US Patent 5,211,938: Scope, Claims, Expiration, and Patent Landscape for 5-Aminolevulinic Acid Fluorescence Diagnosis

US Patent 5,211,938 covered a method of detecting malignant and non-malignant tissue abnormalities by administering a precursor of protoporphyrin IX, illuminating the patient at a wavelength absorbed by protoporphyrin IX, and detecting induced fluorescence. Claim 2 specifically identified 5-aminolevulinic acid, or ALA, as the precursor.

The patent issued on May 18, 1993, and its 17-year term expired on May 18, 2010, assuming no term adjustment or other extension altered the term. The patent is therefore no longer enforceable in the United States. Its commercial importance remains historical and technical: it established a foundational claim set for ALA-induced protoporphyrin IX fluorescence in tumor and lesion detection.

What does US Patent 5,211,938 protect?

The patent protects a diagnostic method based on selective accumulation of protoporphyrin IX, or PpIX, after administration of a heme-biosynthesis precursor.

Patent identification

Field	Information
Patent	US 5,211,938
Title	Photodiagnosis and phototherapy of tumors using 5-aminolevulinic acid
Issue date	May 18, 1993
Patent type	Utility patent
Principal technology	PpIX-induced fluorescence diagnosis
Key active precursor	5-Aminolevulinic acid
Claimed indications	Skin, mucosa, endometrium and urothelium abnormalities and lesions
Current status	Expired
Original term	Generally 17 years from issuance for this pre-June 8, 1995 patent
Expected expiration	May 18, 2010

The patent’s core concept is metabolic imaging. A precursor is administered, abnormal tissue preferentially converts or accumulates the precursor as PpIX, light excites PpIX, and the resulting fluorescence identifies the lesion. The patent is not limited to treatment, surgery, biopsy guidance, or a particular imaging instrument.

What are the elements of claim 1?

Claim 1 is an independent method claim with several cumulative limitations. A potential infringement analysis would require all material elements to be present.

Claim 1 limitation analysis

Claim element	Scope and legal effect
Detecting tissue abnormalities and lesions	The claim is directed to detection, not merely administration or imaging
Malignant and non-malignant abnormalities	The claim covers both cancerous and non-cancerous lesions
Specified anatomical sites	Skin, mucosa, endometrium and urothelium are expressly identified
Administration to a patient	The claimed method requires administration to a patient
Effective amount	The administered amount must induce the claimed biological response
Precursor of PpIX in the heme pathway	The independent claim is broader than ALA alone
Preferential PpIX synthesis	The abnormality or lesion must preferentially synthesize PpIX
Light within PpIX absorbance spectrum	Illumination must excite PpIX
Fluorescence induction	The light must induce fluorescence
Fluorescence detection	The operator must detect fluorescence in the abnormality or lesion

The claim does not recite a specific dose, route of administration, light source, detector, surgical procedure, imaging software, fluorescence threshold, or diagnostic conclusion.

How broad is the precursor limitation?

Claim 1 covers a precursor of PpIX in the biosynthetic pathway for heme. Claim 2 narrows the method to ALA.

ALA is the immediate precursor used in the first committed steps of heme biosynthesis. Exogenous ALA can increase intracellular PpIX concentrations, particularly in certain abnormal tissues. The independent claim could therefore encompass precursor compounds other than ALA if they satisfy the functional and pathway limitations.

The breadth is constrained by the requirement that the precursor induce PpIX synthesis preferentially in the claimed abnormalities or lesions. A compound that merely causes nonspecific fluorescence, or that produces a different fluorophore unrelated to PpIX, would not naturally satisfy the claim.

Claim 2 and ALA

Claim 2 depends on claim 1 and specifies 5-aminolevulinic acid. A method using ALA must still meet every limitation of claim 1, including:

administration to a patient;
detection of malignant or non-malignant lesions;
preferential PpIX synthesis in the lesion;
illumination within the PpIX absorbance spectrum; and
fluorescence detection.

Claim 2 does not cover every use of ALA. It is directed to the claimed fluorescence-detection method in the specified tissue categories.

What tissue types are covered by US 5,211,938?

The claim expressly identifies four tissue categories:

Skin.
Mucosa.
Endometrium.
Urothelium.

The language includes malignant and non-malignant abnormalities and lesions. The claim therefore reaches beyond oncology in the narrow sense. A non-malignant lesion could fall within the claim if the other limitations are satisfied.

The term "mucosa" is potentially broad, but its scope would depend on claim construction and the patent specification. The explicit references to endometrium and urothelium indicate particular interest in gynecologic and urinary-tract applications.

The claim does not expressly identify the brain, gastrointestinal tract, lung, oral cavity, cervix, or other organs. Whether a particular mucosal site falls within the claim would depend on whether it is properly characterized as mucosa and whether the claimed PpIX-selective response occurs.

What technology did the patent establish?

The invention rests on three biological and optical steps.

PpIX accumulation

ALA enters the heme biosynthetic pathway and can increase PpIX production. Tumor and abnormal cells may accumulate more PpIX than surrounding tissue because of differences in uptake, mitochondrial activity, enzyme activity, or heme-pathway regulation.

Optical excitation

PpIX absorbs light in several bands, including a strong absorption region commonly associated with blue-light excitation near 405 nm. Other wavelengths within the PpIX absorption spectrum can also produce fluorescence.

Fluorescence detection

Excited PpIX emits red fluorescence. The claimed method detects that fluorescence in the lesion. The patent does not require a specific camera, endoscope, filter, software algorithm, or numerical fluorescence ratio.

When did US Patent 5,211,938 lose exclusivity?

US Patent 5,211,938 lost patent exclusivity on May 18, 2010, based on the ordinary 17-year term applicable to patents issued before the Uruguay Round Agreements Act changed the patent-term framework.

Exclusivity timeline

Date	Event
1990 or earlier priority period	Foundational ALA/PpIX photodiagnostic work was pursued
May 18, 1993	US 5,211,938 issued
1990s	ALA fluorescence diagnosis moved toward dermatology and urology applications
1999	FDA approved topical ALA hydrochloride for actinic keratosis treatment under the Levulan brand
2010	Cysview, based on hexaminolevulinate, received FDA approval for bladder cancer detection
May 18, 2010	US 5,211,938 ordinary patent term expired
Present	The claims cannot be enforced against new US activity

Patent expiration does not eliminate technical relevance. It removes the exclusionary right created by the patent. Later patents could still protect specific formulations, devices, dosing regimens, imaging systems, or clinical uses.

What is the FDA regulatory status of the technology?

The FDA has authorized products using the ALA/PpIX pathway, but those approvals are not identical to the method claimed in US 5,211,938.

Levulan

Levulan Kerastick contains aminolevulinic acid hydrochloride and is approved for treatment of actinic keratoses when used with blue-light illumination. Its FDA indication is therapeutic rather than a general fluorescence-detection indication. FDA labeling identifies ALA metabolism to PpIX and photodynamic activity as part of the mechanism.[2]

Cysview

Cysview contains hexaminolevulinate hydrochloride and is approved for use with the Karl Storz D-Light C Photodynamic Diagnostic System to assist in the detection of malignant lesions in the bladder in patients with known or suspected bladder cancer.[3]

Cysview is commercially important because it illustrates a later, more specific implementation of the same broad biological principle. It uses an ALA derivative, a specified urinary-tract application, and a dedicated cystoscopic imaging system.

Regulatory comparison

Product	Active precursor	FDA use	Primary purpose	Relationship to US 5,211,938
Levulan Kerastick	ALA hydrochloride	Actinic keratosis	Treatment	Uses the same PpIX pathway but has a therapeutic indication
Cysview	Hexaminolevulinate hydrochloride	Bladder cancer cystoscopy	Detection and visualization	Closely aligned with urothelial fluorescence diagnosis
Metvix	Methyl aminolevulinate	Photodynamic treatment in non-US markets	Treatment	A related ALA-derivative platform

FDA approval does not establish infringement of an expired patent. It reflects regulatory authorization for a particular product, indication, and labeling framework.

What patents protect later ALA fluorescence products?

The original patent should be separated from later patent families directed to narrower commercial implementations.

Formulation patents

Later patent strategies may cover:

stabilized ALA or ALA-derivative compositions;
topical formulations;
esterified precursors such as hexaminolevulinate or methyl aminolevulinate;
pH-controlled or buffered compositions;
solvent systems;
dosage forms for intravesical, topical, or systemic administration;
storage stability and packaging.

These claims can remain relevant after expiration of a broad method patent because they protect the product architecture rather than the underlying discovery alone.

Method-of-use patents

Later claims may focus on:

bladder cancer detection;
fluorescence-guided transurethral resection;
detection of carcinoma in situ;
cervical or endometrial lesion identification;
dermatologic lesion treatment;
treatment protocols combining ALA with specified light sources;
repeat dosing or dose-timing protocols;
use with a particular imaging system.

A later method patent must provide patentable subject matter beyond the expired disclosure. Its strength depends on claim specificity, priority date, written description, enablement, obviousness, and whether the claimed use was already disclosed in the earlier patent or related prior art.

Device and imaging patents

Commercial systems can be protected by separate patent families directed to:

light-emitting diodes or laser illumination;
endoscopic optics;
excitation and emission filters;
fluorescence-sensitive cameras;
image-enhancement algorithms;
lesion mapping;
real-time surgical guidance;
quantitative fluorescence analysis.

These patents can create freedom-to-operate constraints even though US 5,211,938 itself has expired.

How strong was the original patent estate?

The original patent was technically broad but commercially vulnerable in several respects.

Strengths

The claims captured the essential sequence of the platform:

administer a heme-pathway precursor;
induce preferential PpIX production;
illuminate at a PpIX-absorbed wavelength; and
detect lesion fluorescence.

The independent claim did not depend on a particular commercial instrument or narrow formulation. That structure gave it broad conceptual coverage across several anatomical sites.

The claim also covered non-malignant lesions, which expanded its potential application beyond cancer diagnosis.

Limitations

The patent expired in 2010, eliminating current enforcement value. Its scope was also limited by the explicit tissue categories and by the requirement for preferential PpIX synthesis.

The claim does not expressly cover:

diagnostic treatment decisions;
removal or destruction of the lesion;
image processing;
a specific light-emitting device;
a specific concentration or dosage;
a particular ALA salt or ester;
a particular pharmaceutical composition;
a standalone device;
a product sold without performance of the claimed method.

The patent also required fluorescence detection. Administration of ALA without illumination and fluorescence detection would not practice the full method claim.

Are there current Paragraph IV challenges to US 5,211,938?

No commercially meaningful Paragraph IV challenge can target an expired patent. Paragraph IV certifications address listed patents in the FDA Orange Book that an ANDA applicant asserts are invalid, unenforceable, or not infringed.

US 5,211,938 is not a current Orange Book barrier. It is not a live patent that can block an ANDA or support a new infringement action.

Paragraph IV activity may remain relevant to later patents covering ALA products, formulations, or approved methods of use. It is not relevant to the expired foundational claims themselves.

What is the Orange Book status of the technology?

The Orange Book lists patents associated with approved drug products, not every patent that historically disclosed the underlying scientific platform.

For ALA-related products, Orange Book analysis must be conducted product by product. Relevant issues include:

whether the product is approved under an NDA;
whether formulation, drug-substance, method-of-use, or other patents are listed;
whether listed patents remain unexpired;
whether the patent covers the approved indication;
whether an ANDA applicant must address the listed patent through Paragraph III or Paragraph IV certification.

The historical patent number US 5,211,938 should not be treated as an active Orange Book obstacle merely because later products use the same PpIX mechanism.

Which companies developed commercial products around this platform?

The main commercial participants have included:

Company	Product or role	Platform relevance
DUSA Pharmaceuticals	Levulan Kerastick	ALA-based photodynamic therapy
Sun Pharmaceutical Industries	Commercial ownership of DUSA operations	Dermatology and photodynamic therapy
Photocure ASA	Cysview/Hexvix	Hexaminolevulinate fluorescence cystoscopy
Karl Storz	D-Light system	Dedicated fluorescence cystoscopy equipment
Galderma and other regional partners	Methyl aminolevulinate products in certain markets	ALA-derivative photodynamic therapy

The commercial model has generally depended on product-specific drug approvals, procedure reimbursement, physician adoption, and proprietary drug-device combinations. The expired patent alone does not determine current market exclusivity.

What generic entry risks exist?

The direct risk from US 5,211,938 is zero because the patent is expired. Current entry risk depends on later rights.

Small-molecule drug risk

ALA and ALA derivatives are small molecules, not biologics. The relevant regulatory pathway is generally an NDA/ANDA framework rather than a biosimilar pathway.

Potential barriers include:

active formulation patents;
method-of-use patents;
device compatibility claims;
labeling restrictions;
manufacturing know-how;
stability and packaging patents;
regulatory exclusivities attached to later approvals;
commercial dependence on a proprietary imaging system.

Biosimilar risk

There is no biosimilar issue for ALA, hexaminolevulinate, or methyl aminolevulinate because these are chemically synthesized small-molecule drugs. The competitive question is generic substitution, not biosimilar interchangeability.

Generic launch scenarios

A generic entrant could pursue several strategies:

market a formulation after expiration of listed patents;
use a carve-out label excluding protected indications;
challenge later method-of-use patents under Paragraph IV;
develop a competing diagnostic system;
sell the drug for an indication that does not require the incumbent’s proprietary device.

The commercial launch risk is highest where the drug and imaging system are tightly integrated and where reimbursement favors the incumbent workflow.

How does this patent compare with later bladder-cancer patents?

US 5,211,938 is a platform patent. Later bladder-cancer patents tend to be narrower and more operational.

Issue	US 5,211,938	Later bladder fluorescence patents
Molecule	Broad PpIX precursor concept; ALA in claim 2	Often hexaminolevulinate or another defined agent
Anatomy	Urothelium among several tissue categories	Usually bladder-specific
Imaging	Any suitable PpIX excitation and fluorescence detection	Often specified cystoscope, filter, camera, or system
Use	Detection of abnormalities and lesions	Detection during cystoscopy or surgical resection
Product protection	Limited	May include formulation and device claims
Status	Expired	Depends on individual patent family
Current enforcement	None	Potentially active if unexpired and valid

This distinction matters in freedom-to-operate reviews. A company can operate outside the expired patent while still implicating later rights directed to a particular drug, formulation, diagnostic system, or approved use.

What manufacturing and intellectual-property barriers remain?

Manufacturing barriers are practical rather than dependent on US 5,211,938. They may include:

control of impurity profiles in ALA or ALA derivatives;
stability under light and temperature exposure;
sterile or controlled manufacturing requirements for intravesical products;
reproducible concentration and pH;
compatibility with delivery catheters or cystoscopes;
validation of fluorescence performance;
clinical evidence linking fluorescence detection to improved lesion identification;
access to procedure-specific reimbursement.

The expired patent does not disclose or control all manufacturing know-how. Trade secrets, process controls, supplier relationships, regulatory data, and device integration can remain commercially relevant.

Key Takeaways

US 5,211,938 claimed PpIX fluorescence detection after administration of a heme-pathway precursor.
Claim 1 covered malignant and non-malignant abnormalities in skin, mucosa, endometrium, and urothelium.
Claim 2 specifically covered ALA.
The patent did not require a particular dose, formulation, light source, detector, or imaging device.
The patent expired on May 18, 2010, based on the ordinary pre-1995 patent-term rule.
It is not a current US infringement or Paragraph IV barrier.
Levulan and Cysview reflect later regulatory implementations of the ALA/PpIX platform, but their product and method rights must be analyzed separately.
Current competitive risk comes from later formulation, method-of-use, device, and drug-device patents, not from US 5,211,938.
Biosimilar analysis is inapplicable because ALA and its principal derivatives are small-molecule products.
The patent remains important as foundational prior art and as the historical basis for ALA-induced fluorescence diagnosis.

FAQs About US Patent 5,211,938

Did US Patent 5,211,938 cover Levulan?

It covered the underlying ALA-induced PpIX fluorescence method to the extent the marketed use satisfied all claim limitations. Levulan’s approved FDA indication is photodynamic treatment of actinic keratosis, not a general fluorescence-detection indication.

Did US Patent 5,211,938 cover Cysview?

Cysview uses hexaminolevulinate for fluorescence cystoscopy in the bladder, a use closely related to the patent’s urothelial claim scope. The patent expired before Cysview’s 2010 FDA approval and cannot currently be enforced.

Is US 5,211,938 listed in the Orange Book?

It should not be treated as an active Orange Book patent. Its term expired in 2010, and the patent is not a current exclusivity barrier for ALA-related products.

Can a company sell an ALA fluorescence diagnostic in the United States today?

The expired patent does not prevent entry. A company must still satisfy FDA requirements and assess later patents covering the formulation, indication, imaging device, software, or drug-device combination.

Does the patent cover fluorescence imaging outside the listed organs?

The explicit claim language identifies skin, mucosa, endometrium, and urothelium. Use outside those categories would require a separate analysis of claim construction, anatomical classification, and the patent specification.

References

United States Patent and Trademark Office. (1993). Photodiagnosis and phototherapy of tumors using 5-aminolevulinic acid, U.S. Patent No. 5,211,938.
U.S. Food and Drug Administration. (2021). Levulan Kerastick topical solution prescribing information. DUSA Pharmaceuticals, Inc.
U.S. Food and Drug Administration. (2023). Cysview prescribing information. Photocure ASA.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. Center for Drug Evaluation and Research.
U.S. Patent and Trademark Office. (2024). Patent term and patent expiration guidance.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	287709	⤷ Start Trial
Australia	3883293	⤷ Start Trial
Australia	5888796	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 5,211,938