US Patent 6,723,338: Scope, Claims, Expiration, and Vincristine Liposome Patent Landscape

US Patent 6,723,338 protects a treatment method using liposome-encapsulated vincristine for relapsed lymphoma or leukemia in patients previously treated with multi-agent chemotherapy. The patent is a method-of-use patent, not a broad composition patent. Its strongest protection is directed to systemic treatment of relapsed hematologic malignancies after prior combination therapy, with narrower dependent claims covering liposome composition, pH-gradient loading, combination therapy, dosing, and treatment interval.

The patent issued on April 20, 2004, and its ordinary 20-year term from the relevant nonprovisional filing date expired in December 2021, based on the recorded priority and filing history. It therefore does not currently block commercial use of liposomal vincristine in the United States. Later formulation, manufacturing, or regulatory patents may have had separate terms.

What does US Patent 6,723,338 protect?

The patent protects administering liposome-encapsulated vincristine to a human with relapsed lymphoma or leukemia after at least one prior multi-agent combination regimen.

The core claim requires all of the following:

A human patient.
Relapsed cancer.
Lymphoma or leukemia.
Prior treatment with at least one multi-agent combination regimen.
Administration of a pharmaceutical composition containing liposome-encapsulated vincristine.

Claim 1 is the principal scope-defining claim. Claims 2 through 27 narrow that method by specifying disease subtype, liposome chemistry, previous treatment, combination therapy, route, dosage, schedule, and concomitant agents.

The patent does not claim:

Free vincristine as such.
Vincristine sulfate as a standalone compound.
Every liposomal vincristine composition.
A composition claim independent of patient treatment.
Treatment of solid tumors.
First-line treatment of cancer.
Relapsed cancer without the required prior multi-agent regimen.

The patent’s commercial relevance was tied to liposomal vincristine products such as Marqibo, a vincristine sulfate liposome injection later approved for a specific relapsed or refractory acute lymphoblastic leukemia population.

How are the 27 claims organized?

Claim group	Subject matter	Legal effect
Claim 1	Relapsed lymphoma or leukemia after prior multi-agent therapy; liposome-encapsulated vincristine	Broadest independent treatment claim
Claims 2-3	Non-Hodgkin's lymphoma and listed subtypes	Disease-specific narrowing
Claims 4-7	Distearoylphosphatidylcholine or sphingomyelin, with optional cholesterol	Lipid-composition limitations
Claims 8-9	Internal acidic pH gradient	Encapsulation and loading limitation
Claims 10-13	Prior free vinca alkaloid or anthracycline therapy, including doxorubicin	Prior-treatment limitations
Claim 14	Prior partial or complete response before relapse	Clinical-history limitation
Claim 15	Second relapse	Narrow relapse-status limitation
Claim 16	Systemic intravenous administration	Route limitation
Claims 17-18	Co-administration with chemotherapeutic agents	Combination-treatment limitations
Claims 19-22	Co-administration with antibodies, antisense drugs, or vaccines	Broader anti-tumor combination limitations
Claims 23-25	Dose of about 1.4-2.4 mg/m² and 7-21 day schedule, including every 14 days	Dosing and interval limitations
Claims 26-27	Relapsed lymphoma or leukemia	Alternative disease limitations

The supplied text contains typographical errors in several places, including “vinctistine,” “sphingomyclin,” “Lympho a,” and “claim/wherein.” Those errors do not change the intended subject matter when read against the issued patent and specification.

What is the scope of independent claim 1?

Claim 1 is a treatment claim with a multi-element structure. A potentially infringing treatment generally would need to satisfy each required limitation.

Relapsed cancer requirement

The cancer must have relapsed. Claim 1 does not expressly require refractory disease, although some commercial labeling and clinical use may involve relapsed or refractory patients. Relapse generally means recurrence after a prior response or period of disease control.

Lymphoma or leukemia requirement

Claim 1 is limited to lymphoma or leukemia. A liposomal vincristine treatment for breast cancer, lung cancer, ovarian cancer, or another solid tumor would fall outside the literal scope of claim 1, even if the same formulation and dose were used.

Prior multi-agent combination regimen

The patient must previously have undergone at least one multi-agent combination regimen. This requirement is important because the claim is not directed to treatment-naive patients or patients previously treated only with a single agent.

Claims 10 through 13 give examples of qualifying prior therapy, including:

A free-form vinca alkaloid.
Vincristine, vinblastine, vindesine, or vinorelbine.
An anthracycline-containing regimen.
Doxorubicin.

Claim 1 itself is broader than those examples. A prior combination regimen could potentially qualify even if it did not include a vinca alkaloid or doxorubicin, provided it was a multi-agent regimen.

Liposome-encapsulated vincristine

The administered product must contain vincristine encapsulated in liposomes. The claim does not require the specific lipid composition in claims 4 through 9 unless a party relies on one of those narrower claims.

This distinction matters for freedom-to-operate analysis. A product using a different liposomal lipid system could avoid claims 4 through 9 while still raising a question under claim 1, provided the treatment otherwise satisfies claim 1.

What formulations are protected by US 6,723,338?

The patent has limited formulation coverage because its claims are method claims. Claims 4 through 9 narrow the treatment method based on liposome structure and composition.

Distearoylphosphatidylcholine and cholesterol

Claims 4 and 5 cover treatment using liposomes containing distearoylphosphatidylcholine, or DSPC. Claim 5 adds cholesterol.

DSPC and cholesterol are conventional components for relatively stable liposomal bilayers. The claims do not, on their face, specify exact molar ratios, particle size, encapsulation efficiency, or drug-to-lipid ratio.

Sphingomyelin and cholesterol

Claims 6 and 7 cover liposomes containing sphingomyelin, with claim 7 adding cholesterol.

A formulation containing sphingomyelin and cholesterol could fall within these dependent claims when used in the claimed patient population and treatment setting. The composition alone is not the claimed act.

Acidic internal pH gradient

Claims 8 and 9 require a pH gradient in which the liposome interior has a lower pH than the exterior. This limitation is directed to an actively loaded liposome architecture rather than merely passive encapsulation.

The pH-gradient claims may be technically significant because they distinguish formulations according to drug-loading mechanism. They remain dependent on claim 1, meaning that the disease, relapse, prior-treatment, and vincristine requirements continue to apply.

Does the patent cover Marqibo?

The patent is closely related to the clinical and commercial concept underlying Marqibo, but patent scope and FDA labeling are not identical.

Marqibo is vincristine sulfate liposome injection. The FDA approved it in 2012 under the accelerated approval pathway for adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in second or greater relapse. The FDA label specifies intravenous administration and a treatment schedule broadly consistent with the dosing concepts recited in claims 16, 23, and 25. [2]

Patent 6,723,338 is broader in some respects than the FDA indication because it covers relapsed lymphoma or leukemia generally and does not require Philadelphia chromosome-negative disease. It is narrower in other respects because it requires prior multi-agent therapy and liposomal vincristine.

FDA approval does not establish infringement, and a patent claim does not expand the approved indication. The two documents answer different questions:

Issue	Patent 6,723,338	Marqibo FDA labeling
Disease	Relapsed lymphoma or leukemia	Philadelphia chromosome-negative ALL in second or greater relapse
Prior treatment	At least one multi-agent regimen	Clinical indication defined by relapsed disease status
Product	Liposome-encapsulated vincristine	Vincristine sulfate liposome injection
Route	Intravenous limitation in claim 16	Intravenous administration
Dose	About 1.4-2.4 mg/m² in claim 23	Product-specific labeled regimen
Legal function	Exclusionary patent right	Marketing authorization

When did US Patent 6,723,338 lose exclusivity?

The patent’s ordinary term expired in December 2021. The patent issued from an application with a December 2001 filing date, producing an ordinary 20-year term calculated from that filing date, subject to any applicable patent-term adjustment or terminal-disclaimer information recorded by the USPTO. [1]

The patent is therefore expired as a blocking US patent. Any current exclusivity analysis must focus on later patents, regulatory exclusivity, trade secrets, manufacturing know-how, and product-specific approvals rather than on the enforceability of the expired patent.

Regulatory exclusivity

Marqibo received orphan-drug designation and approval for a rare leukemia indication. Orphan-drug exclusivity generally lasts seven years from approval for the same designated indication under the Orphan Drug Act. The 2012 approval therefore produced a seven-year regulatory exclusivity period that did not extend beyond the patent term into the present period. [2][3]

Regulatory exclusivity and patent exclusivity are separate. Orphan exclusivity can prevent FDA approval of another sponsor’s same orphan indication even when no enforceable patent remains.

What was the Orange Book status of the patent?

FDA Orange Book listings are product-specific. A patent may be listed for a drug product if it claims the drug substance, drug product, or an approved method of use. Method-of-use listings are associated with FDA use codes and may be relevant to Paragraph IV certifications.

Patent 6,723,338 was associated with the liposomal vincristine product and the patented treatment concept. Its expiration in 2021 means it is no longer a live patent barrier for a new ANDA filing. An applicant filing while the patent was listed could have faced a Paragraph IV issue, but a post-expiration application would not need to defeat an expired claim.

The Orange Book should be checked by product and current listing status rather than by patent number alone because:

Patent listings can be delisted or expire.
FDA use codes may cover only part of the patented indication.
Later patents can remain listed after an earlier patent expires.
Patent listing does not validate patent enforceability.

Were there Paragraph IV challenges or patent litigation?

No current litigation significance remains for US Patent 6,723,338 itself because the patent has expired. Historical Paragraph IV activity, if any, would have been relevant only before the patent’s expiration.

The main litigation risks associated with a liposomal vincristine product would have involved:

Whether the product was “liposome-encapsulated vincristine.”
Whether the patient had relapsed lymphoma or leukemia.
Whether the patient had received a qualifying multi-agent regimen.
Whether the product used the claimed lipid or pH-gradient structure.
Whether an ANDA applicant’s proposed label induced infringement.

A generic applicant could have pursued several non-infringement positions:

Remove or avoid the patented lymphoma/leukemia use from the proposed label.
Limit the label to a non-covered indication.
Argue that the formulation is not liposome-encapsulated under the claim construction.
Use a different delivery system.
Challenge the meaning or written-description support for broad disease or formulation language.
Rely on patent expiration rather than litigate validity.

There is no continuing settlement leverage based solely on this expired patent.

How strong was the patent estate?

Patent 6,723,338 had meaningful historical value but limited current blocking power.

Historical strengths

It captured a clinically specific use of liposomal vincristine.
It covered patients who had already failed or relapsed after combination chemotherapy.
It included broad disease categories within lymphoma and leukemia.
It included combination-treatment and dose-schedule claims.
It aligned with the development path of a liposomal vincristine product.

Structural weaknesses

It was a method patent rather than a composition patent.
Its principal claim required a prior multi-agent regimen.
Several narrower claims required specific clinical facts that may be difficult to prove.
The claims did not independently protect the liposome product.
A competitor could potentially design around the dependent lipid and pH-gradient claims.
The patent expired before the commercial product reached a broad market.

The strongest historical claim was claim 1 because it avoided the specific lipid and dose limitations. The strongest technical fallback claims were claims 8 and 9, if the accused product used an acidic internal loading gradient. Claims 23 through 25 were narrower and more vulnerable to dosage or schedule differences.

How does this patent compare with later liposomal vincristine patents?

Later patent families concerning liposomal vincristine generally focused more directly on formulation, lipid composition, manufacturing, stability, particle characteristics, drug loading, or product-specific implementation. Examples associated with the Marqibo development program include US 7,232,816 and US 7,598,216, which are distinct from US 6,723,338 and must be analyzed independently. [4][5]

Patent category	US 6,723,338	Later formulation patents
Primary focus	Clinical method of treating relapsed cancer	Product and formulation characteristics
Claim type	Method of use	Composition, formulation, process, or use
Main risk	Treatment of a qualifying patient	Making, using, or selling a particular formulation
Design-around route	Different indication, patient history, or treatment structure	Different lipid system, loading process, or physical properties
Expiration relevance	Expired in 2021	Must be assessed patent by patent

A competitor evaluating a liposomal vincristine program should not assume that expiration of 6,723,338 eliminates all patent risk. Later patents may cover the commercial formulation or its manufacturing process.

What generic entry risks exist for liposomal vincristine?

The likely entry route depends on whether the competitor develops an equivalent injectable product or a different liposomal vincristine product.

ANDA risk

An ANDA applicant would need to establish pharmaceutical equivalence and bioequivalence to the reference product. Liposomal products can present complex equivalence issues involving:

Liposome size distribution.
Encapsulation efficiency.
Free-drug fraction.
Drug release profile.
Lipid composition.
Surface characteristics.
Stability and aggregation.
Pharmacokinetic comparability.

Because these properties can affect clinical performance, FDA may impose product-specific requirements beyond conventional small-molecule tablets or solutions.

505(b)(2) risk

A materially different liposomal vincristine formulation may require a 505(b)(2) application rather than a conventional ANDA. This pathway can address changes in formulation, route, dosage, or clinical use but may require additional clinical or bridging evidence.

Biosimilar risk

Biosimilar risk is not applicable. Vincristine sulfate is a small-molecule cytotoxic drug, and Marqibo is a liposomal drug product, not a biologic subject to the 351(k) biosimilar pathway.

Manufacturing and IP barriers

The main continuing barriers are likely to be formulation reproducibility, sterile injectable manufacturing, controlled encapsulation, release testing, and regulatory comparability. Manufacturing know-how can remain commercially important after patent expiration, but it is not equivalent to enforceable patent exclusivity.

What is the competitive landscape for liposomal vincristine?

The competitive field has historically been narrow because liposomal vincristine occupies a specialized position in relapsed hematologic malignancies. Relevant alternatives include:

Conventional intravenous vincristine.
Other salvage chemotherapy combinations.
Targeted agents for B-cell or T-cell malignancies.
Monoclonal antibodies such as rituximab where clinically appropriate.
Antibody-drug conjugates.
Cellular therapies for selected leukemia and lymphoma populations.
Radiolabeled antibodies and other anti-tumor agents.

The patent claims expressly contemplate co-administration with cyclophosphamide, doxorubicin, prednisone, rituximab, iodine-131 Lym-1, iodine-131 tositumomab, antisense drugs, and anti-tumor vaccines. Those claims do not create exclusivity over the combination partners. They attempt to extend the patented treatment method to combined use of liposomal vincristine with those agents.

What is the commercial and licensing significance?

The patent supported the development value of a liposomal vincristine platform and could have strengthened licensing or acquisition negotiations before expiration. Its value was highest when combined with:

FDA orphan-drug designation.
Clinical data in relapsed leukemia.
Product-specific formulation patents.
Manufacturing know-how.
Regulatory exclusivity.
Distribution rights and supply capability.

After expiration, the patent no longer provides standalone licensing leverage. Commercial value must instead be assessed through later unexpired patents, regulatory exclusivity, market access, manufacturing capacity, clinical differentiation, and any contractual rights held by the product owner.

Key Takeaways

US Patent 6,723,338 is a method-of-use patent for liposome-encapsulated vincristine.
Claim 1 requires relapsed lymphoma or leukemia, prior multi-agent therapy, and administration to a human.
Dependent claims cover non-Hodgkin's lymphoma subtypes, DSPC, sphingomyelin, cholesterol, acidic pH gradients, intravenous delivery, combination therapy, dosing, and 14-day administration.
The patent does not independently claim a liposomal vincristine composition.
It is closely connected to the clinical concept underlying Marqibo but is broader and narrower than the FDA-approved indication in different respects.
The patent’s ordinary US term expired in December 2021.
Biosimilar analysis is not applicable because vincristine is a small-molecule drug product.
Current freedom-to-operate risk must focus on later formulation, manufacturing, regulatory, and product-specific patents.
Expiration of 6,723,338 removes a historical method-of-use barrier but does not establish freedom to operate for every liposomal vincristine formulation.

FAQs About US Patent 6,723,338

Can a company sell liposomal vincristine after US Patent 6,723,338 expired?

Yes, expiration removes the patent’s exclusionary rights. The product must still satisfy FDA requirements and avoid infringement of any later unexpired patents.

Does claim 1 cover free vincristine?

No. Claim 1 requires liposome-encapsulated vincristine. Free-form vincristine appears in the claims as part of the patient’s prior treatment history, not as the patented product.

Does the patent cover first-line lymphoma treatment?

No. Claim 1 requires relapsed cancer and prior treatment with at least one multi-agent combination regimen.

Are liposomal vincristine products biosimilars?

No. Liposomal vincristine products are regulated as small-molecule drug products, generally through an ANDA, 505(b)(2), or another applicable drug pathway rather than the biosimilar pathway.

Does using a different lipid composition avoid all claims?

No. A different lipid composition may avoid claims 4 through 7, but it does not necessarily avoid claim 1 or the other dependent claims. Claim scope must be assessed element by element.

References

United States Patent and Trademark Office. (2004). US Patent No. 6,723,338: Methods of treating cancer using liposome-encapsulated vincristine.
U.S. Food and Drug Administration. (2012). Marqibo (vincristine sulfate liposome injection) prescribing information.
U.S. Food and Drug Administration. (2024). Orange Book: Approved drug products with therapeutic equivalence evaluations.
United States Patent and Trademark Office. (2007). US Patent No. 7,232,816.
United States Patent and Trademark Office. (2009). US Patent No. 7,598,216.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	309786	⤷ Start Trial
Austria	309787	⤷ Start Trial
Austria	442839	⤷ Start Trial
Australia	2001270385	⤷ Start Trial
Australia	4060600	⤷ Start Trial
Australia	7038501	⤷ Start Trial
Australia	7041301	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 6,723,338