United States Drug Patent 5,013,556: Scope, Claims, Expiration, and PEGylated Liposome Patent Landscape

U.S. Patent No. 5,013,556 covered PEGylated, long-circulating liposomes designed to retain drugs in the bloodstream after intravenous administration. Its central inventive concept was the incorporation of approximately 1-20 mole percent of a polyethylene glycol-derivatized vesicle-forming lipid into liposomes. The patent expired on May 7, 2008, based on the 17-year term applicable to the patent.

The patent is historically important to Doxil and the broader “stealth liposome” platform, but it no longer creates a blocking patent position in the United States. Current commercial risk is regulatory and technical rather than infringement risk under this patent.

What does U.S. Patent 5,013,556 cover?

The patent covers liposomal compositions and administration methods that use PEGylated lipids to extend circulation time and alter tissue distribution after intravenous injection.

The core elements are:

Element	Claimed scope
Dosage form	Liposomes containing an entrapped compound
Administration	Intravenous administration
Lipid modification	1-20 mole percent of an amphipathic, vesicle-forming lipid derivatized with PEG
PEG molecular weight	Approximately 1,000-5,000 daltons in dependent claims
Liposome size	Approximately 0.05-0.5 microns
Circulation effect	Severalfold higher blood level after 24 hours compared with non-PEGylated liposomes
Blood retention	More than approximately 5% or 10% of the administered liposome marker or drug after 24 hours
Lipid composition	In certain claims, 10-40 mole percent cholesterol, 40-85 mole percent neutral phospholipid and 5-15 mole percent PEGylated phospholipid
Drug	Doxorubicin, pharmacologically acceptable analogs or salts, and other amphipathic antitumor compounds
Targeting	Antibodies, CD4 peptide, or other ligands directed to cell-surface binding molecules
Cleavability	Esterase- or peptidase-sensitive linkages between the PEG polymer and lipid

The broadest platform concept appears in claims 1 and 18. Claims 23 and 26 extend the protection to methods of administering or selectively delivering a drug.

When did U.S. Patent 5,013,556 expire?

U.S. Patent 5,013,556 expired on May 7, 2008.

Event	Date or status
Patent issued	May 7, 1991
Applicable patent term	17 years from issue for this pre-1995 patent
Expiration	May 7, 2008
Current enforceability	Expired
Current Paragraph IV relevance	None for this patent
Current Orange Book blocking effect	None

The patent was issued before the Uruguay Round Agreements Act changed the United States patent term to 20 years from the earliest effective nonprovisional filing date. The expiration date is therefore determined principally from the issue date, subject to any terminal disclaimer or adjustment recorded in the official patent file. The patent is no longer enforceable against U.S. products.[1]

Expiration of this patent does not eliminate other potential patent issues involving a particular PEG-lipid, liposome manufacturing process, drug-loading method, antibody ligand, dosage regimen, or product-specific formulation.

How do the 33 claims divide into technical groups?

Claims 1-17: PEGylated liposome compositions

Claims 1-17 are composition claims. Claim 1 is the principal platform claim. It requires:

Liposomes made from vesicle-forming lipids.
An entrapped compound.
A PEG-derivatized amphipathic vesicle-forming lipid at 1-20 mole percent.
A severalfold blood-level improvement 24 hours after intravenous injection.

The dependent claims narrow the platform by adding size, PEG molecular weight, lipid class, blood-retention performance, cholesterol and phospholipid ratios, drug identity, cleavable linkages and targeting ligands.

Claim 13 is commercially significant because it specifically identifies doxorubicin. Claims 15-17 address ligand-targeted systems, including antibody-targeted liposomes and CD4-peptide liposomes intended to bind HIV-infected T cells or B cells.

Claims 18-22: Circulation-time and RES-related methods

Claim 18 covers a method for increasing circulation time by incorporating PEGylated lipid at 1-20 mole percent, with the stated effect being substantially independent of the saturation level of the base vesicle-forming lipids.

Claims 19-22 cover ligand-bearing liposomes administered intravenously to influence uptake by the reticuloendothelial system, or RES. These claims combine PEGylation with surface targeting.

The claims distinguish between two biological effects:

PEGylation reduces nonspecific uptake by macrophages and other RES components, increasing blood residence.
A targeting ligand can increase uptake by selected cells carrying the corresponding binding molecule.

The combination creates a targeted long-circulating liposome rather than a conventional rapidly cleared liposome.

Claims 23-25: Intravenous drug administration

Claims 23-25 cover administration methods requiring a specified level of drug or drug-associated material in the bloodstream 24 hours after dosing.

These claims are narrower than a general claim to any PEGylated liposome because they include quantitative pharmacokinetic outcomes. The relevant threshold is at least approximately 5% of the administered compound in claim 23 and at least approximately 10% in claim 25.

Claims 26-33: Selective delivery and disease-targeting methods

Claims 26-33 cover delivery to target tissues with surface-specific ligand-binding molecules. The target can be a solid tumor, and the ligand can be an antibody against a tumor-specific antigen.

Claims 29 and 30 specifically address:

Antibody-directed delivery to solid tumors.
Doxorubicin-loaded liposomes for solid tumors.

Claims 31-33 add PEG molecular weight, phospholipid composition and HIV-infected T-cell or B-cell targeting. Claim 33 appears to contain a drafting or transcription error referring to “D4 peptide”; the corresponding limitation in claim 17 is CD4 peptide.

How strong was the scope of the independent claims?

The patent’s strongest historical position was its broad platform coverage of PEGylated liposomes used intravenously to improve circulation time.

Claim 1

Claim 1 combined structural and functional limitations. The structural limitation was the inclusion of 1-20 mole percent PEGylated amphipathic lipid. The functional limitation required a severalfold higher blood level after 24 hours than the corresponding non-PEGylated liposomes.

This structure-function combination had two effects:

It supported coverage of different drugs, lipid mixtures and PEG-lipid chemistries.
It created potential claim-construction and proof issues because infringement could depend on comparative pharmacokinetic testing.

A product could avoid literal infringement if it did not meet the PEG content, lipid derivatization or 24-hour blood-level limitation. It could also present a dispute over the proper control formulation used to establish the “absence of the derivatized lipid” comparison.

Claim 18

Claim 18 was broad in technical concept but required the claimed circulation-time increase. It also stated that the effect was substantially independent of lipid-chain saturation. This language sought to prevent design-arounds based solely on changing saturated versus unsaturated lipid components.

Claim 23

Claim 23 shifted the focus from liposome retention to drug level in the bloodstream. This could be commercially important because drug retention and intact-liposome retention are not identical measurements. A formulation may retain lipid marker in blood without maintaining the same percentage of free drug.

Claim 26

Claim 26 addressed targeted delivery to a tissue with surface-bound binding molecules. It required:

PEGylated lipid at 1-20 mole percent.
A surface-bound ligand.
Entrapped drug.
Intravenous administration.
Selective delivery to the target tissue.

This claim could cover antibody-targeted PEGylated liposomes, but only where the product and method satisfy the targeting and delivery limitations. It would not necessarily cover an untargeted stealth liposome used for passive tumor accumulation.

What formulations are protected by the patent?

The claims cover a broad family of PEGylated formulations, including formulations with the following characteristics:

Formulation attribute	Claimed or relevant range
PEGylated lipid	1-20 mole percent
PEG size	1,000-5,000 daltons
Liposome diameter	50-500 nanometers
Cholesterol	10-40 mole percent in claim 9
Neutral phospholipid	40-85 mole percent in claim 9
PEGylated phospholipid	5-15 mole percent in claim 9
Phospholipid	Phosphatidylethanolamine in claims 6 and 8
Acyl chains	Predominantly 18-carbon chains with at least one unsaturated bond in claim 7
Drug	Doxorubicin and pharmacologically acceptable analogs or salts
Surface ligand	Antibody, CD4 peptide or another high-affinity ligand
Linkage	Esterase- or peptidase-sensitive PEG-lipid linkage

The patent does not limit every claim to a single PEG-lipid species. Its language reaches PEG attached to an amphipathic vesicle-forming lipid, including PEG-lipid structures in which the polymer is linked through a phospholipid head group or lipid amine group.

Did the patent cover Doxil?

The patent covered formulations within its claim limitations that used PEGylated liposomes containing doxorubicin. Claim 13 expressly recites doxorubicin, while claims 23, 25, 26 and 30 cover related administration and delivery methods.

Doxil is a pegylated liposomal formulation of doxorubicin hydrochloride. The FDA approved Doxil in 1995 for AIDS-related Kaposi’s sarcoma and later expanded its indications to ovarian cancer and multiple myeloma.[2]

The commercial Doxil formulation also depended on product-specific technology involving:

Remote loading of doxorubicin.
Ammonium sulfate or related transmembrane-gradient loading systems.
Defined hydrogenated soy phosphatidylcholine and cholesterol components.
Methoxy-PEG-linked distearoyl phosphatidylethanolamine, commonly referred to as MPEG-DSPE.
Controlled particle-size distribution.
Sterile injectable manufacturing.

Those product attributes could implicate patents other than U.S. Patent 5,013,556. The expired patent should therefore be treated as a foundational platform patent, not as a complete description of every Doxil-related intellectual-property right.

What is the Orange Book status of U.S. Patent 5,013,556?

U.S. Patent 5,013,556 no longer creates an Orange Book barrier to generic entry. Orange Book-listed patents for a drug product are tied to the approved product and the NDA holder’s patent certifications. The existence of the expired patent does not prevent an ANDA applicant from relying on an expired platform patent.[3]

For liposomal doxorubicin products, regulatory competition is more complex than conventional doxorubicin injection because the reference product has critical quality attributes involving liposome size, encapsulation, leakage, release and composition.

The main U.S. regulatory pathway is an ANDA when the applicant can demonstrate pharmaceutical equivalence and bioequivalence. FDA has approved generic versions of pegylated liposomal doxorubicin, including products marketed by manufacturers such as Sun Pharma under the Lipodox name.[4]

Which companies challenged or commercialized the technology?

The technology moved through the early liposome biotechnology sector before becoming associated with Sequus Pharmaceuticals and then Johnson & Johnson’s ALZA organization.

Company	Role
Liposome Technology, Inc.	Early developer and patent holder associated with the platform
Sequus Pharmaceuticals	Developed and commercialized Doxil technology
ALZA Corporation	Acquired Sequus and continued Doxil commercialization
Johnson & Johnson	Acquired ALZA and became the major commercial sponsor of Doxil
Sun Pharmaceutical Industries	Commercialized a generic pegylated liposomal doxorubicin product
Other generic manufacturers	Compete through ANDA approvals and formulation development

The principal commercial licensing and acquisition path was corporate rather than a simple single-product license. Sequus acquired or obtained rights to the liposome technology developed by Liposome Technology, Inc.; ALZA later acquired Sequus; Johnson & Johnson acquired ALZA. These transactions transferred commercial control over Doxil and related liposome assets.[5]

What patent landscape surrounded the patent?

The patent landscape included several overlapping categories.

Foundational PEG-liposome patents

These patents addressed the use of PEG or related hydrophilic polymers on liposome surfaces to reduce RES clearance and increase circulation time. U.S. Patent 5,013,556 is one of the principal early U.S. patents in this category.

Other patent families pursued:

Alternative PEG-lipid structures.
Different polymer molecular weights.
Cleavable PEG linkages.
Polymer coating densities.
Long-circulating liposome compositions with specific lipid mixtures.

Doxorubicin-loading patents

A separate group covered loading anthracyclines into liposomes using transmembrane gradients. These patents were important to Doxil because remote loading permits high doxorubicin encapsulation and helps control leakage.

The commercial value of this area was tied to:

Drug-to-lipid ratio.
Encapsulation efficiency.
Release rate.
Stability during storage.
Reduction of free doxorubicin.

Formulation patents

Formulation patents addressed the precise lipid composition and injectable product characteristics, including:

Hydrogenated phosphatidylcholine.
Cholesterol.
MPEG-DSPE.
Buffer systems.
Cryoprotectants.
Particle size.
Sterility and storage stability.

A generic manufacturer can avoid an expired composition patent while still needing to reproduce the reference product’s performance and quality attributes.

Method-of-use patents

Method patents covered administration of liposomal doxorubicin for:

Ovarian cancer.
AIDS-related Kaposi’s sarcoma.
Multiple myeloma.
Solid tumors.
Combination regimens.

Method-of-use claims can remain relevant after a platform composition patent expires, particularly where the label includes a patented indication or dosing schedule. Their practical value depends on listing status, expiration, carve-out feasibility and the applicant’s proposed label.

Targeted liposome patents

Targeted liposome patents covered antibodies, peptides and receptor-binding ligands attached to the liposome surface. Claims 15-17 and 26-33 are examples of this category.

The main design variables are:

Ligand identity.
Linker chemistry.
Ligand density.
Target antigen.
Tumor or cell type.
Internalization mechanism.
PEG placement relative to the ligand.

A product using a non-targeted PEGylated liposome generally would not fall within the antibody-targeting limitations of claims 15-17 or 26-33.

Are there biosimilar risks for this patent?

No biosimilar issue applies directly to U.S. Patent 5,013,556. Doxil is a small-molecule drug product in a liposomal delivery system, not a biologic subject to the biosimilar pathway under the Public Health Service Act.

The relevant competitive pathway is generic or follow-on liposomal drug approval under the Federal Food, Drug, and Cosmetic Act. The technical challenge is demonstrating equivalence for a complex drug-delivery system rather than proving biosimilarity to a therapeutic protein.[2][4]

What generic launch risks exist after patent expiration?

The patent expiration removed the principal platform barrier, but generic launch risk remains in four areas.

Pharmaceutical equivalence

A follow-on product must match the active ingredient, dosage form, route and strength. For pegylated liposomal doxorubicin, this requires control of the liposomal carrier as well as the drug.

Bioequivalence

Conventional plasma pharmacokinetic testing may not fully describe the behavior of encapsulated versus free doxorubicin. FDA has therefore treated liposomal products as complex formulations requiring product-specific analytical and clinical-development strategies.[4]

Manufacturing barriers

Manufacturing know-how can be more difficult to replicate than the expired patent. Key barriers include:

Consistent liposome formation.
Remote loading.
Removal of unencapsulated drug.
Control of free doxorubicin.
Particle-size distribution.
PEG-lipid incorporation.
Aseptic processing.
Long-term stability.

Commercial barriers

The launch profile depends on:

Number of approved ANDA competitors.
Supply reliability.
Hospital contracting.
Oncology distribution.
Reimbursement.
Shortage risk.
Reference-product switching behavior.

The expired patent supports entry but does not guarantee rapid substitution.

How does this patent compare with a modern liposomal drug patent?

U.S. Patent 5,013,556 is a broad, platform-oriented patent. Modern liposomal patents are usually narrower and more product-specific.

Issue	U.S. Patent 5,013,556	Modern liposomal patent
Primary focus	PEGylation and circulation time	Defined product, process or treatment
Claim style	Broad composition and method claims	Narrow structural and performance limitations
Pharmacokinetics	24-hour blood retention and blood/RES ratio	Often release, exposure or tissue-distribution parameters
Drug coverage	Broad compound language with doxorubicin species	Usually one active ingredient or combination
Targeting	Broad ligand concepts	Defined ligand, antigen or conjugation chemistry
Manufacturing	Limited compared with later patents	Often central to claim scope
Current status	Expired	Depends on filing and term dates

The patent’s historical strength came from claiming the platform before PEGylated liposomes became a standard delivery architecture. Its current commercial strength is zero because the patent has expired.

What is the geographic coverage?

U.S. Patent 5,013,556 provides only U.S. patent rights. Corresponding protection would have depended on separately filed foreign applications and national patents.

For a current freedom-to-operate review, the relevant jurisdictions include:

United States.
European Patent Convention states.
Canada.
Japan.
Australia.
China.
South Korea.
India.

The expiration of the U.S. patent does not establish freedom to operate in other countries. Foreign counterparts may have had different filing dates, prosecution histories, patent-term adjustments, supplementary protection rights or earlier expiration dates.

Key Takeaways

U.S. Patent 5,013,556 covered PEGylated long-circulating liposomes for intravenous drug delivery.
The principal claimed range was 1-20 mole percent PEGylated amphipathic lipid.
Dependent claims addressed 0.05-0.5 micron liposomes, 1,000-5,000 dalton PEG, phosphatidylethanolamine, cholesterol, doxorubicin and targeting ligands.
Claims 1, 18 and 23 were the principal platform and pharmacokinetic claims.
Claims 13 and 30 specifically connected the patent to doxorubicin and tumor delivery.
The patent expired on May 7, 2008.
It no longer blocks generic entry or creates a Paragraph IV risk.
Doxil competition is governed by complex formulation, manufacturing, regulatory and product-specific patent issues rather than this expired patent.
No biosimilar pathway applies; follow-on products compete through generic or equivalent liposomal drug approval routes.
The patent remains important as prior art and as a historical foundation for stealth liposome technology.

FAQs About U.S. Patent 5,013,556

Was U.S. Patent 5,013,556 the main Doxil patent?

It was a foundational PEGylated-liposome patent relevant to Doxil, but Doxil also depended on separate drug-loading, formulation, manufacturing and method-of-use technology.

Can a company still sue over U.S. Patent 5,013,556?

No. The patent expired in 2008 and cannot support a new infringement action for currently marketed products.

Did the patent cover all PEGylated liposomes?

No. The claims required specific limitations, including vesicle-forming lipids, PEG derivatization, a stated PEG-lipid concentration and, in several claims, specified pharmacokinetic results.

Does PEGylated doxorubicin require a biosimilar application?

No. Pegylated liposomal doxorubicin is regulated as a complex small-molecule drug product. The relevant approval route is generally an ANDA or another applicable drug application pathway, not a biosimilar application.

Are antibody-targeted liposomes still exposed to patent risk?

Yes. The expired patent does not create current risk, but later patents may cover specific antibodies, tumor antigens, linker chemistries, ligand densities, manufacturing processes or targeted-liposome formulations.

References

United States Patent and Trademark Office. (1991). U.S. Patent No. 5,013,556, Liposomes with enhanced circulation time. U.S. Department of Commerce.
U.S. Food and Drug Administration. (2022). Doxil (doxorubicin hydrochloride liposome injection) prescribing information.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
U.S. Food and Drug Administration. (2018). Draft guidance on doxorubicin hydrochloride liposome injection. Center for Drug Evaluation and Research.
Johnson & Johnson. (2000). Annual report. Johnson & Johnson.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0496835	⤷ Start Trial	960031	Netherlands	⤷ Start Trial
European Patent Office	0496835	⤷ Start Trial	SPC/GB96/053	United Kingdom	⤷ Start Trial
European Patent Office	0496835	⤷ Start Trial	C960031	Netherlands	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 5,013,556