Details for Patent: 4,649,151

Summary for Patent: 4,649,151

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.
Inventor(s):	Thomas J. Dougherty, William R. Potter, Kenneth R. Weishaupt
Assignee:	Health Research Inc
Application Number:	US06/609,991
Patent Claim Types: see list of patent claims	Compound; Process;

United States Patent 4,649,151: Scope, Claims, Expiration, and Photofrin Patent Landscape

US Patent 4,649,151 covers a hematoporphyrin-derived photodynamic therapy drug and its manufacturing process. The claims define a porphyrin mixture by chemical composition, spectroscopic fingerprints, mass-spectrometry peaks, tumor localization, fluorescence, photosensitization, and formulation characteristics. The patent issued on March 10, 1987, and its original 17-year term expired on March 10, 2004, absent a valid patent-term adjustment or extension. It therefore does not present a current US patent barrier to generic or alternative porfimer sodium development.[1][2]

The patent is historically important because its product claims correspond to porfimer sodium, marketed as Photofrin. Its practical commercial value has shifted from exclusivity to technical disclosure, manufacturing know-how, regulatory precedent, and freedom-to-operate analysis for photodynamic therapy products.

What drug does US Patent 4,649,151 protect?

US 4,649,151 protects a hematoporphyrin derivative mixture used as a photosensitizing drug in photodynamic therapy. The claimed product is characterized by:

• A mixture of porphyrins.
• At least 50% of the mixture consisting of specified porphyrin molecules.
• Fluorescence and photosensitizing activity.
• Preferential localization and retention in tumor tissue.
• Formation of a high-molecular-weight aggregate.
• Defined ultraviolet, visible, infrared, carbon-13 nuclear magnetic resonance, and fast-atom-bombardment mass-spectrometry signals.

This claim structure reflects the chemistry of porfimer sodium, which is not a single small molecule. Porfimer sodium is a purified mixture of oligomeric hematoporphyrin derivatives. Its composition is therefore described through a combination of chemical, physical, biological, and analytical characteristics rather than through one conventional molecular formula.

The chemical structure embedded in the supplied version of claim 1 is not rendered. That omission affects precise structure-level analysis, but the remaining limitations establish the principal claim boundaries.

What are the independent claims in US 4,649,151?

The patent has two independent claims: claim 1, directed to the drug, and claim 6, directed to its production and purification.

Claim	Subject matter	Principal limitations
1	Drug composition	Porphyrin mixture; at least 50% of specified porphyrin; fluorescence; photosensitization; tumor localization; high-molecular-weight aggregate; defined spectral properties
6	Manufacturing process	React hematoporphyrin with acetic and sulfuric acids; precipitate by sodium acetate neutralization; dissolve in sodium hydroxide; adjust to pH 9.5; purify through a porous membrane excluding low-molecular-weight by-products

Claims 2 through 5 depend from claim 1. Claims 7 and 8 depend from claim 6.

The product claim is open-ended because it begins with “a drug comprising.” A competing product could therefore contain additional excipients or porphyrin species, but it would still face the claim if the required porphyrin mixture and defining characteristics were present.

How broad is claim 1?

Claim 1 is broad in product category but narrow in analytical definition. It does not cover every porphyrin photosensitizer. It targets a specific hematoporphyrin-derived composition with a characteristic analytical profile.

Chemical composition limitation

At least 50% of the porphyrins must consist of the claimed molecule or molecules. This creates a quantitative threshold. A mixture containing less than 50% of the specified species would not literally satisfy that limitation, assuming the percentage is measured using a legally and scientifically accepted analytical method.

The claim also requires at least some molecules having the specified molecular formula. Because the formula is absent from the supplied text, the scope cannot be reduced to a complete atom-by-atom structure here. The claim nonetheless requires the accused product to contain the identified porphyrin species, not merely a chemically unrelated photosensitizer.

Functional limitations

The molecules must be:

• Fluorescent.
• Photosensitizing.
• Capable of localizing in and being retained in tumor tissue compared with normal tissue.

These limitations link the composition to photodynamic therapy. A structurally similar porphyrin without the claimed tumor-retention or photosensitizing properties would have a stronger noninfringement position, although the evidentiary test would depend on claim construction and the patent record.

Aggregate limitation

The claimed molecules must form a high-molecular-weight aggregate with specified adsorption peaks in water. This is a significant limitation because porfimer sodium is an aggregated, polymeric porphyrin preparation rather than a uniform molecular entity.

The visible-spectrum peaks are approximately 365, 505, 537, 575, and 615 nanometers. The claim also recites infrared peaks at approximately 3.0, 3.4, 6.4, 7.1, 8.1, 9.4, 12, and 15 microns.

Nuclear magnetic resonance limitations

Claim 1 recites carbon-13 nuclear magnetic resonance peaks at approximately:

• 9.0 ppm
• 18.9 ppm
• 24.7 ppm
• 34.5 ppm
• 62 ppm
• 94.5 ppm
• 130 to 145 ppm
• 171.7 ppm
• Potentially 118 and 127 ppm
• 27.9 ppm
• 68.4 ppm

The claim uses different reference conditions, including dimethyl sulfoxide and tetramethylsilane in deuterated chloroform. These details may create substantial analytical and claim-construction issues. Spectral peak positions can vary with solvent, concentration, instrument calibration, aggregation state, temperature, and sample preparation. In litigation, the parties would likely dispute whether the peaks are strict numerical limitations, approximate identifying characteristics, or evidence supporting identity of the claimed mixture.

What do claims 2 through 5 protect?

Claims 2 through 5 narrow the product claim by adding mass-spectrometry and formulation limitations.

Claim	Added limitation	Commercial significance
2	Fast-atom-bombardment mass numbers of 1899, 1866, 1809, 1290, 1200, 609, 591, 219, and 149	Identifies the mixture through a defined mass-spectral fingerprint
3	Liquid form at approximately 2.5 mg/cc	Narrows the claim to a specified concentration
4	Isotonic saline at pH approximately 7.0 to 7.2	Covers a clinically usable injectable formulation
5	Orange-red color	Adds a visual product characteristic

Claim 2 is narrower than claim 1 and may be difficult to apply to a modern product if the same mass peaks are not reproducible under identical testing conditions. Claim 3 is narrower still. A product supplied as a lyophilized powder, a different concentration, or a non-saline formulation would have a stronger literal noninfringement position under claims 3 through 5, even if it were chemically similar.

The color limitation in claim 5 is particularly narrow. Orange-red color can vary with concentration, lighting, container material, degradation, and formulation pH. It would likely function as an identifying characteristic rather than the main commercial limitation.

What manufacturing process does claim 6 protect?

Claim 6 covers a specific sequence for producing and purifying the porphyrin drug:

1. React hematoporphyrin with acetic and sulfuric acids.
2. Precipitate the crude product by neutralization in sodium acetate.
3. Dissolve the crude product in sodium hydroxide.
4. Adjust the solution to pH 9.5.
5. Pass the impure solution through a porous membrane system.
6. Exclude low-molecular-weight by-products through membrane purification.

The claim is process-specific. It does not cover every method of manufacturing a hematoporphyrin derivative. A process using different acids, a different precipitation system, chromatographic purification, dialysis, ultrafiltration at another stage, or a different pH sequence could avoid literal infringement of claim 6, subject to any applicable doctrine-of-equivalents analysis.

The membrane step is commercially significant. It identifies purification by molecular-size exclusion rather than merely claiming the resulting product. That limitation may protect process know-how even where a resulting product has similar spectral properties.

What do claims 7 and 8 add?

Claim 7 requires sodium chloride to be added to the impure solution before membrane purification so that the solution becomes isotonic.

Claim 8 requires preparation of the drug at approximately 2.5 mg/cc by adding or removing liquid.

These dependent process claims combine manufacturing and final formulation operations. They are narrower than claim 6 and would not cover a process that performs isotonic adjustment after membrane purification or achieves concentration through a different sequence.

When did US Patent 4,649,151 expire?

US 4,649,151 issued on March 10, 1987. For a pre-June 8, 1995 US application subject to the former patent-term rule, the baseline term was generally 17 years from grant. On that basis, the patent expired on March 10, 2004.[1][3]

Event	Date
Patent issued	March 10, 1987
Baseline 17-year expiration	March 10, 2004
Current enforceability	Expired
Current patent-based US generic barrier	None from this patent

Patent-term extension under 35 U.S.C. § 156 can extend certain patents covering approved products, but the operative expiration date must be confirmed in the USPTO patent-term records and the FDA Orange Book. The historical exclusivity analysis for Photofrin should not assume that the original patent remained enforceable after 2004.[3][4]

What is the Orange Book status of US 4,649,151?

The relevant FDA product is Photofrin, whose active ingredient is porfimer sodium. Photofrin was approved under NDA 020451 for photodynamic treatment of certain cancers, including esophageal and endobronchial indications.[5]

The Orange Book distinguishes between:

• Listed patents that protect the drug substance, formulation, or method of use.
• Regulatory exclusivity.
• Patent certification consequences for abbreviated applications.

An expired patent cannot block an ANDA through an active Paragraph IV dispute. Historical listing of US 4,649,151 would not create current enforceable exclusivity. A current applicant would still need to evaluate any later patents, regulatory exclusivity, manufacturing rights, and FDA requirements associated with the reference product.

Photofrin is a small-molecule or non-biologic drug product for Hatch-Waxman purposes. It is not a biosimilar reference product. A competitor would generally analyze an ANDA or, depending on formulation and equivalence issues, a 505(b)(2) application rather than a biosimilar pathway.

What Paragraph IV challenges and litigation affect this patent?

US 4,649,151 is expired, so a new Paragraph IV challenge to this patent would not ordinarily produce a meaningful current litigation barrier. The commercial disputes surrounding porfimer sodium have more relevance to:

• Approval of competing photodynamic therapy products.
• Pharmaceutical equivalence and bioequivalence.
• Manufacturing comparability for a complex porphyrin mixture.
• Process patents or later formulation patents.
• Regulatory exclusivity and product availability.

The patent’s claim format could have supported Paragraph IV litigation while active. A challenger could have asserted that:

• The product did not contain at least 50% of the claimed porphyrin species.
• The required spectral or mass-spectral peaks were absent.
• The product did not form the claimed aggregate.
• The process did not use the required acid, precipitation, pH, or membrane sequence.
• The claims were indefinite because of approximate analytical values or ambiguous molecular characterization.
• The claims were anticipated or obvious over prior hematoporphyrin derivative disclosures.

No current litigation strategy should rely on US 4,649,151 as an enforceable patent right. Any live dispute would have to arise from a different patent, contract, trade secret, regulatory submission, or product liability theory.

How strong is the patent estate for porfimer sodium?

The historical estate was strong against an exact copy of the patented product and manufacturing process. It was weaker against:

• Structurally different photosensitizers.
• Porphyrin mixtures with a different percentage distribution.
• Non-aggregated or differently aggregated compounds.
• Alternative purification methods.
• Different formulation concentrations.
• Non-tumor-localizing photosensitizers.
• Photodynamic therapy products using other wavelengths or delivery systems.

The patent did not create broad exclusivity over photodynamic therapy. It covered one important hematoporphyrin-derived product profile and a defined preparation route.

Risk category	Historical risk under US 4,649,151	Current risk
Exact porfimer sodium composition	High	None from expired patent
Different porphyrin mixture	Medium to low	None from expired patent
Same product made by claimed process	High	None from expired patent
Same product made by alternative process	Medium	None from expired patent
Different concentration or vehicle	Lower under dependent claims	None from expired patent
Alternative photosensitizer	Low	None from expired patent
Photofrin method-of-use claims	Depends on separate patents	Requires separate patent review
Biosimilar-style competition	Not applicable	Not applicable

What formulation patents protect Photofrin or competing products?

The asserted claims include formulation limitations, but they are not broad formulation claims. Claims 3 through 5 cover a liquid product at approximately 2.5 mg/cc, in isotonic saline, at pH 7.0 to 7.2, with an orange-red color.

They do not expressly cover:

• Liposomal delivery.
• Nanoparticle delivery.
• Targeted antibody conjugates.
• Intratumoral depot systems.
• Alternative injectable vehicles.
• Oral or inhaled dosage forms.
• Light-activated implants.
• New photosensitizers unrelated to the claimed porphyrin mixture.

Later photodynamic therapy patent estates generally focus on different photosensitizers, light-delivery systems, tumor targeting, dosimetry, administration protocols, and combination therapies. Those rights must be reviewed separately from the expired composition and process claims of US 4,649,151.

How does porfimer sodium compare with newer photosensitizers?

Attribute	Porfimer sodium	Chlorins and phthalocyanines	Targeted or nanoparticle photosensitizers
Chemical type	Porphyrin derivative mixture	Often more defined molecular entities or mixtures	Drug-delivery system plus photosensitizer
Light activation	Commonly red light near 630 nm	Often longer wavelengths	Varies by platform
Tissue retention	Prolonged, with prolonged photosensitivity	Often designed for shorter persistence	Depends on carrier and targeting ligand
Patent risk from US 4,649,151	Direct historical relevance	Usually outside literal scope	Usually outside literal scope
Regulatory pathway	Established Photofrin precedent	Product-specific	May involve combination-product issues

Porfimer sodium’s complex mixture creates a manufacturing and analytical barrier even after patent expiration. A competitor must establish consistent composition, impurity control, aggregation behavior, potency, sterility, and clinical comparability. Those requirements can delay entry without creating patent exclusivity.

What manufacturing and intellectual-property barriers remain after expiration?

The main post-expiration barriers are regulatory and technical rather than patent-based.

Manufacturing comparability

A porfimer sodium competitor must control:

• Starting hematoporphyrin quality.
• Acid reaction conditions.
• Oligomer distribution.
• Low-molecular-weight impurities.
• Aggregate size and stability.
• Spectral profile.
• Mass-spectral profile.
• Concentration and pH.
• Sterility and container compatibility.

The process in claim 6 provides a public technical roadmap, but it does not eliminate the need to reproduce a clinically acceptable product.

Trade secrets and know-how

Expiration of a patent does not disclose every manufacturing detail. Critical operating parameters may remain in batch records, validation protocols, analytical methods, supplier controls, and scale-up experience. Those matters can affect development cost and launch timing even when the patent itself is expired.

Regulatory pathway

Because porfimer sodium is a complex mixture, a competitor may encounter difficult pharmaceutical-equivalence and bioequivalence questions. FDA may require extensive chemistry, manufacturing, and controls data. Depending on the reference-product and product-class analysis, an ANDA may be possible, but a 505(b)(2) pathway could become relevant if equivalence cannot be demonstrated through standard methods.[5][6]

Are there biosimilar risks for porfimer sodium?

No. Porfimer sodium is not a biologic subject to the US biosimilar pathway under the Public Health Service Act. The competitive question is generic or follow-on drug entry, not biosimilar substitution.

The product’s mixture complexity can create biosimilar-like analytical challenges, but those challenges do not convert the product into a biologic or create 351(k) exclusivity.

What licensing deals and commercial rights matter?

Photofrin was commercialized through entities associated with QLT and later other rights holders, including Pinnacle Biologics in the US market. Licensing and distribution arrangements can affect product supply, reference-product access, manufacturing rights, and regulatory submissions, but they do not revive an expired patent.[5][7]

A commercial diligence review should separate:

1. Patent ownership.
2. FDA application ownership.
3. Manufacturing authorization.
4. Product supply agreements.
5. Territory-specific commercialization rights.
6. Trade-secret access.
7. Clinical-data or regulatory-data rights.

Those categories have different legal effects. A license to manufacture or distribute Photofrin is not equivalent to a license under US 4,649,151.

What generic launch scenarios exist?

A competitor has three principal US strategies:

ANDA pathway

An ANDA applicant would seek to establish pharmaceutical equivalence and bioequivalence to the reference listed drug. The main technical risks would involve mixture composition, aggregation, impurity profile, analytical comparability, and clinical equivalence.

505(b)(2) pathway

A 505(b)(2) application may be relevant if the proposed product differs in concentration, formulation, route, delivery system, or other clinically meaningful attribute. The applicant may rely partly on FDA’s prior findings for porfimer sodium while providing additional data.

New molecular or platform product

A competitor could avoid the patent historically by developing a different photosensitizer or delivery platform. This approach carries greater clinical and regulatory cost but reduces dependence on porfimer sodium composition and manufacturing knowledge.

What geographic coverage did US 4,649,151 provide?

The patent’s enforceable rights were territorial. US 4,649,151 covered acts in the United States, including making, using, selling, offering for sale, or importing the claimed product or practicing the claimed process during its enforceable term.

Foreign protection required separate national or regional patents. Patent expiration in the United States did not automatically determine expiration in Canada, Europe, Japan, or other jurisdictions. A global freedom-to-operate review must examine corresponding applications, national-phase grants, continuations, divisionals, maintenance status, and local patent-term rules.

Key Takeaways

• US 4,649,151 covers a hematoporphyrin-derived porphyrin mixture associated with porfimer sodium and Photofrin.
• Claim 1 is a product claim defined by composition, tumor localization, photosensitization, aggregation, and multiple analytical fingerprints.
• Claims 2 through 5 narrow the product by mass-spectrometry, concentration, saline vehicle, pH, and color.
• Claim 6 covers a specific acid-reaction, precipitation, pH-adjustment, and membrane-purification process.
• Claims 7 and 8 add isotonic sodium chloride and final concentration-control steps.
• The patent issued March 10, 1987, and its baseline term expired March 10, 2004.
• It is not a current US patent barrier to porfimer sodium entry.
• Porfimer sodium is not a biosimilar product. Competition would proceed through generic, 505(b)(2), or new-product pathways.
• Current commercial risk is more likely to arise from regulatory comparability, manufacturing know-how, later patents, supply rights, or foreign patents than from US 4,649,151.
• The patent did not broadly cover all photodynamic therapy drugs or all porphyrin photosensitizers.

FAQs

Can a company make porfimer sodium in the United States after US 4,649,151 expired?

Yes, expiration removes the patent-based prohibition from this patent. FDA approval, manufacturing compliance, product-quality controls, and any other live intellectual-property rights remain separate requirements.

Does US 4,649,151 cover Photofrin’s method of use?

The supplied claims primarily cover the drug composition, formulation, and production process. They do not broadly claim every photodynamic treatment method. Any method-of-use protection must be analyzed through separate patent claims.

Could a different porphyrin mixture avoid claim 1?

Potentially. The mixture must satisfy the claimed molecular, functional, aggregation, and analytical limitations, including the 50% composition threshold. A materially different porphyrin distribution could avoid literal infringement, subject to claim construction and equivalents analysis.

Is membrane purification required for every porfimer sodium product?

No. Membrane purification is required by claim 6, not by the chemical identity of porfimer sodium itself. A competitor using a different purification sequence would analyze process-claim exposure separately from product-claim exposure.

Does patent expiration eliminate the regulatory difficulty of developing a Photofrin competitor?

No. Expiration removes one legal exclusivity barrier. It does not eliminate the need to demonstrate manufacturing consistency, impurity control, aggregate characterization, sterility, stability, and FDA-acceptable equivalence or clinical performance.

References

1. United States Patent and Trademark Office. (1987). U.S. Patent No. 4,649,151, Hematoporphyrin derivative for use in photodynamic therapy. https://patents.google.com/patent/US4649151
2. Food and Drug Administration. (n.d.). Orange Book: Approved drug products with therapeutic equivalence evaluations. https://www.accessdata.fda.gov/scripts/cder/ob/
3. United States Code, 35 U.S.C. §§ 154, 156. (2024). Patent term and patent term extension provisions. https://uscode.house.gov/
4. United States Patent and Trademark Office. (n.d.). Patent term adjustment and patent term extension. https://www.uspto.gov/patents/laws/patent-term-adjustment
5. Food and Drug Administration. (1998). Photofrin (porfimer sodium) prescribing information. Drugs@FDA. https://www.accessdata.fda.gov/scripts/cder/daf/
6. Food and Drug Administration. (2024). ANDA submissions: Content and format. https://www.fda.gov/drugs/generic-drugs
7. Pinnacle Biologics, Inc. (n.d.). Photofrin product information. https://www.pinnacle-biologics.com/

Drugs Protected by US Patent 4,649,151

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 4,649,151

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	53204
Australia	2032283
Australia	4246185