: 9,855,215