United States Patent 10,864,183: Melphalan-Sulfobutyl Ether-β-Cyclodextrin Formulation Claims and Patent Landscape

U.S. Patent No. 10,864,183 protects narrowly defined injectable melphalan formulations using sulfobutyl ether-β-cyclodextrin, commonly known as SBECD or sulfobutyl ether sodium beta-cyclodextrin. The principal limitations are a pH of 5, specified melphalan concentrations, a minimum SBECD-to-melphalan weight ratio of 54:1, sodium chloride in selected claims, room-temperature stability, and, in the later claims, increased melphalan exposure measured by AUC.

The strongest commercial relevance is to Captisol-enabled melphalan products, including EVOMELA. The patent does not broadly cover every melphalan formulation or every cyclodextrin formulation. It targets a defined formulation architecture and associated stability and pharmacokinetic performance.

What does U.S. Patent 10,864,183 cover?

The patent claims two principal formulation configurations:

A higher-concentration formulation containing 5 mg/mL melphalan, generally in an 8.5 mL volume.
A lower-concentration formulation containing 0.45 mg/mL melphalan, generally in a 10 mL volume.

Both configurations require SBECD and a SBECD-to-melphalan weight ratio of at least 54:1. The 5 mg/mL claims generally require an exact 54:1 ratio, while the 0.45 mg/mL claims permit a ratio of 54:1 or greater.

The claims also use functional limitations:

Stability at room temperature for at least one hour or four hours.
Less than 2% melphalan degradation after five hours.
Less than 4% degradation after 10 hours.
Up to a 30% increase in AUC in one dependent claim.
At least a 20% increase in AUC in claims 9 and 10.

These limitations make the patent narrower than a basic composition patent, but they create several infringement and validity questions concerning testing protocols, reference formulations, inherent properties, and claim construction.

How are the claims structured?

Claim-by-claim scope

Claim	Core formulation	Key concentration and volume	Ratio	Performance limitation
1	SBECD, melphalan, sodium chloride	5 mg/mL; 8.5 mL	Exactly 54:1	Stable at room temperature for at least one hour
2	Depends on claim 1	Same as claim 1	54:1	Less than 2% degradation after five hours
3	Depends on claim 1	Same as claim 1	54:1	Less than 4% degradation after 10 hours
4	SBECD and melphalan	0.45 mg/mL; 10 mL	At least 54:1	Stable at room temperature for at least four hours
5	Depends on claim 4	Same as claim 4	At least 54:1	Less than 2% degradation after five hours
6	Depends on claim 4	Same as claim 4	At least 54:1	Less than 4% degradation after 10 hours
7	SBECD, melphalan, sodium chloride, plus at least one listed excipient category	5 mg/mL; 8.5 mL	Exactly 54:1	Stable at room temperature for at least one hour
8	Depends on claim 1, 4, or 7	Varies	Varies	Up to 30% increase in melphalan AUC
9	SBECD, melphalan, sodium chloride	5 mg/mL	Exactly 54:1	Stable at least one hour and AUC at least 20% higher
10	SBECD, melphalan, sodium chloride	0.45 mg/mL	At least 54:1	Stable at least four hours and AUC at least 20% higher

The independent claims are claims 1, 4, 7, 9, and 10. Claims 2, 3, 5, 6, and 8 depend on those independent claims.

What formulation parameters are protected?

Melphalan concentration

The patent has separate protection for 5 mg/mL and 0.45 mg/mL formulations.

The 5 mg/mL claims are more compositionally constrained because they also specify an 8.5 mL solution in claims 1 and 7. Claim 9 does not expressly require the 8.5 mL volume, which expands its scope relative to claims 1 and 7.

The 0.45 mg/mL claims specify a 10 mL formulation in claim 4. Claim 10 does not expressly include the 10 mL volume, creating a broader concentration-based claim subject to the remaining limitations.

SBECD-to-melphalan ratio

The 54:1 ratio is the central numeric limitation.

For the 5 mg/mL configuration:

Melphalan concentration: 5 mg/mL.
SBECD concentration implied by a 54:1 ratio: 270 mg/mL.
In 8.5 mL, the formulation contains approximately 42.5 mg melphalan.
At exactly 54:1, the corresponding SBECD amount is approximately 2,295 mg.

For the 0.45 mg/mL configuration:

Melphalan concentration: 0.45 mg/mL.
Minimum SBECD concentration at 54:1: 24.3 mg/mL.
In 10 mL, the formulation contains 4.5 mg melphalan.
The minimum corresponding SBECD amount is approximately 243 mg.

The ratio is calculated by weight, not molar amount. A formulation using a different SBECD grade, degree of substitution, moisture content, or assay convention could create disputes over how the ratio is measured.

Sodium chloride

Claims 1, 7, 9, and 10 require 9 g/L sodium chloride. At an 8.5 mL volume, this corresponds to approximately 76.5 mg sodium chloride.

Claim 4 does not expressly require sodium chloride. That omission is commercially significant because a formulation may potentially avoid claims 1, 7, 9, and 10 while still falling within claim 4 if it meets the lower concentration, ratio, pH, volume, and stability limitations.

pH

The claims require a pH of 5. A formulation at pH 4.9 or 5.1 could raise an infringement question depending on the patent's specification, analytical tolerance, and claim-construction record. A materially different pH, such as pH 6 or pH 7, would provide a clearer design-around path, although it could affect melphalan stability and clinical suitability.

Excipients and “consisting of”

Claims 1, 4, and 9 use “consisting of” language in describing the formulation components. That language can exclude unlisted ingredients, subject to the patent's interpretation of impurities, incidental components, buffers, pH adjusters, and pharmaceutical processing materials.

Claim 7 is drafted differently. It recites “at least one” of an antioxidant, preservative, or buffer, together with sodium chloride, SBECD, and melphalan. This creates a broader excipient variation than claim 1, but the interaction between “consisting of” and “at least one” may be litigated if a competing formulation includes additional excipients.

How strong are the stability limitations?

The stability limitations are both a potential enforcement advantage and a validity risk.

Claims 1 and 7 require stability for at least one hour at room temperature. Claims 4 and 10 require at least four hours. Dependent claims add degradation thresholds after five and 10 hours.

The claims compare the SBECD formulation with a cyclodextrin-free reference melphalan standard. The comparison raises several technical issues:

The identity and preparation of the reference formulation.
The definition of “room temperature.”
The analytical method used to measure melphalan degradation.
Whether degradation includes only chemical decomposition or also precipitation and loss of assayable drug.
Whether the formulation must be tested immediately after preparation or after storage.
Whether stability is measured at the claimed concentration and volume.
Whether the stability property is inherent in every formulation within the compositional scope.

A generic or competing manufacturer could challenge infringement by showing that its product does not satisfy the specified stability threshold. The patent holder could respond that the stability result is an inherent property of the claimed composition.

What do the pharmacokinetic claims protect?

Claim 8 requires that administration provide up to a 30% increase in melphalan AUC compared with a cyclodextrin-free formulation. Claims 9 and 10 require an AUC increase of at least 20%.

The AUC limitations are technically narrower than the composition limitations because they require a comparative pharmacokinetic result. The relevant variables include:

AUC interval, particularly AUC0-t.
Patient or animal population.
Route and rate of administration.
Equivalent melphalan dose.
Sampling duration.
Bioanalytical method.
Formulation used as the cyclodextrin-free comparator.
Statistical treatment of the comparison.

Claims 9 and 10 are particularly important because they combine composition, stability, and pharmacokinetic limitations in a single claim. A product could meet the composition limitations but avoid infringement if the required AUC increase is not demonstrated, depending on how the claims are construed.

What generic entry risks exist for an SBECD-enabled melphalan product?

A competing injectable melphalan product faces several possible patent barriers:

A formulation using 5 mg/mL melphalan, pH 5, 9 g/L sodium chloride, and a 54:1 SBECD ratio could implicate claims 1, 7, and 9.
A 0.45 mg/mL formulation at pH 5 with at least a 54:1 ratio could implicate claims 4 and 10.
A formulation with the same composition but without the claimed AUC increase could still implicate the purely formulation-based claims.
A product with a different cyclodextrin, pH, ratio, concentration, or excipient profile could reduce literal infringement risk.
A formulation that meets the composition limitations but fails the claimed stability test could create a factual noninfringement defense.

For an ANDA applicant, the principal statutory route would likely be a Paragraph IV certification if the patent is listed in the Orange Book for the relevant reference product and remains unexpired. Whether a particular patent is listed, and for which approved indications, must be determined from the current FDA Orange Book and the applicable product listing.[1]

What is the Orange Book and FDA status relevant to this patent?

EVOMELA is an FDA-approved injectable melphalan product. The FDA approved EVOMELA under NDA 209500 in October 2016 for use as a conditioning treatment before autologous stem-cell transplantation in multiple myeloma and for palliative treatment of patients with multiple myeloma for whom oral melphalan is not appropriate.[2]

FDA approval does not itself establish that U.S. Patent 10,864,183 is listed in the Orange Book. Orange Book listing depends on submission by the NDA holder and FDA acceptance of the patent information under applicable FDA rules. The relevant distinction is between:

Composition or formulation patents that may be eligible for listing.
Method-of-use patents that may be listed for approved uses.
Process patents, which generally do not create the same Orange Book blocking mechanism.
Patents that are expired, delisted, withdrawn, or listed only for particular uses.

A regulatory diligence review should compare the patent number against the current Orange Book entry for EVOMELA and any successor or related NDA listing.[1]

What is the broader patent landscape for EVOMELA and melphalan?

The relevant landscape has four layers.

Core melphalan drug patents

Older patents covering melphalan, melphalan hydrochloride, and basic pharmaceutical uses are generally less important because melphalan is an established cytotoxic agent and early composition patents are likely expired.

SBECD-enabled formulation patents

The commercially relevant layer covers the use of SBECD to improve melphalan solubility, stability, handling time, and potentially exposure. U.S. Patent 10,864,183 belongs to this layer. The claims are narrower than a generic “melphalan plus cyclodextrin” concept because they specify concentration, pH, ratio, sodium chloride, volume, stability, and AUC limitations.

Method-of-use patents

Melphalan patents can also cover conditioning regimens, transplantation protocols, dosing schedules, and treatment of multiple myeloma. A formulation patent and a method-of-use patent create different litigation and Paragraph IV issues. A generic applicant may avoid an indication-specific method claim through a section viii statement while still facing formulation claims.

Manufacturing and fill-finish protection

Manufacturing barriers may include preparation of melphalan solutions, control of degradation products, aseptic filling, vial reconstitution, SBECD quality attributes, and container-closure compatibility. These rights may be difficult to identify from the claim set alone and should not be assumed to overlap with the composition claims.

How does this patent compare with a conventional melphalan formulation?

Attribute	Claimed SBECD formulation	Conventional cyclodextrin-free melphalan
Cyclodextrin	Required SBECD	Absent
pH	pH 5	May vary
Stability comparison	Must outperform or satisfy stated stability test	Reference standard
SBECD-to-melphalan ratio	54:1 or greater, depending on claim	Not applicable
Sodium chloride	Required in several claims	Not necessarily required
AUC limitation	Required only in claims 8-10	Comparator
Design-around potential	pH, ratio, concentration, excipients, or different cyclodextrin	Avoids SBECD limitations

The patent's commercial value depends on whether the approved product uses the claimed formulation parameters and whether alternative formulations can deliver acceptable stability and clinical performance without SBECD.

What litigation and settlement issues should be reviewed?

The supplied claim set does not establish a litigation judgment, Paragraph IV notice, settlement agreement, or license. Those matters must be verified through PACER, district court dockets, Federal Circuit decisions, FDA correspondence, and company disclosures.

The principal litigation issues would likely include:

Written description and enablement for the full ratio and stability ranges.
Obviousness based on known SBECD use in injectable formulations.
Indefiniteness of “stable,” “room temperature,” and comparative AUC language.
Whether the AUC limitations are product limitations or require a particular use.
Whether the “consisting of” language excludes ordinary pH adjusters or processing residues.
Whether a reference formulation is sufficiently defined for a reliable comparison.
Whether the accused product meets the exact 54:1 ratio.

No biosimilar pathway is directly relevant. Melphalan is a small-molecule drug, so competitive entry would ordinarily proceed through an ANDA or, for a materially different product, an NDA, rather than a biosimilar application under the Public Health Service Act.

When does U.S. Patent 10,864,183 lose exclusivity?

The grant date alone does not determine the patent's expiration date. The controlling date depends on the patent's earliest effective nonprovisional priority date, patent-term adjustment, terminal disclaimers, and any patent-term extension.

The patent's term must be checked in the USPTO Patent Center record and the face of the patent. Any Orange Book patent-term statement should be compared against the FDA listing and the applicable regulatory exclusivity period.[1,3]

FDA regulatory exclusivity is separate from patent exclusivity. EVOMELA's approval date and any applicable orphan-drug, new-chemical-entity, or other regulatory exclusivity period do not establish the expiration of U.S. Patent 10,864,183.[2]

Key Takeaways

U.S. Patent 10,864,183 is a formulation patent centered on SBECD-enabled injectable melphalan.
The key numeric limitation is a SBECD-to-melphalan weight ratio of 54:1.
The claims cover 5 mg/mL and 0.45 mg/mL melphalan configurations.
pH 5 is required throughout the independent claim set.
Sodium chloride at 9 g/L is required in claims 1, 7, 9, and 10 but not expressly in claim 4.
Stability and AUC are important claim limitations, particularly for claims 8-10.
A formulation using a different pH, concentration, cyclodextrin, ratio, or excipient profile may reduce literal infringement risk.
The patent's Orange Book status, exact expiration date, litigation record, and settlement history cannot be established from the claim text alone.
No biosimilar pathway applies because melphalan is a small-molecule drug.

FAQs

Does claim 4 require sodium chloride?

No. Claim 4 recites SBECD and 0.45 mg/mL melphalan but does not expressly recite 9 g/L sodium chloride. Claims 1, 7, 9, and 10 do include sodium chloride.

Can a formulation with a 53:1 SBECD-to-melphalan ratio avoid the patent?

A 53:1 ratio would not literally satisfy claims requiring a ratio of 54:1 or greater. The patent holder could still assert an equivalents theory, depending on the facts and prosecution history.

Does changing SBECD to another cyclodextrin avoid the claims?

Likely, for literal infringement, if the substituted excipient is not sulfobutyl ether-β-cyclodextrin. The commercial and technical consequences would depend on whether the substitute provides adequate solubility, stability, safety, and regulatory comparability.

Are the AUC claims likely to block an ANDA by themselves?

They can create a patent issue if listed and applicable, but their enforceability depends on how the claims are characterized and whether the proposed product satisfies the comparative AUC limitation. A formulation-only claim may present a more direct ANDA barrier.

Is EVOMELA's approval evidence that every claim is valid?

No. FDA approval does not adjudicate patent validity, infringement, written description, enablement, or obviousness. Approval may provide evidence concerning the commercial formulation and approved use, but patent questions remain governed by the Patent Act and judicial precedent.

References

U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, 44th edition: Orange Book. https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book
U.S. Food and Drug Administration. (2016). EVOMELA prescribing information. Drugs@FDA, NDA 209500. https://www.accessdata.fda.gov/scripts/cder/daf/
United States Patent and Trademark Office. (2021). U.S. Patent No. 10,864,183. Patent Center. https://patentcenter.uspto.gov/

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Acrotech Biopharma	EVOMELA	melphalan hydrochloride	POWDER;INTRAVENOUS	207155-001	Mar 10, 2016		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

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2010253905	⤷ Start Trial
Brazil	PI1012301	⤷ Start Trial
Canada	2763365	⤷ Start Trial
China	102458114	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 10,864,183

Which drugs does patent 10,864,183 protect, and when does it expire?

Summary for Patent: 10,864,183