Details for Patent: 5,028,621

Summary for Patent: 5,028,621

Title:	Drugs comprising porphyrins
Abstract:	To obtain tumor-selective, photosensitizing drugs useful in the localization of neoplastic tissue and treatment of abnormal neoplastic tissue such as tumors, one of two methods is used. In the first method, a hydrolyzed mixture of the products of reaction of hematoporphyrin with acetic acid and sulfuric acid is cycled through a microporous membrane system to exclude low molecular weight products. In the second method, drugs are synthesized or derived from other pyrrole compounds. The drugs (1) include two covalently bound groups, each with four rings, some of which are pyrroles such as phlorins, porphyrins, chlorins, substituted pyrroles, substituted chlorins or substituted phlorins, each group being arranged in a ring structure, connected covalently to another group and have a triplet energy state above 37.5 kilocalories per mole; (2) are soluble in water, forming an aggregate of over 10,000 molecular weight in water and have an affinity for each other compared to serum protein such that 10 to 100 percent remain self aggregated in serum protein; and (3) are lipophyllic and able to disaggregate and attach to cell plasma, nuclear membrane, mitochondria, lysosomes and tissue. The drug obtained by the first method has an empirical formula of approximately C68H70N8O11 or C68H66N8O11Na4. Neoplastic tissue retains the drug after it has cleared normal tissues and illumination results in necrosis. Moreover, other photosensitizing materials may be combined with a carrier that enters undesirable tissues and cells of the reticular endothelial system such as macrophages. These photosensitizing materials: (1) must have a triplet energy state above 3.5 kilocalories per mole; (2) cannot be easily oxidized; and (3) not physically quench any required energy state. Preferably, this photosensitizing material should be lipophlic.
Inventor(s):	Thomas J. Dougherty, William R. Potter, Kenneth R. Weishaupt
Assignee:	Health Research Inc
Application Number:	US07/352,774
Patent Claim Types: see list of patent claims	Composition; Compound;

United States Patent 5,028,621: Scope, Claims, Expiration, and Photodynamic Therapy Patent Landscape

U.S. Patent No. 5,028,621 covers tumor-localizing, fluorescent and photosensitizing porphyrin, chlorin and phlorin conjugates, including pharmaceutical compositions containing those conjugates. The claims are directed to product characteristics rather than a defined clinical treatment protocol. The patent issued July 2, 1991, and, as a pre-URAA U.S. patent, its ordinary 17-year term ended July 2, 2008, absent an earlier terminal disclaimer or an unusual term adjustment. The patent is therefore expired and does not currently block generic or competing photodynamic-therapy products.

The claims are most closely associated with the porfimer sodium and hematoporphyrin-derivative photodynamic-therapy technology used in Photofrin. The claims do not, however, simply cover every formulation of porfimer sodium or every porphyrin photosensitizer. They require a combination of structural, physicochemical, photophysical and tumor-localization limitations.

What does U.S. Patent 5,028,621 cover?

The patent covers biologically active compositions containing covalently linked porphyrin-family molecules that:

1. Fluoresce.
2. Photosensitize.
3. Localize in tumor tissue or tumor cells more than in normal tissue.
4. Form aggregates larger than 10 kilodaltons in aqueous environments.
5. Dissociate into sufficiently lipophilic species in tissue.
6. Have triplet energy above 37.5 kcal/mol.
7. Resist oxidation.
8. Do not physically quench the required energy state.

Claims 1 through 3 divide the covered compositions into three chemical classes:

Claim	Core molecular class	Principal product limitation
1	Porphyrin conjugates	At least one porphyrin has the recited formula
2	Chlorin conjugates	At least one chlorin has the recited formula
3	Phlorin conjugates	At least one phlorin has the recited formula
4	Porphyrin composition	Structural, photophysical and detailed spectral fingerprint
5	Porphyrin mixture	Specific conjugate composition, vinyl substitution and spectral fingerprint
6	Pharmaceutical composition	Claim 1 composition plus pharmaceutically acceptable excipient
7	Pharmaceutical composition	Claim 2 composition plus pharmaceutically acceptable excipient
8	Pharmaceutical composition	Claim 3 composition plus pharmaceutically acceptable excipient

The structural formulas are essential to the claim scope. In the text supplied, the structures appear as missing image placeholders such as “##STR3##” and “##STR7##.” The patent’s exact chemical boundaries therefore cannot be reconstructed from the text alone. The functional and spectral limitations can still be analyzed, but a definitive structure-by-structure infringement opinion cannot be made from the reproduced claims.

How broad are claims 1 through 3?

Claims 1 through 3 are broad genus claims, but their breadth is constrained by multiple cumulative requirements.

Claim 1: porphyrin conjugates

Claim 1 requires a conjugate containing at least two covalently linked porphyrin molecules. At least one porphyrin must have the structure shown in the original patent. The conjugate must also satisfy all of the aggregation, lipophilicity, tumor-localization and photophysical limitations.

A monomeric porphyrin would not fall within claim 1 solely because it is fluorescent and photosensitizing. The claim requires a covalently linked multimeric or oligomeric structure.

Claim 2: chlorin conjugates

Claim 2 applies the same functional limitations to conjugates containing two or more covalently linked chlorin molecules. A chlorin is a partially hydrogenated porphyrin derivative. The claim is separate from claim 1 and does not automatically cover every porphyrin-chlorin hybrid.

Claim 3: phlorin conjugates

Claim 3 covers conjugates containing at least two covalently linked phlorin molecules. Phlorins are reduced porphyrin-related structures. The claim requires the recited phlorin formula and the same tumor-localization and photophysical profile.

Key scope limitation

The claims are not pure structure claims. They are hybrid product claims requiring:

• A specified molecular architecture.
• A specified number of linked chromophores.
• A tumor-localizing biological property.
• An aqueous aggregate size above 10 kDa.
• Tissue dissociation behavior.
• A triplet-energy threshold.
• Oxidative stability.
• Absence of physical quenching.

An accused product that has a similar porphyrin scaffold but fails one of these limitations would not literally meet the claim. The doctrine of equivalents would depend on the prosecution history, claim amendments and estoppel record.

What do the aggregate and lipophilicity limitations require?

The claims describe a delivery mechanism based on reversible aggregation.

In aqueous media, the conjugates must form aggregates larger than 10 kDa. In tissue, those aggregates must dissociate because the conjugates are sufficiently lipophilic. The intended technical model is a large circulating species with tissue-level release of smaller, more lipophilic photosensitizing units.

This limitation creates several enforcement issues:

• Aggregate size must be measured under defined aqueous conditions.
• “Greater than 10 kDa” describes an apparent molecular-size property, not necessarily the molecular weight of a single covalent molecule.
• Dissociation in tissue requires testing in a biological or tissue-relevant environment.
• “Sufficiently lipophilic” is relative and lacks a numerical partition-coefficient threshold in the claim.
• The claim does not specify pH, ionic strength, protein concentration, temperature or analytical method.

A competitor could challenge infringement by showing that its product is monomeric, forms only sub-10-kDa species, remains aggregated in tissue, or lacks the claimed reversible aggregation profile.

What do claims 4 and 5 protect?

Claims 4 and 5 are narrower composition claims using analytical fingerprints.

Claim 4: spectral fingerprint composition

Claim 4 requires a porphyrin composition with:

• Visible-water absorption peaks near 365, 505, 537, 575 and 615 nanometers.
• Infrared absorption peaks near 3.0, 3.4, 6.4, 7.1, 8.1, 9.4, 12 and 15 microns.
• Specified carbon-13 nuclear magnetic resonance resonances.
• The porphyrin structure shown in the original patent.
• The same aggregation, tissue-dissociation and photophysical properties required by claim 1.

The spectral limitations operate as identity or composition constraints. They are unlikely to cover an unrelated photosensitizer merely because it absorbs light in one of the listed regions. A product would need to satisfy the claimed combination of structural and analytical characteristics.

The terms “approximately” and “possibly” create claim-construction issues. “Approximately” permits some analytical variation, but the permissible deviation would likely depend on the specification, testing method and scientific practice at the relevant time. The word “possibly” is particularly unusual because it may make the presence of the 118- and 127-ppm peaks nonmandatory.

Claim 5: mixture associated with porfimer-type material

Claim 5 covers a drug comprising a mixture of porphyrins in which at least some molecules contain conjugates of the formula shown in the patent, with one or more hydroxyethyl substituents replaced by vinyl groups.

It adds the same visible, infrared and carbon-13 NMR profile found in claim 4, along with the aggregate and photophysical limitations.

Claim 5 is commercially significant because it is directed to a mixture rather than a single molecular entity. That format is consistent with hematoporphyrin-derivative products, which contain distributions of porphyrin monomers, dimers and higher oligomers rather than one uniform active molecule.

The claim still requires the precise formula and spectral profile from the patent. It does not necessarily cover all hematoporphyrin derivatives, all porfimer products or all oligomeric porphyrins.

What do claims 6 through 8 add?

Claims 6 through 8 are pharmaceutical-composition claims dependent on claims 1 through 3.

They require:

• The relevant claim 1, 2 or 3 active composition.
• A pharmaceutically acceptable excipient.
• A composition that “consists essentially of” the claimed active ingredient and excipient.

“Consists essentially of” permits components that do not materially change the basic and novel characteristics of the claimed composition. It is narrower than “comprising” and broader than “consisting of.”

The claims do not specify:

• Dose.
• Route of administration.
• Injection volume.
• Light wavelength.
• Light dose.
• Treatment interval.
• Tumor type.
• Excipient identity.
• Sterility or container system.

A conventional injectable formulation would fall within claims 6 through 8 only if the active material already meets the underlying porphyrin, chlorin or phlorin claim.

When did U.S. Patent 5,028,621 lose exclusivity?

Event	Date or status
U.S. patent issued	July 2, 1991
Ordinary pre-URAA patent term	17 years from issuance
Ordinary expiration date	July 2, 2008
Current enforceability	Expired
Current Paragraph IV risk from this patent	None
Current injunction risk based solely on this patent	None

Because the patent issued before the June 8, 1995 effective date of the Uruguay Round Agreements Act patent-term provisions, the standard term was generally 17 years from grant rather than 20 years from the earliest effective nonprovisional filing date. The expiration analysis should be confirmed against the official USPTO record for any terminal disclaimer, disclaimer, reexamination certificate or other post-grant event.

Patent expiration does not eliminate historical damages exposure for infringement occurring before expiration. It does eliminate prospective enforcement based on the expired patent.

What was the FDA and Orange Book relevance?

The claims are relevant to porfimer sodium and Photofrin-type photodynamic therapy, but the patent itself is not an FDA approval or an Orange Book entry.

Photofrin is porfimer sodium, a mixture of oligomeric hematoporphyrin derivatives. FDA approved Photofrin for obstructing esophageal cancer and later for certain patients with endobronchial non-small-cell lung cancer. The FDA label describes intravenous administration followed by activation with specified light treatment. [2]

The regulatory implications are:

• Patent protection and FDA exclusivity are separate rights.
• U.S. Patent 5,028,621 has expired.
• Any historical Orange Book listing would no longer create an active patent barrier.
• A current abbreviated new drug application could not be blocked by this expired patent.
• A porfimer sodium product would still face pharmaceutical equivalence, bioequivalence, chemistry, manufacturing and controls, sterility, labeling and photodynamic-treatment requirements.

Porfimer sodium is a complex mixture. That complexity can create regulatory and manufacturing barriers even after patent expiration. A generic applicant may need to demonstrate comparability of oligomer distribution, impurities, aggregation behavior, optical absorption, stability and clinical performance.

Were Paragraph IV challenges or settlements associated with this patent?

No current Paragraph IV challenge can create a live dispute under U.S. Patent 5,028,621 because the patent expired in 2008.

The claim format predates the modern commercial development of many ANDA patent challenges. Paragraph IV litigation would have been relevant only while the patent was listed and unexpired for an applicable product. The expired status means:

• No 30-month stay can be based on this patent today.
• No prospective launch date is delayed by this patent.
• A historical settlement, if any, would not preserve an expired exclusionary right.
• Contractual covenants in a private settlement could have separate effects, but they cannot revive patent enforceability.

The principal historical competitor to Photofrin was not necessarily a generic porfimer sodium product. The commercial field included alternative photosensitizers with different chemical structures and different patent estates.

What patents and technologies competed with this patent?

The relevant patent landscape falls into several groups.

Technology group	Representative commercial or technical subject	Relationship to U.S. 5,028,621
Hematoporphyrin derivatives	Porfimer sodium and related oligomeric mixtures	Closest technology
Purified porphyrins	Defined porphyrin photosensitizers	May avoid multimer and mixture limitations
Chlorins	Chlorin e6 and related derivatives	Potentially outside porphyrin-only products
Phthalocyanines	Metallated and nonmetallated phthalocyanine photosensitizers	Chemically distinct
Benzoporphyrin derivatives	Verteporfin and related compounds	Separate chemical and therapeutic estate
Texaphyrins	Expanded porphyrin photosensitizers	Separate composition and method claims
Second-generation agents	Temoporfin, talaporfin and padeliporfin-related compounds	Separate patents and regulatory pathways
Delivery systems	Liposomes, nanoparticles, conjugates and targeted carriers	May implicate formulation and platform patents

The closest prior and parallel patent families concern:

• Hematoporphyrin derivative preparation.
• Oligomerization and purification.
• Tumor treatment using light-activated porphyrins.
• Injectable formulations.
• Specific irradiation wavelengths and dosimetry.
• Photosensitizer delivery through liposomes or targeting ligands.
• Improved clearance and reduced skin photosensitivity.

U.S. Patent 5,028,621 is strongest against a product deliberately engineered to reproduce the claimed oligomeric porphyrin mixture and its analytical profile. It is much less relevant to a chemically distinct monomeric photosensitizer, a phthalocyanine, a purely vascular-targeted agent or a formulation that does not exhibit the claimed aggregate-dissociation behavior.

How strong is the patent estate?

The patent is historically important but commercially weak today because it is expired.

Historical strength

The patent had meaningful historical scope because it combined:

• Composition claims.
• Porphyrin, chlorin and phlorin species.
• Functional tumor-localization language.
• Aggregation and tissue-dissociation properties.
• Spectroscopic identity limitations.
• Pharmaceutical-composition claims.

That combination could have complicated design-around efforts for Photofrin-like products, particularly products containing oligomeric porphyrin mixtures.

Present strength

Its present patent strength is zero for prospective exclusion because the patent has expired. Any current commercial value would arise from:

• Know-how.
• Manufacturing controls.
• Regulatory history.
• Analytical methods.
• Clinical data.
• Trade secrets concerning oligomer distribution and purification.

Those assets are separate from the expired patent claims.

Claim-by-claim durability

Claim group	Historical breadth	Current enforceability
Claims 1-3	Moderate to broad, subject to multiple functional limits	None
Claim 4	Narrow, fingerprint-based	None
Claim 5	Narrow to a defined mixture and spectral profile	None
Claims 6-8	Narrow pharmaceutical-composition claims dependent on claims 1-3	None

What generic-entry risks exist for Photofrin-type products?

The expired patent removes the primary patent barrier represented by U.S. 5,028,621. Generic-entry risk would instead depend on regulatory and technical factors.

Regulatory barriers

A porfimer sodium applicant would likely need to address:

• Complex mixture characterization.
• Oligomer molecular-weight distribution.
• Optical absorption profile.
• Aggregate behavior in solution.
• Impurity and degradation-product controls.
• Sterile injectable manufacturing.
• Photodynamic dosing and labeling.
• Demonstration of pharmaceutical equivalence and bioequivalence or an alternative FDA-supported approach.

Manufacturing and intellectual-property barriers

Potential non-patent barriers include:

• Proprietary purification procedures.
• Control of porphyrin oligomer distributions.
• Reproducible batch-to-batch spectral properties.
• Stability in aqueous or mixed-solvent systems.
• Container and light-protection requirements.
• Clinical adoption and physician familiarity.

A competitor could avoid the expired claims by developing a different photosensitizer, but it would then face separate patent, clinical and regulatory requirements.

What geographic coverage did the patent have?

U.S. Patent 5,028,621 provided protection only in the United States. Foreign counterparts, if filed, would have had independent prosecution histories, claim scope and expiration dates. U.S. expiration does not establish the status of corresponding patents in Europe, Canada, Japan, Australia or other jurisdictions.

For a global freedom-to-operate review, the relevant questions are:

• Whether a foreign counterpart was granted.
• Whether it remained in force after 2008.
• Whether supplementary protection or regulatory-term extensions applied.
• Whether later continuation, divisional or improvement patents were granted.
• Whether separate formulation or method-of-use patents survived.

The U.S. patent itself does not provide current geographic protection in any jurisdiction.

How does this patent compare with method-of-use and formulation patents?

U.S. Patent 5,028,621 is primarily a composition patent. It does not claim:

• Treating a named tumor type.
• Administering a specified dose.
• Illuminating at a defined wavelength.
• Applying a defined fluence or power density.
• Using a particular treatment interval.
• Combining the photosensitizer with surgery, chemotherapy or radiation.
• A specific vial, buffer or injectable formulation.

Method-of-use patents can create a separate enforcement pathway, particularly where a product label includes patented treatment instructions. Formulation patents can also remain relevant after a composition patent expires if they cover a distinct excipient system, concentration, container or stability profile.

For Photofrin-like products, the most important post-expiration diligence therefore shifts from this patent to later patents covering formulations, treatment protocols, manufacturing methods and specific clinical indications.

Key Takeaways

• U.S. Patent 5,028,621 covers tumor-localizing fluorescent photosensitizer compositions based on covalently linked porphyrin, chlorin and phlorin molecules.
• The claims require a specific combination of chemical structure and functional properties.
• Claims 4 and 5 use visible, infrared and carbon-13 NMR characteristics as composition fingerprints.
• Claims 6 through 8 cover pharmaceutical compositions containing the claimed active materials and excipients.
• The patent’s ordinary term ended July 2, 2008.
• The patent creates no current Paragraph IV, Orange Book or injunction risk.
• Photofrin and porfimer sodium remain technically relevant because they are complex oligomeric mixtures, but regulatory and manufacturing issues now matter more than this expired patent.
• The missing structural drawings prevent a definitive analysis of the exact substituent boundaries in formulas 3 through 7.
• Later formulation, manufacturing and method-of-use patents must be analyzed separately from U.S. Patent 5,028,621.

FAQs

Does U.S. Patent 5,028,621 cover porfimer sodium itself?

It may cover products with the claimed oligomeric porphyrin characteristics, but the claims do not automatically cover every porfimer sodium batch. The product must satisfy the structural, aggregation, photophysical and, for claims 4 and 5, spectral limitations.

Can a generic manufacturer launch after expiration of U.S. Patent 5,028,621?

Yes, this patent no longer blocks launch. The manufacturer would still need to satisfy FDA requirements and avoid any separate unexpired patents covering formulation, manufacturing, treatment instructions or a related product.

Are claims 1 through 3 limited to tumor treatment?

They are composition claims requiring tumor-localizing capability. They do not recite a treatment method, light exposure step or patient-treatment protocol.

Does a product need to contain both porphyrins and chlorins to infringe?

No. Claim 1 addresses porphyrin conjugates, claim 2 addresses chlorin conjugates and claim 3 addresses phlorin conjugates. Each claim has its own molecular-class requirement.

Can an analytical fingerprint alone establish infringement?

It may support infringement of claims 4 or 5, but the other claim limitations also must be met. The fingerprint must be interpreted with the structural formula, approximate peak language and specified aggregation and photophysical properties.

References

1. United States Patent No. 5,028,621. (1991). Tumor-localizing porphyrin compositions. United States Patent and Trademark Office.
2. U.S. Food and Drug Administration. (2011). Photofrin (porfimer sodium) prescribing information.
3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
4. United States Patent and Trademark Office. (2024). Patent term and patent expiration guidance.
5. U.S. Food and Drug Administration. (2024). Drugs@FDA: FDA-approved drugs database.

Drugs Protected by US Patent 5,028,621

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

International Family Members for US Patent 5,028,621

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	53204
Australia	2032283
Australia	4246185
Australia	581840
Australia	588806
Canada	1265450
Canada	1271746