US Patent 6,406,713: Scope, Claim Construction, Expiration, and Amphotericin B Patent Landscape

US Patent 6,406,713 protects a manufacturing process for a non-liposomal drug-lipid complex containing a polyene antifungal, particularly amphotericin B. The patent does not broadly claim amphotericin B itself, all amphotericin B formulations, or every lipid-based delivery system. Its central limitation is a process that produces a complex with 25% to 50% amphotericin B by mole, no captured aqueous volume, and substantially no liposomes.

The patent was issued on June 18, 2002. Its enforceable term has ended under the 20-year US patent-term framework. It therefore presents no current US patent barrier to commercial manufacture, although other patents, regulatory requirements, trade secrets, and process patents may remain relevant. [1, 2]

What does US Patent 6,406,713 cover?

The patent covers a method of preparing a drug-lipid complex through solvent processing and aqueous-phase addition.

The independent claim requires all of the following:

Claim element	Required limitation
Lipid	A fatty acid or phospholipid
Lipid solvent	Chloroform, methanol, DMSO, methylene chloride, chloroform:methanol, or benzene:methanol
Drug	A polyene antifungal agent
Drug solvent	An organic solvent
Mixing	Lipid and drug solutions are combined
Aqueous phase	Added to the combined organic mixture
Solvent removal	Organic solvent is removed
Product structure	No captured volume
Product structure	Substantially free of liposomes
Composition	Polyene antifungal comprises about 25% to 50% of the complex on a molar basis

The claim is therefore a process claim with structural and compositional product limitations. A process that uses the listed preparation steps but produces conventional liposomes, or a complex containing less than approximately 25 mole percent or more than approximately 50 mole percent antifungal, may fall outside claim 1.

The patent’s commercial relevance is greatest for amphotericin B lipid-complex products resembling Abelcet, also known as amphotericin B lipid complex or ABLC. ABLC uses amphotericin B with dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol in a 7:3 molar ratio. [3]

What is the scope of independent claim 1?

Claim 1 has two separate dimensions of scope: process limitations and product-result limitations.

Process limitations

The claimed process requires:

Dissolution of the lipid in a specified solvent or solvent mixture.
Dissolution of the polyene antifungal in an organic solvent.
Combination of the two solutions.
Addition of an aqueous phase.
Removal of the organic solvent.

The claim does not require a particular solvent-removal technology. It does not expressly require evaporation, dialysis, spray drying, lyophilization, or a particular temperature or pressure. Those details may be supplied by the specification or dependent claims, but they are not independent limitations of claim 1.

The phrase "adding an aqueous phase" is broad enough to cover buffered and unbuffered aqueous systems unless another claim limitation narrows the process. Claim 9 narrows the aqueous phase to buffered saline.

Product limitations

The resulting complex must have:

No captured volume; and
Substantially no liposomes.

These limitations distinguish the claimed complex from conventional liposomal amphotericin B products such as AmBisome. In a conventional liposome, aqueous material is entrapped within vesicles. Claim 1 instead targets a non-liposomal lipid complex, commonly described for ABLC as ribbon-like or particulate rather than vesicular.

The claim also requires a relatively high drug loading. The amphotericin B must constitute approximately 25% to 50% of the complex on a molar basis. A formulation containing amphotericin B at a materially lower molar proportion may not satisfy the claim even if it uses the same lipid pair.

What do claims 2 through 11 add?

The dependent claims progressively narrow the process toward the ABLC formulation.

Claim	Added limitation	Commercial or technical significance
2	Phosphatidylcholine or phosphatidylglycerol	Limits lipid class
3	Dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol	Identifies the principal ABLC lipid pair
4	DMPC:DMPG at 7:3 molar ratio	Tracks the marketed ABLC composition
5	Methylene chloride for the lipid solvent	Narrows the lipid-processing solvent
6	Amphotericin B as the antifungal	Removes other polyene antifungals from the claim
7	DMSO as the drug solvent	Narrows amphotericin B dissolution conditions
8	Acidified ethanol as the drug solvent	Provides an alternative drug-solvent embodiment
9	Buffered saline as the aqueous phase	Narrows the aqueous processing medium
10	Heating at 25°C to 60°C for 10 to 400 minutes	Covers a post-formation thermal treatment
11	Combines the principal ABLC limitations	Narrow, highly specific process claim

Claim 11 is the most commercially targeted claim. It requires:

DMPC and DMPG;
A 7:3 molar ratio;
Amphotericin B;
Methylene chloride as the lipid solvent;
DMSO as the amphotericin B solvent;
Buffered saline as the aqueous phase; and
Amphotericin B at approximately 25% to 50% mole percent.

A manufacturer using the same product composition but a substantially different process may avoid claim 11 if it does not practice each listed process step. Conversely, a process that uses the same solvents but produces a liposomal product rather than a non-liposomal complex would face an argument that the product-result limitations are not met.

Does US Patent 6,406,713 claim Abelcet?

It closely tracks the formulation and process architecture associated with amphotericin B lipid complex products, but it does not claim the Abelcet trade name.

The patent does not use a simple composition claim in the supplied claims. Instead, it claims preparation of a specific class of drug-lipid complexes. The strongest commercial overlap is with products using amphotericin B, DMPC, DMPG, and the 7:3 lipid ratio.

The distinction from AmBisome is material:

Product	Active ingredient	Delivery structure	Principal lipid concept
Abelcet	Amphotericin B	Amphotericin B lipid complex, substantially non-liposomal	DMPC:DMPG, commonly 7:3
AmBisome	Amphotericin B	Liposome	Hydrogenated soy phosphatidylcholine, cholesterol, distearoyl phosphatidylglycerol
Amphotericin B deoxycholate	Amphotericin B	Conventional deoxycholate formulation	Sodium deoxycholate
Amphotericin B colloidal dispersion	Amphotericin B	Colloidal dispersion	Cholesteryl sulfate

The patent’s "substantially free of liposomes" limitation is a central separation point from AmBisome-type formulations. FDA labeling identifies these products as separate amphotericin B formulations with different excipient systems and pharmacologic properties. [3-6]

What formulations are protected by the patent?

The most clearly covered formulation process is:

Amphotericin B;
DMPC and DMPG;
7:3 DMPC:DMPG molar ratio;
Methylene chloride to dissolve the lipid;
DMSO or acidified ethanol to dissolve amphotericin B;
Buffered saline as the aqueous phase;
Amphotericin B at approximately 25% to 50% mole percent; and
A final product substantially free of liposomes.

The patent also reaches broader embodiments under claim 1, including other fatty acids, other phospholipids, and other polyene antifungals. The breadth of claim 1 is reduced by the requirement that the final material be a non-liposomal complex with no captured volume.

Polyene antifungals

Claim 1 is not limited to amphotericin B. It recites a "polyene antifungal agent." Claim 6 narrows the invention to amphotericin B, but the independent claim could potentially cover other polyene agents if they satisfy the remaining process and product limitations.

The practical commercial value of this broader language is limited because amphotericin B is the principal clinically established polyene antifungal associated with lipid-complex products. Other polyenes may present separate issues involving toxicity, formulation feasibility, clinical development, and regulatory approval.

Phospholipid combinations

Claims 2 through 5 focus on phosphatidylcholine and phosphatidylglycerol, particularly DMPC and DMPG. A process using a different phospholipid pair may avoid the dependent claims but could remain within claim 1 if the alternative lipid qualifies as a phospholipid and all other limitations are satisfied.

Drug loading

The 25% to 50% mole-percent range is important. It is not a weight-percent limitation. A freedom-to-operate analysis must normalize the active ingredient and lipid components on a molar basis rather than relying on weight ratios shown in a product specification.

How strong is the patent estate for amphotericin B lipid complexes?

The patent estate represented by US 6,406,713 was technically focused rather than comprehensive. Its main strengths were:

A defined manufacturing sequence;
A non-liposomal product limitation;
A high amphotericin B loading range;
Specific coverage of DMPC and DMPG;
A 7:3 lipid ratio in the narrow claims; and
Direct alignment with the ABLC formulation platform.

Its limitations were equally important:

It is a method patent, not a broad composition claim in the supplied claims.
It requires specified process steps.
It contains the difficult-to-prove "no captured volume" and "substantially free of liposomes" limitations.
Claim 1 covers a broad solvent menu but requires a narrow product architecture.
The patent term has expired.

A historic infringement case would likely have turned on process evidence, product characterization, and the interpretation of "substantially free of liposomes." Relevant evidence could include batch records, solvent-use records, manufacturing instructions, transmission electron microscopy, particle-size analysis, encapsulated-volume testing, lipid-to-drug ratios, and release specifications.

When did US Patent 6,406,713 lose exclusivity?

US Patent 6,406,713 is no longer enforceable because its statutory patent term has ended. The patent was granted on June 18, 2002. US utility patents generally expire 20 years after the earliest effective nonprovisional filing date, subject to patent-term adjustment, patent-term extension, terminal disclaimers, and continuity rules. [1, 2]

For commercial planning in 2026, the relevant conclusion is straightforward: US 6,406,713 does not create a live patent exclusionary right.

The expiration of this patent does not automatically eliminate:

Other patents in the amphotericin B lipid-complex family;
Patents covering a particular manufacturing apparatus;
Patents covering sterile injectable production;
Trade secrets concerning particle formation or scale-up;
FDA exclusivity;
Data exclusivity;
cGMP requirements; or
Patent rights outside the United States.

What is the Orange Book status of US Patent 6,406,713?

US 6,406,713 should not be treated as a current Orange Book barrier.

The Orange Book identifies patents submitted for approved drug products and lists patent-use codes, expiration dates, and exclusivity information where applicable. A patent directed primarily to a manufacturing process may not provide the same generic-launch leverage as a listed formulation or method-of-use patent. Orange Book treatment also depends on the NDA holder's submission and FDA's listing determination. [7]

For amphotericin B lipid complex, the principal regulatory product is Abelcet, approved by FDA as an injectable amphotericin B lipid complex. The product is not a biologic, so biosimilar pathway analysis does not apply. A competing product would generally be assessed through the abbreviated new drug application framework if the reference-product and product-specific requirements are met, although complex injectable formulations can create substantial pharmaceutical-equivalence and sameness issues. [3, 8]

Are there Paragraph IV challenges involving this patent?

A Paragraph IV certification is relevant only if the patent is listed in the Orange Book for the applicable reference product and remains an unexpired patent that the applicant contests.

Because US 6,406,713 has expired, it cannot support a current Paragraph IV launch block. Historical Paragraph IV activity, if any, would have depended on:

Whether the patent was listed for Abelcet;
Whether the listing covered the proposed generic product;
Whether the generic applicant certified that the patent was invalid, unenforceable, or not infringed; and
Whether the NDA holder brought suit within the statutory 45-day period.

The patent itself is now a prior-art and prosecution-history reference rather than a current enforcement asset. Patent litigation databases and FDA Orange Book archival records should be used to verify any historic certification or litigation event. [7, 9]

What patent litigation affects amphotericin B lipid-complex products?

The most relevant litigation risk historically would have been a process-infringement action against a manufacturer producing an ABLC-like product. The patent's claim structure would have made discovery central because infringement cannot be determined solely by comparing trade names or active ingredients.

The principal litigation questions would include:

Whether the accused process dissolves the lipid and drug separately.
Whether the solvents fall within the claimed solvent classes.
Whether an aqueous phase is added before solvent removal.
Whether the resulting complex has no captured volume.
Whether the product is substantially free of liposomes.
Whether amphotericin B represents 25% to 50% of the complex on a molar basis.
Whether process changes occurred after the patent expired.
Whether the accused product is made outside the United States and imported into the United States.

No current infringement exposure arises from an expired patent. Historic settlements or licenses would remain commercially relevant only if they contain surviving confidentiality, royalty, supply, or know-how provisions.

Were licensing deals important to this patent family?

The technology was associated with the commercial development of amphotericin B lipid complex products and was connected to the corporate ownership and commercialization history of The Liposome Company and Enzon. Corporate transactions involving those companies could have transferred patent rights, product rights, or licenses.

A patent assignment is different from a product license. The assignment record establishes ownership of the patent. A commercial license may contain additional restrictions not visible in the issued patent. Because US 6,406,713 has expired, any continuing value of historic licensing agreements would likely relate to know-how, manufacturing assistance, territorial rights, royalties accrued before expiration, or other contractual provisions rather than current patent exclusivity.

What generic entry risks exist for amphotericin B lipid complex?

Generic entry remains technically difficult even after patent expiration.

Pharmaceutical-equivalence risk

A generic applicant must address the active ingredient, dosage form, route of administration, strength, excipients, and product performance. Amphotericin B lipid complex is an injectable complex formulation rather than a simple aqueous solution.

Manufacturing risk

The critical manufacturing variables may include:

Lipid hydration;
Solvent exchange;
Amphotericin B incorporation;
Drug-to-lipid molar ratio;
Particle morphology;
Residual solvent levels;
Sterility;
Endotoxin;
Particle-size distribution;
Aggregation; and
Stability during storage.

These issues can create regulatory barriers independent of patent rights.

Clinical and labeling risk

Amphotericin B products have different toxicity profiles, dosing regimens, pharmacokinetics, and indications. A formulation that is chemically similar may still require extensive comparative characterization to establish equivalence under FDA requirements.

Manufacturing-IP risk

Expired patent claims do not eliminate trade-secret risk. A former patent disclosure may describe the broad process while omitting scale-up parameters, mixing conditions, filtration controls, equipment geometry, and acceptance criteria that remain in confidential manufacturing records.

How does US 6,406,713 compare with competing amphotericin B patent strategies?

Patent strategy	Typical protection	Relevance to US 6,406,713
Composition claim	Defines drug, lipid, ratio, or particle structure	US 6,406,713 claims the process with product-result limitations rather than a simple composition in the supplied claims
Manufacturing-process claim	Defines solvent, mixing, aqueous addition, and solvent removal	This is the patent's principal strategy
Liposome claim	Defines vesicle structure and lipid composition	Generally distinguished by the patent's non-liposomal limitation
Method-of-use claim	Covers treatment of fungal infections or a patient population	Not present in the supplied claims
Formulation claim	Covers injectable composition, excipients, concentration, or stability	Only indirectly implicated by the claimed preparation method
Device or container claim	Covers vial, infusion system, or delivery apparatus	Outside the supplied claims
Trade-secret protection	Covers undisclosed scale-up and quality controls	Potentially relevant after patent expiration

What is the geographic coverage?

US 6,406,713 provides rights only in the United States. It does not establish protection in Europe, Japan, Canada, China, or other markets.

International protection would depend on related national filings and their individual expiration dates. Patent-family analysis must distinguish:

Priority applications;
PCT filings;
National-stage applications;
Continuations;
Divisionals;
Continuation-in-part applications;
Granted patents; and
Abandoned applications.

A US expiration date does not establish that every foreign counterpart has expired, although patents from the same priority family often reach the end of their terms at similar times under their respective national rules.

Key Takeaways

US 6,406,713 is a process patent for preparing a non-liposomal drug-lipid complex.
The core product must have no captured volume, be substantially free of liposomes, and contain approximately 25% to 50% polyene antifungal by mole.
The commercial center of gravity is amphotericin B lipid complex using DMPC and DMPG, commonly in a 7:3 molar ratio.
Claims 5, 7, 9, and 11 narrow the process toward the ABLC manufacturing sequence.
The patent does not broadly claim all amphotericin B formulations or all lipid-based delivery systems.
The patent has expired and cannot support a current US patent injunction or Paragraph IV launch block.
AmBisome is structurally distinct because it is a liposomal amphotericin B product.
Current competitive risk is driven more by regulatory equivalence, sterile manufacturing, process know-how, and other patent families than by US 6,406,713.

FAQs

Does US 6,406,713 cover liposomal amphotericin B?

No. The claims require a complex with no captured volume and substantially free of liposomes. Those limitations distinguish the claimed technology from conventional liposomal amphotericin B products such as AmBisome.

Can a company manufacture an ABLC-type product after expiration of US 6,406,713?

Yes, expiration removes the patent's current US exclusionary effect. The manufacturer must still address FDA approval, pharmaceutical equivalence, cGMP compliance, other unexpired patents, trade secrets, and product-specific regulatory requirements.

Is amphotericin B itself protected by US 6,406,713?

No. The patent claims a preparation method for a drug-lipid complex. It does not create exclusive rights in the amphotericin B molecule.

Does changing the lipid ratio avoid every claim?

No. Changing the DMPC:DMPG ratio may avoid claims 3, 4, and 11, but claim 1 is broader and may cover other qualifying lipids if the remaining process and product limitations are met. Because the patent has expired, this distinction is primarily relevant to historical infringement analysis.

Does the patent cover oral or topical amphotericin B products?

Not based on the supplied claims. The claims target preparation of a drug-lipid complex through organic-solvent and aqueous-phase processing. An oral or topical product would require separate analysis of whether its manufacturing process satisfies every claim limitation.

References

United States Patent and Trademark Office. (n.d.). Patent term adjustment and patent term basics. https://www.uspto.gov/patents/laws/patent-term-adjustment
United States Patent and Trademark Office. (2002). U.S. Patent No. 6,406,713, Drug-lipid complexes and methods of making and using same.
U.S. Food and Drug Administration. (n.d.). Abelcet: Amphotericin B lipid complex injection prescribing information.
U.S. Food and Drug Administration. (n.d.). AmBisome: Amphotericin B liposome for injection prescribing information.
U.S. Food and Drug Administration. (n.d.). Amphotericin B deoxycholate prescribing information.
U.S. Food and Drug Administration. (n.d.). Amphotericin B colloidal dispersion prescribing information.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, Orange Book.
U.S. Food and Drug Administration. (2018). Product-specific guidance for generic drug development: Amphotericin B lipid complex injection.
U.S. Food and Drug Administration. (n.d.). Patent certifications and 30-month stays under the Hatch-Waxman Act.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	113468	⤷ Start Trial
Austria	118169	⤷ Start Trial
Australia	1799088	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,406,713

Summary for Patent: 6,406,713