Details for Patent: 7,247,655

Summary for Patent: 7,247,655

Title:	Esters of 5-aminolevulinic acid as photosensitizing agents in photochemotherapy
Abstract:	The present invention relates to compounds being esters of 5-aminolevulinic acids or pharmaceutically acceptable salts thereof, including compounds of formula (I) R22N—CH2COCH2—CH2CO—OR1 (wherein R1 may represent alkyl optionally substituted by hydroxy, alkoxy, acyloxy, alkoxycarbonyloxy, amino, aryl, oxo or fluoro groups and optionally interrupted by oxygen, nitrogen, sulphur or phosphorus atoms; and R2 represents a hydrogen atom or a group R1, and both R2 groups may be the identical or different), and their use in diagnosis and photochemotherapy of disorders or abnormalities of external or internal surfaces of the body, and products and kits for performing the invention.
Inventor(s):	Karl E. Gierskcky, Johan Moan, Qian Peng, Harald Steen, Trond Warloe, Alf Bjorseth
Assignee:	Photocure ASA
Application Number:	US10/410,636
Patent Claim Types: see list of patent claims	Use; Composition; Formulation; Device;

United States Patent 7,247,655: Scope, Claims, Expiration, Orange Book Status, and Cysview Patent Landscape

U.S. Patent No. 7,247,655 protects aqueous compositions, two-container kits, and bladder-diagnosis methods using hexyl 5-aminolevulinate, also known as hexaminolevulinate or HAL. The patent issued July 24, 2007, and its 20-year term from the relevant U.S. filing date expired in February 2021, subject to any applicable patent-term adjustment. The patent therefore does not currently provide an enforceable U.S. exclusivity barrier.

The commercial product associated with the patent is Cysview, a formulation of hexaminolevulinate hydrochloride marketed by Photocure ASA for blue-light cystoscopy in patients with suspected or known bladder cancer. FDA approved Cysview under NDA 022555 in 2010. The patent covers the diagnostic composition and use architecture, but it does not broadly claim the hexaminolevulinate molecule itself, every manufacturing process, or the cystoscope hardware.

What does U.S. Patent 7,247,655 cover?

U.S. Patent 7,247,655 covers four related subject-matter categories:

1. Aqueous compositions containing hexyl 5-aminolevulinate or a pharmaceutically acceptable salt.
2. Compositions containing the active ingredient and a physiologically acceptable carrier.
3. Kits that separate the active ingredient from the carrier before use.
4. Methods for diagnosing urinary-bladder abnormalities through administration, photoactivation, fluorescence detection, and comparison with control levels.

The independent claims are composition claims 1, 3, 5, and 8; kit claim 11; and method claim 14. Claims 2, 4, 6, 7, 9, 10, 12, 13, 15, 16, and 17 narrow those independent claims.

The patent does not require every formulation to be labeled for bladder cancer. Claims 2, 6, 9, 12, and 15 add bladder-cancer diagnosis as a narrower intended use.

How do the independent claims differ?

Claim	Claim type	Principal limitation	Commercial relevance
1	Composition	HAL or salt plus aqueous solution, optionally with carrier or excipient	Broad aqueous-product claim
3	Composition	HAL or salt plus aqueous base	Broad formulation claim
5	Composition	HAL or salt plus physiologically acceptable carrier, “consisting essentially of”	Narrower closed-transition composition
8	Composition	HAL or salt plus physiologically acceptable carrier	Broad carrier-based composition
11	Kit	First container with HAL and second container with carrier	Two-component presentation
14	Method	Bladder administration, 300–800 nm light exposure, fluorescence measurement, comparison with controls	Core diagnostic-use claim

Claims 1 and 3 use “comprising,” an open-ended transition. A product containing the recited HAL and aqueous components could fall within the literal scope even if it includes additional excipients, buffers, stabilizers, or other ingredients, provided the remaining limitations are met.

Claim 5 uses “consisting essentially of.” That language generally permits components that do not materially alter the basic and novel characteristics of the claimed composition. It presents a narrower infringement theory than claims 1, 3, and 8 because substantial additional formulation ingredients may create a scope dispute.

Claims 8 and 5 overlap substantially. Claim 8 is open-ended and requires a physiologically acceptable carrier. Claim 5 is materially narrower because it uses “consisting essentially of.” Claims 7 and 10 further specify water as the carrier.

What is the chemical and formulation scope?

The active ingredient is hexyl 5-aminolevulinate, commonly supplied as hexaminolevulinate hydrochloride. The claims expressly cover the free compound and pharmaceutically acceptable salts.

The formulation claims do not require:

• A particular HAL concentration.
• A particular pH.
• A specified buffer.
• A particular osmolality.
• A particular storage condition.
• A specified reconstitution time.
• A particular vial size.
• A defined stabilizer or preservative.
• A particular delivery catheter or cystoscope.

The broadest formulation concepts are therefore the presence of HAL or an acceptable salt in an aqueous system or with a physiologically acceptable carrier. Claim 7 and claim 10 expressly identify water, while claim 4 permits inert carriers or diluents in the aqueous base.

The patent is not a narrow claim to the marketed Cysview formulation alone. A materially different aqueous HAL product could have been captured during the patent term if it satisfied the claim language, even if it used a different buffer system, container, concentration, or reconstitution procedure.

What does the kit claim protect?

Claim 11 covers a kit with:

• A first container containing HAL or a pharmaceutically acceptable salt; and
• A second container containing a physiologically acceptable carrier.

Claims 12 and 13 narrow the kit to bladder-cancer diagnosis and water as the carrier.

The kit claims are directed to the divided presentation of the product rather than only to the final reconstituted solution. This distinction matters because the active ingredient and carrier may be packaged separately to improve stability, simplify transportation, or support point-of-care reconstitution.

A commercial kit that includes the active vial, diluent container, and instructions for the claimed diagnostic use would have presented a direct historical infringement risk if sold during the patent term. A single-container ready-to-use product would require a separate analysis under the composition claims, rather than the two-container kit claim.

What diagnostic method does claim 14 require?

Claim 14 requires all of the following steps:

1. Administering a composition containing HAL or a pharmaceutically acceptable salt into the urinary bladder.
2. Exposing the bladder lining to photoactivating light in the 300–800 nm spectrum.
3. Ascertaining the fluorescence level.
4. Comparing that fluorescence level with control levels to locate bladder abnormalities.

Claim 15 narrows the abnormality to bladder cancer. Claim 16 narrows the light spectrum to 350–500 nm. Claim 17 further requires application through an optical fiber inserted through a needle.

The method claim is narrower than a simple “use HAL for bladder imaging” concept. A practicing party would need to perform each recited step. The claim does not expressly require:

• A particular dose.
• A one-hour dwell time.
• A particular cystoscope manufacturer.
• A specific fluorescence threshold.
• Resection or biopsy.
• A particular blue-light wavelength within the claimed range.
• A diagnosis limited to carcinoma in situ.

The claim’s “comparing” requirement is important. A procedure that merely illuminates the bladder and observes fluorescence, without comparing the result to control levels, could raise a claim-construction issue. In a commercial diagnostic protocol, however, interpretation against normal or control tissue would likely support the comparison limitation.

What formulations were associated with Cysview?

Cysview is supplied as a sterile powder containing hexaminolevulinate hydrochloride for intravesical solution. The product is reconstituted with its supplied solvent and administered into the bladder before blue-light cystoscopy. FDA labeling identifies the product for photodynamic detection of papillary bladder cancer and carcinoma in situ in patients with known or suspected bladder cancer (U.S. Food and Drug Administration, 2010).

The marketed product’s clinical workflow generally includes:

• Reconstitution of the vial.
• Intravesical instillation.
• A dwell period before cystoscopy.
• White-light and blue-light examination.
• Fluorescence-based identification of lesions.

Those operational details may be relevant to regulatory compliance and clinical equivalence, but they are not all limitations of Patent 7,247,655. The patent’s composition claims are broader than the approved label in some respects and less specific in others.

When did U.S. Patent 7,247,655 expire?

Event	Date
Earliest priority associated with the patent family	February 4, 2000
U.S. application filing	February 2, 2001
U.S. patent grant	July 24, 2007
Standard 20-year term measured from the relevant U.S. filing framework	February 2021
Current enforceability	Expired

The patent is identified in public patent databases as expired after the end of its ordinary term. The exact terminal date should be read from the USPTO patent-term calculation and any applicable patent-term adjustment record. No current U.S. patent right under Patent 7,247,655 should be treated as blocking an otherwise approvable HAL product.

Patent expiration eliminates infringement liability for post-expiration conduct, but it does not eliminate regulatory requirements. A sponsor still must establish product quality, safety, efficacy, manufacturing compliance, and labeling eligibility through the appropriate FDA pathway.

What is the Orange Book status of Patent 7,247,655?

Patent 7,247,655 was associated with Cysview and NDA 022555 in the FDA’s Orange Book patent-listing framework. Cysview is a small-molecule diagnostic drug, not a biologic, and its relevant exclusivity analysis is based on drug patents and FDA regulatory exclusivity rather than biosimilar interchangeability rules.

The patent’s historical Orange Book relevance was significant because it covered the active pharmaceutical ingredient in its intended aqueous diagnostic presentation and the associated bladder-diagnosis method. Its expiration removed the principal listed-patent barrier associated with that patent number.

Orange Book listing does not establish validity or infringement. A listed patent can be challenged through Paragraph IV certification, declaratory judgment, litigation, or post-grant proceedings. Conversely, the absence of a currently enforceable listed patent does not guarantee immediate generic approval because FDA may still require a complete regulatory submission.

Were there Paragraph IV challenges or patent litigation?

No major publicly established U.S. Paragraph IV litigation against Patent 7,247,655 is identified in the core Cysview patent record. The practical explanation is timing. Cysview had a specialized diagnostic market, and the patent reached expiration before a large generic-entry dispute developed around the product.

A Paragraph IV challenger would have had several potential arguments:

• Anticipation by earlier HAL compositions or photodynamic-diagnosis disclosures.
• Obviousness based on 5-aminolevulinic acid derivatives and known fluorescence cystoscopy.
• Written-description or enablement concerns regarding the breadth of aqueous carriers and diagnostic amounts.
• Indefiniteness arguments directed to “diagnostically effective amount,” “physiologically acceptable carrier,” or “control levels.”
• Noninfringement based on a nonaqueous product, a different administration route, or a method that does not perform the claimed comparison step.

Because the patent has expired, those defenses now have limited commercial value except in historical damages analysis, ownership disputes, or validity proceedings tied to earlier conduct.

How strong was the patent estate?

Composition-claim strength

The composition claims had meaningful commercial breadth because they did not depend on a narrow concentration or proprietary excipient combination. A competing HAL product in an aqueous carrier could have faced literal claim exposure.

Their weaknesses included:

• Broad functional language.
• Limited structural detail in the independent claims.
• Potential prior-art exposure from earlier 5-ALA and aminolevulinate photodynamic-diagnosis work.
• Ambiguity over the boundaries of “diagnostically effective amount.”
• Overlap among claims 1, 3, 5, and 8.

Method-claim strength

Claim 14 had a stronger tie to the clinical use of HAL in bladder imaging because it required administration, photoactivation, fluorescence measurement, and comparison. Its weaknesses were enforcement-related:

• Direct proof of physician performance can be difficult.
• The comparison step may be fact-intensive.
• The claim covers a broad 300–800 nm range.
• Several clinical protocols could differ in interpretation or control methodology.
• Hospitals and physicians may have been less attractive defendants than manufacturers.

Kit-claim strength

The kit claim offered a direct product-based theory against a two-container commercial presentation. It was easier to identify in a product catalog or regulatory filing than a treatment-method claim. Its scope was narrower because it required separate containers and a physiologically acceptable carrier.

Overall, the estate was commercially relevant during the pre-expiration period but is no longer a blocking asset in the United States.

What FDA exclusivity did Cysview receive?

Cysview’s principal U.S. protection came from FDA approval, market adoption, and patent coverage rather than from a long period of new chemical entity exclusivity. Hexaminolevulinate is an ester derivative of 5-aminolevulinic acid, and the applicable regulatory exclusivity should be determined from the NDA record rather than inferred solely from the active ingredient’s novelty.

The critical commercial milestones were:

Milestone	Date or status
FDA product	Cysview
NDA	022555
Sponsor	Photocure ASA
FDA approval	2010
Use	Photodynamic detection of bladder cancer
Patent barrier	U.S. Patent 7,247,655, expired
Current U.S. patent barrier under this patent	None

Is there biosimilar risk for Cysview?

No. Cysview is a chemically synthesized small-molecule drug. A competing product would generally proceed through an abbreviated or alternative small-molecule drug pathway, such as an ANDA or potentially a 505(b)(2) application, depending on formulation, route, clinical differences, and reference-product reliance.

The relevant competitive risks are therefore:

• An ANDA for a pharmaceutically equivalent intravesical product.
• A 505(b)(2) product with different formulation or presentation.
• A hospital-use diagnostic product supported by bridging clinical data.
• A competing fluorescence agent using a different active compound.
• Non-drug imaging technologies, including narrow-band imaging and enhanced white-light systems.

What generic-entry risks exist after patent expiration?

The principal legal barrier under Patent 7,247,655 has ended. A generic or alternative sponsor could pursue:

1. A ready-to-use aqueous HAL product.
2. A lyophilized HAL vial with separate diluent.
3. A 505(b)(2) product with a different carrier or container system.
4. A hospital-use kit supported by comparative diagnostic data.
5. A formulation with different stability or reconstitution characteristics.

The remaining barriers are primarily regulatory and commercial:

• Demonstrating pharmaceutical equivalence or an acceptable clinical bridge.
• Establishing sterility and stability for intravesical administration.
• Validating the reconstitution and delivery system.
• Obtaining access to compatible blue-light cystoscopy equipment.
• Generating physician and hospital adoption.
• Supporting reimbursement for photodynamic cystoscopy.
• Managing any later-filed formulation, process, device, or use patents.

Patent expiration does not automatically create an approved generic. It removes the patent exclusion, while FDA approval remains necessary.

How does the U.S. patent landscape compare with Europe?

The claimed technology originated in a broader international patent family associated with Photocure and HAL photodynamic diagnosis. Foreign counterparts may have different claim sets, term dates, prosecution histories, supplementary protection certificates, and validity outcomes.

A U.S. freedom-to-operate conclusion cannot be transferred directly to Europe, Canada, Japan, or other jurisdictions. Key differences include:

• European patent validation by country.
• Supplementary protection certificate availability.
• National claim amendments.
• Different treatment of medical-use claims.
• Separate regulatory exclusivity periods.
• Country-specific litigation and opposition outcomes.

The U.S. Patent 7,247,655 expiration is therefore relevant only to U.S. conduct. International commercial entry requires a separate country-by-country review of the patent family, later continuations, formulation patents, device patents, and manufacturing rights.

What manufacturing and intellectual-property barriers remain?

Patent 7,247,655 does not claim a detailed manufacturing process. It does not require a particular synthetic route, purification technique, particle-size profile, lyophilization cycle, or container-closure system.

Manufacturing barriers can still arise from:

• HAL hydrochloride purity and impurity control.
• Stability of the active ingredient in the selected presentation.
• Sterile manufacturing and aseptic filling.
• Compatibility between the drug product and intravesical catheter.
• Light sensitivity and packaging controls.
• Reconstitution performance.
• Supply of qualified pharmaceutical-grade starting materials.

A sponsor must also review later patents that may claim improved formulations, storage systems, delivery devices, diagnostic workflows, or combination use with particular cystoscopy systems. Those rights are separate from Patent 7,247,655 and cannot be assumed to expire on the same date.

What is the commercial competitive landscape?

Cysview competes in a specialized bladder-cancer imaging market. The principal alternatives are:

• Conventional white-light cystoscopy.
• Narrow-band imaging.
• Other enhanced cystoscopic imaging technologies.
• Urinary biomarkers used as adjuncts rather than direct replacements.
• Alternative photodynamic agents, where approved or clinically developed.

Cysview’s commercial value depends on the ability of blue-light cystoscopy to identify lesions that may be less visible under white light, particularly carcinoma in situ. The drug and cystoscope function as a linked diagnostic system, even though the drug patent does not claim the hardware.

A generic HAL entrant would need to address both product approval and system access. Hospitals may need compatible light sources, scopes, training, and workflow integration. Those factors can delay entry after patent expiration even when the drug composition itself is no longer patented.

Key Takeaways

• U.S. Patent 7,247,655 covers HAL aqueous compositions, carrier-based formulations, two-container kits, and fluorescence-based bladder-diagnosis methods.
• Claims 1, 3, 5, and 8 are formulation claims with broad overlap but different transition language.
• Claim 11 covers a separate-active-and-carrier kit.
• Claim 14 requires bladder administration, photoactivation, fluorescence assessment, and comparison with controls.
• The patent does not claim the HAL molecule generally or a detailed manufacturing process.
• The patent issued in 2007 and expired in February 2021 under its ordinary U.S. term framework.
• The patent was historically relevant to Cysview and NDA 022555.
• No current enforceable U.S. exclusivity remains under Patent 7,247,655.
• Cysview is a small-molecule drug, so biosimilar analysis does not apply.
• Future entrants face FDA, sterile-manufacturing, formulation, device-compatibility, and commercial adoption barriers rather than this expired patent.

FAQs

Can a company market hexaminolevulinate in the United States after Patent 7,247,655 expired?

Yes, the expired patent no longer blocks U.S. manufacture, sale, or use. The product must still satisfy FDA approval requirements and avoid infringement of any later unexpired patents.

Does Patent 7,247,655 cover hexaminolevulinate hydrochloride itself?

No. The patent claims compositions and diagnostic use containing HAL or a pharmaceutically acceptable salt. It is not a broad compound patent covering the molecule in every context.

Does a ready-to-use HAL solution infringe the expired kit claim?

The kit claim requires separate containers for the active ingredient and carrier. A ready-to-use solution would not satisfy that limitation, although it could historically have implicated the composition claims.

Could a different wavelength avoid the method claims?

A wavelength outside the expressly claimed 300–800 nm range could avoid literal infringement of claim 14, subject to other claims and any doctrine-of-equivalents analysis applicable during the patent term. Wavelength alone would not resolve the composition claims.

Is Cysview eligible for an ANDA-based generic competitor?

Potentially. An ANDA sponsor would need to establish the required pharmaceutical equivalence and other FDA conditions. A formulation, presentation, or clinical difference could instead make a 505(b)(2) pathway more appropriate.

References

1. Photocure ASA. (2007). U.S. Patent No. 7,247,655: Hexyl 5-aminolevulinate compositions and methods for diagnosis. United States Patent and Trademark Office.

2. U.S. Food and Drug Administration. (2010). Cysview (hexaminolevulinate hydrochloride) prescribing information. NDA 022555.

3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. Center for Drug Evaluation and Research.

4. United States Patent and Trademark Office. (2024). Patent term adjustment and patent term information for U.S. Patent No. 7,247,655.

5. Photocure ASA. (2023). Annual report and Cysview commercial information. Photocure ASA.

Drugs Protected by US Patent 7,247,655

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

Foreign Priority and PCT Information for Patent: 7,247,655

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	9504948.2	Mar 10, 1995
United Kingdom	9525822.4	Dec 18, 1995

International Family Members for US Patent 7,247,655

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0820432		SPC024/2002	Ireland
European Patent Office	0820432		SPC/GB02/038	United Kingdom
European Patent Office	0820432		300176	Netherlands
European Patent Office	0820432		300207	Netherlands
European Patent Office	0820432		SPC/GB05/044	United Kingdom