US Patent 7,247,316: Scope, Claims, Expiration, Orange Book Status, and Marqibo Patent Landscape

US Patent 7,247,316 protects a specific three-vial kit for preparing liposomal vincristine, commercially associated with Marqibo. Its claims are directed to the kit architecture and reconstitution chemistry rather than to vincristine generally, liposomes generally, or every method of treating lymphoma. The core limitations are the vincristine concentration, acidic pH, sphingomyelin-to-cholesterol ratio, phosphate-buffer composition, and pH-driven loading or neutralization process.

The patent term ended in December 2022 based on the reported patent expiration date. The patent therefore no longer creates a current US exclusionary right, although it remains relevant to historical Orange Book analysis, prior generic-entry timing, and freedom-to-operate assessments concerning earlier commercial activity. [1][2]

What does US Patent 7,247,316 protect?

US 7,247,316 protects a kit containing three separate vials:

Vial	Required contents	Key limitations
First vial	Vincristine or vincristine sulfate solution	Concentration of approximately 1 mg/mL under claims 1 and 3; 1-5 mg/mL under claim 2; pH 3.5-5.5
Second vial	Liposomes in citrate-buffered solution	Sphingomyelin and cholesterol at a 75/25 to 50/50 molar ratio
Third vial	Phosphate buffer	Dibasic sodium phosphate heptahydrate at approximately 14.2 mg/mL under claims 1 and 3
Instructions	Reconstitution directions	Instructions must direct preparation of a liposomal composition for treating neoplasia

Claim 2 adds a process-oriented pH limitation. The second vial must contain liposomes with acidic internal and external environments. The third vial must contain an alkaline phosphate buffer with a pH higher than the second vial. Mixing the components must neutralize the external liposome environment.

The patent is therefore a product-by-process and kit-combination patent. It does not merely require liposomal vincristine. It requires a defined set of components packaged for use together.

How do claims 1 through 3 differ?

Claims 1 and 3 are materially similar. Both require:

A vincristine solution containing approximately 1 mg/mL vincristine or vincristine sulfate;
Approximately 100 mg/mL mannitol;
Solution pH of 3.5-5.5;
Citrate-buffered liposomes;
Sphingomyelin and cholesterol at a 75/25 to 50/50 molar ratio;
A phosphate buffer containing approximately 14.2 mg/mL dibasic sodium phosphate heptahydrate; and
Instructions for preparing a liposomal formulation for neoplasia treatment.

Claim 2 is broader as to the vincristine concentration because it covers 1-5 mg/mL. It is narrower in other respects because it expressly requires:

Acidic pH inside and outside the liposomes;
An alkaline phosphate buffer in the third vial;
A pH differential between the second and third vials; and
Neutralization of the external liposome environment after mixing.

The overlap between claims 1 and 3 may reflect claim-drafting or prosecution-history structure. Both should be analyzed independently because each is a separate enforceable claim, but the duplicated technical limitations make them vulnerable to the same non-infringement and invalidity arguments.

What are the key limitations in claim 1?

Vincristine concentration and pH

The first vial must contain vincristine sulfate at approximately 1 mg/mL, mannitol at approximately 100 mg/mL, and a pH between 3.5 and 5.5.

The term “approximately” creates a fact-specific range rather than an unrestricted concentration limitation. A court would likely evaluate the term through the specification, prosecution history, and technical context. A materially different concentration could avoid literal infringement, but a small deviation may remain vulnerable under claim construction or the doctrine of equivalents.

The pH range is an express numerical limitation. A formulation at pH 6.0 would not literally satisfy a 3.5-5.5 limitation. A formulation at pH 5.6 could raise a closer equivalence question.

Lipid composition

The second vial must contain liposomes made with sphingomyelin and cholesterol at a molar ratio from 75/25 to 50/50.

Claim 6 narrows this range to approximately 55/45. The claimed ratio is a composition limitation, not merely a manufacturing preference. A liposome using phosphatidylcholine, a different sphingolipid, or a materially different sphingomyelin-to-cholesterol ratio may fall outside the literal scope of the claims.

Phosphate buffer

Claims 1 and 3 require approximately 14.2 mg/mL dibasic sodium phosphate heptahydrate. This is narrower than a generic requirement for “a phosphate buffer.” A product using a different phosphate salt, a different hydrate, or a materially different concentration could present a non-infringement position, depending on the patent’s specification and prosecution history.

What does claim 2 add to the patent scope?

Claim 2 captures the pH-gradient reconstitution system. The claim requires acidic liposomes and an alkaline phosphate buffer that neutralizes the external liposome environment when the components are combined.

This limitation is important because it links the physical contents of the vials to the intended reconstitution operation. A kit may contain the same general ingredients but avoid claim 2 if:

The liposome interior is not acidic;
The exterior solution is not acidic before mixing;
The phosphate buffer is not alkaline;
The third-vial pH is not higher than the second-vial pH; or
The combination does not produce a neutral external liposome environment.

Claim 7 specifies an alkaline phosphate buffer pH of approximately 9.0. A formulation meeting the other claim 2 requirements but using a materially different buffer pH could avoid claim 7 while potentially remaining within claim 2.

How do dependent claims 4 through 7 narrow protection?

Claim	Added limitation	Practical effect
4	Relapsed lymphoma or leukemia	Limits the neoplasia indication
5	Liposome interior and exterior pH approximately 4.0	Adds a specific acidic pH target
6	Sphingomyelin/cholesterol ratio approximately 55/45	Narrows the lipid ratio
7	Alkaline phosphate buffer pH approximately 9.0	Narrows the reconstitution buffer condition

Claim 4 is relevant to Marqibo’s clinical use in relapsed acute lymphoblastic leukemia. It does not cover every neoplasia if the underlying claim is interpreted as requiring the specific disease setting. Claims 5-7 are narrower formulation and reconstitution positions and would generally be easier to design around than the broader independent claims.

What FDA product is associated with US 7,247,316?

The patent is associated with Marqibo, a liposomal formulation of vincristine sulfate. The FDA approved Marqibo in 2012 for adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in second or greater relapse. The product is supplied as a multi-vial kit that is reconstituted before administration. [3]

Marqibo’s product design corresponds closely to the claimed kit structure:

A vincristine sulfate injection component;
A sphingomyelin/cholesterol liposome component;
A phosphate-buffer component; and
Reconstitution instructions.

The FDA label identifies Marqibo as a liposomal formulation requiring controlled preparation before administration. That regulatory configuration is consistent with the technical architecture recited in claims 1-7. [3]

What was the expiration date of US 7,247,316?

The reported expiration date for US 7,247,316 is December 8, 2022. The patent was issued on July 24, 2007. [1]

Event	Date
Patent issued	July 24, 2007
Reported patent expiration	December 8, 2022
Current enforceable patent term	Expired

The expiration date reflects the relevant patent-term calculation, including any applicable patent-term adjustment. Regulatory exclusivity and patent term are separate rights. FDA approval did not extend the patent beyond its statutory term, although pediatric exclusivity or other FDA exclusivities could affect the timing of an ANDA approval during the active period. [2][4]

What was the Orange Book status of US 7,247,316?

US 7,247,316 was listed in connection with Marqibo in the FDA’s Orange Book patent framework. Orange Book listing provides notice of patents submitted by an NDA holder or patent owner, but it does not establish that every listed claim is valid, infringed, or enforceable. [2]

For a generic applicant, a listed patent could trigger one of four certification pathways:

Certification	Meaning
Paragraph I	No patent information is listed
Paragraph II	Patent has expired
Paragraph III	Applicant will wait until patent expiration
Paragraph IV	Patent is invalid, unenforceable, or will not be infringed

After December 2022, a Paragraph II certification would generally address the expired patent. During the active term, an ANDA applicant seeking earlier entry could have used a Paragraph IV certification, potentially creating Hatch-Waxman litigation if the NDA holder sued within the statutory period. [4]

Were there Paragraph IV challenges or generic litigation?

The commercial relevance of US 7,247,316 was concentrated before its December 2022 expiration. A Paragraph IV challenge against a listed Marqibo patent could have targeted:

The narrow three-vial kit configuration;
The sphingomyelin-to-cholesterol range;
The acidic liposome environment;
The phosphate-buffer concentration;
The kit’s instructions; or
The validity of the claims for lack of written description, enablement, anticipation, obviousness, or indefiniteness.

Publicly available FDA and patent records do not establish that US 7,247,316 alone produced a reported final judgment invalidating the asserted claims. The absence of a reported decision does not establish that the claims were never challenged. Litigation review should distinguish between the 7,247,316 patent, other Marqibo patents, and any confidential or unreported ANDA disputes.

Because the patent has expired, new generic entry no longer faces an injunction based on this patent. Any current dispute would more likely concern other unexpired patents, regulatory requirements, product substitution, manufacturing know-how, or damages relating to pre-expiration conduct.

How strong was the patent estate for liposomal vincristine?

US 7,247,316 was commercially important but technically narrow. Its strengths were:

Direct alignment with the approved Marqibo kit;
Multiple component limitations that collectively made simple design-around difficult;
Coverage of the reconstitution system rather than only the active ingredient; and
Dependent claims directed to the product’s pH and lipid ratio.

Its weaknesses were:

No protection for vincristine as a molecule;
No broad protection for all liposomal vincristine formulations;
Dependence on precise kit packaging and composition;
Potential design-around options involving lipid ratio, buffer chemistry, vial structure, concentration, or pH;
Expiration in 2022; and
Potential vulnerability to obviousness arguments based on known liposome-loading techniques and known vincristine formulations.

The patent did not create biosimilar-style exclusivity. Vincristine is a small-molecule active ingredient, so a competing product would ordinarily proceed through the ANDA pathway rather than the biosimilar pathway. The principal technical barrier was developing a pharmaceutically equivalent liposomal product, demonstrating stability and bioequivalence, and satisfying FDA requirements for a complex injectable formulation. [4][5]

What generic entry risks exist for Marqibo?

The patent-specific risk from US 7,247,316 is now expired. Earlier generic-entry risk would have depended on whether a competing product copied all material limitations of the kit.

Potential design-around routes included:

Using a different sphingomyelin-to-cholesterol ratio;
Replacing dibasic sodium phosphate heptahydrate with another buffer system;
Changing the phosphate concentration;
Using a different vial arrangement;
Altering the pH gradient;
Providing a ready-to-use formulation rather than the claimed three-vial kit; or
Pursuing a regulatory pathway that did not require reliance on the listed product configuration.

These approaches could create new regulatory or formulation challenges. Avoiding one patent limitation does not establish FDA approval, pharmaceutical equivalence, or clinical substitutability.

How does this patent compare with conventional vincristine patents?

Issue	US 7,247,316	Conventional vincristine product protection
Active ingredient	Vincristine or vincristine sulfate	Usually vincristine sulfate
Protected subject matter	Three-vial liposomal preparation kit	Solution, container, dose, or manufacturing process
Lipid requirement	Sphingomyelin/cholesterol ratio required	Usually absent
pH-gradient mechanism	Central to claim 2 and claim 7	Usually absent
Treatment indication	Neoplasia; narrower dependent claim for relapsed lymphoma/leukemia	May cover broader oncology use
Regulatory product	Marqibo-type liposomal injectable	Conventional vincristine injection
Current patent status	Expired in 2022	Depends on separate patent family

A conventional vincristine injection does not necessarily infringe this patent because it lacks the claimed liposome and three-vial architecture. Conversely, a liposomal vincristine product could face infringement risk if it reproduces the claimed lipid ratio, pH conditions, phosphate buffer, vial structure, and instructions.

What manufacturing and intellectual-property barriers remain?

Patent expiration does not eliminate the technical complexity of the product. A competing manufacturer still must address:

Reproducible liposome size and drug loading;
Control of sphingomyelin and cholesterol composition;
Stability during storage;
Sterility and particulate control;
Consistent pH before and after reconstitution;
Compatibility of the three-vial system;
Manufacturing scale-up;
Analytical methods for free and encapsulated vincristine;
Container-closure integrity; and
FDA requirements for complex injectable products.

The most durable competitive barrier may therefore be manufacturing know-how, validated analytical methods, clinical data, and regulatory execution rather than US 7,247,316 itself.

Key Takeaways

US 7,247,316 covers a specific three-vial kit for preparing liposomal vincristine.
The core limitations are vincristine concentration, acidic pH, sphingomyelin/cholesterol ratio, phosphate-buffer chemistry, and reconstitution instructions.
Claim 2 adds the pH-gradient mechanism and neutralization requirement.
Claims 4-7 narrow the protection to relapsed lymphoma or leukemia, pH near 4.0, a 55/45 lipid ratio, and phosphate buffer near pH 9.0.
The patent is associated with Marqibo, the FDA-approved liposomal vincristine product.
The reported patent expiration date was December 8, 2022.
The patent is no longer an active US barrier to generic entry.
The patent did not protect conventional vincristine injection or all liposomal vincristine formulations.
Current commercial risk depends on other patents, FDA requirements, manufacturing capability, and market access rather than this expired patent.

Frequently Asked Questions

Does US 7,247,316 cover all liposomal vincristine products?

No. The claims require a defined kit, lipid composition, pH configuration, phosphate buffer, and reconstitution instructions. A liposomal vincristine product outside those limitations may avoid the claims.

Is US 7,247,316 still enforceable?

No. The reported patent term ended in December 2022.

Does a conventional vincristine sulfate injection infringe this patent?

Generally, no. A conventional injection does not ordinarily contain the claimed sphingomyelin/cholesterol liposomes or the three-vial reconstitution system.

Is Marqibo a biologic requiring a biosimilar application?

No. Marqibo contains vincristine sulfate, a small-molecule active ingredient. A competing product would generally be evaluated under the ANDA framework rather than the biosimilar pathway.

Can a company launch a generic liposomal vincristine product solely because this patent expired?

No. Patent expiration removes this patent as an exclusionary barrier, but FDA approval, pharmaceutical equivalence, manufacturing validation, regulatory exclusivity, and any other unexpired patents remain relevant.

References

United States Patent and Trademark Office. (2007). Liposomal formulations of vincristine, U.S. Patent No. 7,247,316.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
U.S. Food and Drug Administration. (2012). Marqibo (vincristine sulfate liposome injection) prescribing information.
U.S. Food and Drug Administration. (2017). Approved drug products with therapeutic equivalence evaluations, 37th edition.
U.S. Food and Drug Administration. (2018). ANDAs for certain highly purified synthetic peptide drug products that refer to listed drugs of recombinant origin: Guidance for industry.

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

Details for Patent: 7,247,316

Summary for Patent: 7,247,316