United States Patent 5,213,804: Claim Scope, Expiration, Doxil Landscape, and Generic Entry Risk

U.S. Patent No. 5,213,804 covers long-circulating, polyethylene glycol-modified liposomes designed to accumulate in solid tumors through prolonged bloodstream circulation and tumor extravasation. Its core limitations are narrow: 1% to 20% polymer-derivatized lipid, a mean particle diameter of approximately 70 to 120 nanometers, substantially prolonged blood residence, and, for the anthracycline claims, high drug loading and at least 80% drug entrapment.

The patent issued on May 25, 1993, and, as a pre-1995 patent, generally had a 17-year term from issuance. The patent therefore expired on May 25, 2010, absent a legally operative extension or adjustment. The patent is no longer an enforceable barrier to commercial products, but it remains important as a foundational patent for pegylated liposomal doxorubicin, including Doxil and later generic products.

What does U.S. Patent 5,213,804 protect?

The patent protects a platform technology rather than a single drug. Its claims combine four technical elements:

Claim element	Scope under the supplied claims
Carrier	Liposomes composed of vesicle-forming lipids
Polymer modification	1% to 20% mole percent of an amphipathic lipid derivatized with PEG, polylactic acid, polyglycolic acid, or related copolymers
Particle size	Approximately 0.07 to 0.12 microns, or 70 to 120 nanometers
Pharmacokinetic result	Blood lifetime 24 hours after intravenous injection that is several times greater than unmodified liposomes
Biological objective	Tumor localization through liposome extravasation
Drug payload	Broadly, any compound; more narrowly, anthracyclines including doxorubicin, epirubicin, and daunorubicin
Loading limitations	At least 80% entrapped drug and, for certain claims, more than 50 micrograms per micromole of liposome lipid
Administration	Intravenous administration
Therapeutic use	Localization in solid tumors and treatment of breast or colon carcinoma

The invention is commonly associated with the “stealth liposome” or long-circulating liposome platform. The patent’s technical theory is that hydrophilic polymer chains on the liposome surface reduce uptake by the mononuclear phagocyte system, increasing circulation time and permitting accumulation in tumors with abnormal vasculature. U.S. Patent No. 5,213,804 describes this approach through the claim limitations rather than through a purely structural definition of PEGylated liposomes.

How are the claims organized?

Claims 1 through 7: Liposome compositions

Claims 1 through 6 cover composition categories. Claim 1 is the broadest composition claim. It requires:

A liposome formulation;
A polymer-derivatized amphipathic vesicle-forming lipid;
Polymer content of 1% to 20% by mole;
A particle size of 70 to 120 nanometers;
Entrapped compound; and
A prolonged blood lifetime measured 24 hours after intravenous administration.

Claim 2 narrows the polymer to PEG with a molecular weight of 1,000 to 5,000 daltons. Claim 4 narrows the payload to an anti-tumor agent and requires at least 80% entrapment. Claims 5 and 6 narrow the payload further to high-loading anthracyclines, including doxorubicin, epirubicin, and daunorubicin.

Claim 7 is a more concentrated anthracycline formulation claim. It requires PEG, the 70-to-120-nanometer size range, more than 50 micrograms of drug per micromole of lipid, and at least 80% drug entrapment.

Claims 8 through 10: Preparation methods

Claim 8 covers preparing an agent for tumor localization by entrapping the agent in liposomes with the claimed polymer content, size range, and extended circulation characteristic.

Claim 9 adds remote loading across an ion or pH gradient. This limitation is commercially important because Doxil-type products use active loading methods to place doxorubicin into preformed liposomes at high concentration.

Claim 10 limits the drug to doxorubicin, epirubicin, or daunorubicin, including pharmaceutically acceptable salts and acids.

Claims 11 through 15: Tumor-localization and treatment methods

Claim 11 covers intravenous administration to a subject, with tumor accumulation measured 48 hours after dosing. It requires substantially greater tumor localization than liposomes lacking the derivatized lipid.

Claim 13 is the principal disease-treatment claim. It covers treating breast or colon carcinoma with an anthracycline-containing liposome formulation that satisfies the polymer, particle-size, circulation, loading, and entrapment limitations.

Claim 14 narrows claim 13 to PEG with a molecular weight of 1,000 to 5,000 daltons and the listed anthracyclines. Claim 15 further narrows the composition in claim 7 to the same anthracycline group.

Which limitations create the greatest claim-construction risk?

The patent’s strongest limitations are quantitative, but several are also potential litigation vulnerabilities.

Polymer content

The claims require between 1% and 20% mole percent of the derivatized lipid. A product with less than 1% or more than 20% would fall outside the literal range, subject to possible application of the doctrine of equivalents. The relevant calculation would depend on how the parties define total vesicle-forming lipid and whether all lipid components are included in the denominator.

Particle size

The 70-to-120-nanometer limitation is central. The relevant metric is described as mean or average size, not necessarily every particle size. A manufacturer could create claim risk even where the distribution extends outside the range if the reported mean remains within it.

Particle-size testing methodology would likely matter. Dynamic light scattering, electron microscopy, and other techniques can produce different measurements. Batch specifications, release testing, and stability data would be important evidence in a dispute.

“Several times greater” blood lifetime

Claims 1, 7, 8, and related claims require a blood lifetime 24 hours after injection that is “several times greater” than the lifetime of liposomes without the derivatized lipid. This is a relative, comparative limitation.

The claim does not state a universal numerical threshold for “several times.” A court would likely examine the specification, examples, prosecution history, and experimental protocol. The comparison requires an appropriate control formulation lacking the derivatized lipid. Differences in lipid composition, size, dose, marker, species, sampling, and assay could materially affect the result.

“Substantially greater” tumor localization

Claim 11 requires tumor localization 48 hours after intravenous administration that is substantially greater than that of non-derivatized liposomes. This creates a second comparative performance limitation. It may be difficult to establish infringement from commercial product specifications alone because the comparison requires experimental data.

Drug loading and entrapment

Claims 5, 7, 9, 13, and 14 require more than 50 micrograms of drug per micromole of lipid. Claims 4, 7, and 13 also require at least 80% of the drug to be entrapped.

These are formulation-specific limitations. A product may contain doxorubicin in a liposome but avoid literal infringement if its drug-to-lipid ratio is 50 micrograms per micromole or less, or if its entrapment percentage falls below 80%. The measurement protocol must distinguish entrapped drug from free drug and account for assay variability.

Claim 3’s dependency problem

Claim 3 depends on claim 2 but recites polylactic acid, polyglycolic acid, and their copolymers rather than PEG. Read literally, claim 3 incorporates claim 2’s PEG molecular-weight limitation while identifying a different polymer class. That creates an apparent internal inconsistency.

A court may interpret the claim to preserve the parent limitations, construe the language in light of the specification and prosecution history, or find the limitation indefinite. The issue weakens claim 3 relative to a cleanly drafted independent claim, but it does not necessarily affect the validity or scope of the other claims.

What is the patent’s expiration date?

Event	Date or status
Patent issued	May 25, 1993
Applicable basic term	Generally 17 years from issuance for a pre-June 8, 1995 patent
Expected basic expiration	May 25, 2010
Current enforceability	Expired
Current use of patent	Historical prior art and patent-landscape reference, not an active exclusionary right

The term framework derives from the pre-1995 patent-term rules in 35 U.S.C. § 154. Patent-term adjustment rules that apply to later-filed patents do not ordinarily change the basic analysis for a patent issued in 1993. The patent should still be checked against the USPTO patent record and any terminal disclaimer or extension record when conducting a litigation-grade freedom-to-operate review. The available public record identifies the patent as an expired foundational patent.

What was the relationship to Doxil and pegylated liposomal doxorubicin?

Doxil is a pegylated liposomal formulation of doxorubicin hydrochloride. The formulation uses long-circulating liposomes and active drug loading, the same technical category addressed by claims 7, 9, 13, and 14. The FDA approved Doxil for AIDS-related Kaposi’s sarcoma, ovarian cancer after prior chemotherapy, and multiple myeloma in specified treatment combinations. [U.S. Food and Drug Administration, n.d.-a]

The patent’s claim scope maps most closely to:

PEGylated liposome composition;
Approximate nanoscale particle size;
Intravenous delivery;
High doxorubicin entrapment;
Active loading of doxorubicin into preformed liposomes;
Prolonged circulation;
Tumor localization; and
Treatment of specified solid tumors.

The patent did not by itself define every commercial characteristic of Doxil. Doxil’s regulatory and commercial product profile also depends on manufacturing controls, lipid composition, particle-size distribution, release specifications, sterility, infusion instructions, stability, and quality attributes in the approved application.

What patents protected Doxil beyond U.S. Patent 5,213,804?

The Doxil patent estate included more than one patent family. The estate generally divided into several layers:

Patent layer	Typical subject matter	Relevance
Foundational stealth-liposome patents	Polymer-coated, long-circulating liposomes	Platform protection
Anthracycline formulation patents	Doxorubicin or related anthracyclines in PEGylated liposomes	Product composition
Active-loading patents	Loading across pH or ion gradients	Manufacturing and formulation
Process patents	Lipid hydration, extrusion, loading, purification, and sterilization	Manufacturing barriers
Method-of-use patents	Cancer treatment and tumor localization	Therapeutic use
Regulatory listings	Patents identified in the FDA Orange Book	ANDA patent-certification obligations

The exact enforceability of each patent depended on its own filing date, patent term, terminal disclaimer, patent-term extension, listed claims, and litigation history. U.S. Patent 5,213,804 was a core historical platform patent, but it was not the only possible intellectual-property right relevant to a Doxil-type product.

What was the Orange Book status of U.S. Patent 5,213,804?

The patent was associated historically with the Doxil regulatory patent estate. Orange Book listings matter during the active patent term because an ANDA applicant must address listed patents through a Paragraph I, II, III, or IV certification, depending on the patent and the applicant’s position.

After expiration, the patent no longer blocks approval through a Paragraph III certification. A Paragraph IV challenge to an expired patent generally has no practical exclusionary effect, although historical litigation records may remain relevant to prosecution strategy and patent-validity analysis.

The Orange Book does not replace a complete patent search. It identifies patents submitted by a new drug application holder and accepted for listing, but it does not capture every manufacturing patent, foreign patent, pending application, trade secret, or non-listed patent claim. [U.S. Food and Drug Administration, n.d.-b]

Which companies challenged or competed against Doxil?

The commercial competition involved generic or alternative suppliers of pegylated liposomal doxorubicin, rather than biosimilar applicants. Doxorubicin is a chemically synthesized small molecule, so products competing with Doxil proceed through the ANDA pathway, not the biosimilar pathway under the Public Health Service Act.

Sun Pharmaceutical Industries obtained FDA approval for a generic pegylated liposomal doxorubicin product marketed as Lipodox in the United States. FDA product records identify generic liposomal doxorubicin products separately from conventional doxorubicin hydrochloride injections. [U.S. Food and Drug Administration, n.d.-c]

The competitive categories are:

Brand Doxil;
Generic pegylated liposomal doxorubicin;
Conventional doxorubicin hydrochloride injection;
Other anthracycline products, including daunorubicin and epirubicin; and
Non-anthracycline therapies for ovarian cancer, multiple myeloma, Kaposi’s sarcoma, and related indications.

A conventional doxorubicin injection is not automatically substitutable for pegylated liposomal doxorubicin. The products differ in pharmacokinetics, formulation, dosing, toxicity profile, administration, and labeled use.

Are there biosimilar risks for this patent?

There is no biosimilar risk directly associated with U.S. Patent 5,213,804. The relevant competitive risk is generic entry through the ANDA pathway.

The formulation presents technical equivalence issues that are more complex than those for a simple immediate-release tablet. An ANDA applicant must establish pharmaceutical equivalence and bioequivalence under FDA requirements applicable to complex liposomal products. Relevant characteristics can include:

Lipid composition;
Drug-to-lipid ratio;
Particle-size distribution;
Surface PEG density;
Encapsulation efficiency;
Free-drug content;
Release profile;
Morphology;
Zeta potential;
Stability;
Sterility; and
Pharmacokinetic behavior.

These requirements can create regulatory and manufacturing barriers even after composition patents expire. They do not extend the term of an expired patent.

What generic launch scenarios exist?

Immediate post-expiry entry

This is the lowest patent-risk scenario for claims in U.S. Patent 5,213,804. A compliant generic could launch after patent expiration, subject to FDA approval and any surviving patents or regulatory exclusivities.

Formulation-design-around entry

A product could avoid literal claim scope by using a different polymer, polymer percentage, particle-size mean, loading ratio, or entrapment profile. This approach still requires FDA demonstration of equivalence and may create new patent exposure under later formulation or process patents.

Paragraph IV launch before expiration

Before expiration, an ANDA applicant could certify that the listed patent was invalid, unenforceable, or not infringed. A timely Paragraph IV notice could trigger patent litigation and a 30-month stay under the Hatch-Waxman framework. [U.S. Congress, 1984] For this patent, that route is now historical because the patent expired in 2010.

Post-expiry market entry with manufacturing constraints

Even without active patent barriers, complex liposome manufacturing can limit entry. The principal barriers are process reproducibility, scale-up, sterile filtration, active-loading consistency, product characterization, and FDA inspection readiness.

How strong is the patent estate today?

The enforceability of U.S. Patent 5,213,804 is zero because the patent expired. Its historical technical breadth was substantial, but the claim scope was constrained by cumulative requirements:

Polymer derivatization;
1% to 20% mole percent;
70-to-120-nanometer average size;
Comparative circulation performance;
Comparative tumor localization for some method claims;
High entrapment;
High drug-to-lipid loading; and
Specified anthracycline or disease limitations in narrower claims.

The patent was strongest against products that closely reproduced the canonical PEGylated liposomal doxorubicin architecture. It was weaker against products that used materially different polymer chemistry, particle-size specifications, drug-loading ratios, or delivery mechanisms. Its current business value is historical and evidentiary rather than exclusionary.

What licensing and settlement issues matter?

The supplied information does not establish a specific license, settlement, covenant not to sue, or patent assignment agreement for U.S. Patent 5,213,804. The patent was associated with the Liposome Technology and Doxil technology lineage, but commercial rights could have changed through assignments, acquisitions, sublicenses, or product-specific arrangements.

For present diligence, expired-patent licensing has limited exclusionary value. The relevant commercial questions are whether a surviving patent family, manufacturing know-how, regulatory file, trademark, or supply agreement remains in force. A license to an expired patent alone would not prevent generic commercialization.

Key Takeaways

U.S. Patent 5,213,804 covers long-circulating PEGylated and related polymer-modified liposomes.
The key quantitative limitations are 1% to 20% derivatized lipid, 70-to-120-nanometer average size, prolonged circulation, at least 80% entrapment, and more than 50 micrograms of anthracycline per micromole of lipid.
Claims 7, 9, 13, and 14 are the most relevant to Doxil-type pegylated liposomal doxorubicin products.
Claim 3 contains an apparent dependency and polymer-selection inconsistency.
The patent issued May 25, 1993, and expired May 25, 2010, under the standard pre-1995 patent-term framework.
The patent no longer blocks generic entry.
Doxil competition proceeds through the generic drug pathway, not the biosimilar pathway.
Generic pegylated liposomal doxorubicin products, including Sun Pharma’s Lipodox, demonstrate that commercial competition exists beyond the original patent term.
Manufacturing complexity remains a practical barrier even where foundational patents have expired.
Current freedom-to-operate analysis must focus on later formulation, process, manufacturing, and regulatory patents rather than U.S. Patent 5,213,804 alone.

Frequently Asked Questions

Does U.S. Patent 5,213,804 cover all PEGylated liposomes?

No. It covers products and methods meeting the listed limitations, including the 1% to 20% polymer-lipid range, 70-to-120-nanometer average size, and prolonged blood-lifetime requirement. It does not cover every PEGylated liposome irrespective of size, composition, polymer density, or use.

Does the patent cover conventional doxorubicin injection?

No. Conventional doxorubicin hydrochloride injection generally lacks the claimed liposomal carrier, PEG-derivatized lipid, particle-size limitation, and liposome entrapment requirements.

Is Doxil still protected by U.S. Patent 5,213,804?

No. The patent expired in 2010. Doxil may have been subject to other patents, regulatory protections, trademarks, or commercial rights, but this patent is not an active exclusionary right.

Can a generic liposomal doxorubicin product avoid the patent by changing particle size?

Historically, a product outside the claimed 70-to-120-nanometer average range could avoid literal infringement of that limitation. Because the patent is expired, particle-size changes are now primarily relevant to FDA equivalence, product performance, and later patent families.

Is PEGylated liposomal doxorubicin a biosimilar?

No. Doxorubicin is a small-molecule active ingredient. Competing liposomal doxorubicin products generally use the ANDA framework, although complex liposome equivalence requirements can make development technically demanding.

References

U.S. Congress. (1984). Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585.
U.S. Food and Drug Administration. (n.d.-a). Doxil (doxorubicin hydrochloride liposome injection) prescribing information. https://www.accessdata.fda.gov
U.S. Food and Drug Administration. (n.d.-b). Approved drug products with therapeutic equivalence evaluations: 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. (n.d.-c). Drugs@FDA: FDA-approved drugs. https://www.accessdata.fda.gov/scripts/cder/daf/
U.S. Patent No. 5,213,804. (1993). Long-circulating liposomes for use in therapeutic applications. United States Patent and Trademark Office.
United States Code. (2024). 35 U.S.C. § 154: Contents and term of patent; provisional rights. Legal Information Institute, Cornell Law School. https://www.law.cornell.edu/uscode/text/35/154

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
European Patent Office	0496835	⤷ Start Trial	96C0047	Belgium	⤷ Start Trial
Austria	115401	⤷ Start Trial
Austria	122229	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,213,804

Summary for Patent: 5,213,804