United States Drug Patent 6,372,449: Claim Scope, Expiration, and Ophthalmic Patent Landscape

U.S. Patent No. 6,372,449 protects a method of using trypan blue to make intraocular membranes or structures visually identifiable during eye surgery. Its core protection is a use claim, not a composition claim. The patent does not claim trypan blue itself, a formulation, a container, or a surgical instrument.

The patent’s enforceable term has ended. Based on its 2002 issue date and the applicable U.S. patent-term rules, the patent expired no later than April 16, 2019, absent an unusual term adjustment or terminal-disclaimer issue. It therefore does not currently block generic, branded, or compounded use of trypan blue for intraocular visualization. Current commercial risk would come from later patents, regulatory requirements, trade secrets, or product-specific formulation and device rights.

What does U.S. Patent 6,372,449 cover?

The patent covers a surgical identification method with three functional elements:

Trypan blue solution is instilled into the eye.
The solution marks an intraocular membrane or structure in a visually identifiable manner.
The marking is used to identify the membrane or structure.

Claim 1 is the broadest independent claim:

A method for the identification of intraocular membranes and structures within the eye, comprising instilling into the eye a trypan blue solution that marks the membranes or structures in a visually identifiable manner.

The claim is directed to the act and purpose of use. It does not require a particular surgical instrument, illumination system, container, pH, osmolarity, excipient, dosage volume, or treatment outcome.

What are the dependent claims?

Claim	Added limitation	Commercial significance
1	Instilling trypan blue to visually identify intraocular membranes or structures	Broad method-of-use claim
2	Trypan blue concentration of 0.05% w/w to 3% w/w	Covers common dilute ophthalmic staining solutions, including approximately 0.06% products
3	Membrane is the epiretinal membrane or internal limiting membrane	Targets vitreoretinal surgery
4	Membrane is pathological	Narrows use to disease-associated membranes
5	Pathological membrane results from proliferative vitreoretinopathy	Specific retinal-surgery indication
6	Membrane is surgically treated after visual identification	Adds a post-identification treatment step
7	Treatment is removal, lifting, repositioning, or reduction in size	Covers membrane peeling and related surgical manipulation

Claim 1 does not require surgical removal. A procedure in which trypan blue is used only to identify a membrane could fall within the claim if the other limitations are met.

How broad is claim 1 of U.S. Patent 6,372,449?

Claim 1 is broad in subject matter but narrow in mechanism. It requires trypan blue to be placed into the eye and to mark an intraocular membrane or structure visibly.

Covered uses

The claim potentially reaches use of trypan blue for:

Epiretinal membrane identification
Internal limiting membrane visualization
Pathological retinal membrane staining
Proliferative vitreoretinopathy membrane identification
Identification of other intraocular membranes
Visualization before membrane peeling or other surgery
Intraocular structure identification where the dye produces a visible mark

The claim is not limited to retinal surgery. The phrase “intraocular membranes and structures” is broader than “epiretinal membrane,” although claims 3 through 5 expressly narrow the subject matter to retinal and pathological membranes.

What is not expressly required?

Claim 1 does not expressly require:

A particular concentration
A particular route within the eye, such as intravitreal or anterior-chamber delivery
A specified exposure time
A specified volume
A particular surgical procedure
Removal of the dye
A diagnosis
Treatment of disease
A commercial product
A particular formulation vehicle
A particular concentration of sodium chloride, phosphate, or other excipient

The claim’s functional language creates an infringement issue around whether the solution actually “marks” the membrane in a “visually identifiable manner.” A formulation that contains trypan blue but is used for a purpose unrelated to intraocular visualization would present a weaker infringement case.

What concentration range does claim 2 protect?

Claim 2 covers trypan blue concentrations from 0.05% w/w through 3% w/w. The range is broad compared with commonly marketed ophthalmic trypan blue products.

A product containing approximately 0.06% trypan blue would fall within the numerical limitation of claim 2, provided that the product is used according to the other limitations of claim 1. Concentration alone would not determine infringement because claim 2 depends on claim 1.

The claim uses weight percentage rather than a molar concentration or volume percentage. Analytical and litigation issues could include:

Whether the concentration is measured in the finished solution
Whether the stated percentage is w/w or nominal label concentration
Whether the product is diluted before use
Whether a premixed product and a separately diluted product should be assessed at the time of instillation
Whether the solution is technically “trypan blue” despite salt, hydration, or purity differences

A formulation outside the 0.05% to 3% range could avoid claim 2 but would not necessarily avoid claim 1, because claim 1 has no express concentration limitation.

What retinal procedures are covered by claims 3 through 7?

Claims 3 through 7 target posterior-segment surgery.

Epiretinal and internal limiting membrane surgery

Claim 3 covers identification of either:

An epiretinal membrane, or
The internal limiting membrane of the retina

These membranes are relevant to pars plana vitrectomy and membrane-peeling procedures. Trypan blue can improve contrast between the membrane and the retinal surface, particularly when the tissue is thin or transparent.

Proliferative vitreoretinopathy

Claim 5 depends on claims 4 and 1 and covers pathological membranes resulting from proliferative vitreoretinopathy. The claim requires:

A pathological membrane;
The membrane results from proliferative vitreoretinopathy;
Trypan blue is instilled to identify it.

The claim does not cover all retinal surgery. It requires the claimed staining and identification function.

Surgical treatment

Claim 6 adds treatment after visual identification. Claim 7 specifies four forms of treatment:

Removal
Lifting
Repositioning
Reduction in size

The claims therefore reach a complete surgical workflow, but the broadest claim does not require the surgeon to complete that workflow.

Is U.S. Patent 6,372,449 still enforceable?

No. The patent’s term has ended.

Event	Date or rule
Patent issued	April 16, 2002
Governing term framework	Generally 20 years from the earliest effective nonprovisional filing date for applications subject to the Uruguay Round Agreements Act
Alternative issue-date rule	Patents subject to the pre-1995 framework generally ran 17 years from issue
Latest ordinary expiration based solely on issue date	April 16, 2019
Current status	Expired; no present infringement injunction or damages claim based solely on this patent

The governing statute is 35 U.S.C. § 154, which generally provides a term ending 20 years after the earliest effective U.S. nonprovisional filing date, subject to patent-term adjustment, terminal disclaimers, and other statutory provisions.[2] A patent cannot be enforced after expiration, although damages for pre-expiration infringement may remain relevant if properly preserved.

Because the patent issued in 2002, even a 17-year-from-issue calculation produces an April 16, 2019 expiration date. The patent therefore cannot presently support a Paragraph IV lawsuit or an injunction against a new entrant.

What patent rights did U.S. Patent 6,372,449 not claim?

The patent does not, based on the supplied claims, claim:

Trypan blue as a chemical compound
A sterile ophthalmic trypan blue composition
A particular preservative-free formulation
A glass or plastic vial
A prefilled syringe
A surgical cannula
A dye-delivery instrument
A combination of trypan blue with another staining agent
A manufacturing process for trypan blue
A specific pH or osmolarity
A particular dosing volume
A sustained-release formulation
A product label or commercial brand
A treatment outcome independent of identification

That distinction matters. A later patent could protect a formulation or delivery system that uses the same underlying staining concept. Expiration of the method patent would not eliminate later-filed patent rights.

What is the Orange Book status of trypan blue products?

The Orange Book is not the primary patent-clearance database for ophthalmic surgical aids such as trypan blue products. The FDA Orange Book lists approved drug products and associated patents and exclusivity information under the Hatch-Waxman framework. Products regulated as medical devices or ophthalmic surgical aids may instead be cleared or approved through device pathways and may not have Orange Book listings.[3]

VisionBlue, a trypan blue ophthalmic product associated with DORC, received FDA marketing authorization as an ophthalmic surgical aid for anterior capsule staining in cataract surgery through the device regulatory system.[4] That regulatory authorization does not establish that U.S. Patent 6,372,449 remains active, nor does it establish freedom to operate for every posterior-segment use.

FDA regulatory implications

Trypan blue products may be regulated differently depending on:

Intended use
Concentration
Sterility claims
Route of administration
Whether the product is used for anterior capsule staining
Whether the product is used for retinal membrane visualization
Product classification and FDA authorization pathway

A product authorized for anterior capsule staining should not automatically be treated as authorized for every retinal or vitreoretinal use. The FDA-approved indication, labeling, and product classification remain separate from patent scope.

Are Paragraph IV challenges relevant to this patent?

No current Paragraph IV challenge would be meaningful against U.S. Patent 6,372,449 because the patent has expired.

Paragraph IV certifications apply when an abbreviated new drug application applicant asserts that a listed patent is invalid, unenforceable, or not infringed. A patent that has already expired does not provide a continuing Hatch-Waxman barrier to approval or launch.[5]

The practical implications are:

No current 30-month stay can be based on this expired patent.
A generic applicant does not need to wait for this patent to expire because the term has already ended.
The patent cannot support a new infringement complaint against a future generic entrant.
Any remaining regulatory exclusivity would have to arise from a separate statute, listed patent, or product-specific approval issue.

Does biosimilar risk apply?

No. Biosimilar law is not the relevant framework for trypan blue.

Trypan blue is a small-molecule dye used in ophthalmic surgery. A competing trypan blue product would ordinarily raise generic-drug, device, compounding, or product-classification issues rather than biosimilar interchangeability issues under the Biologics Price Competition and Innovation Act.[6]

The relevant competitive risks are more likely to involve:

Abbreviated drug approval, where applicable
Device clearance or approval
Compounded sterile ophthalmic products
Hospital purchasing contracts
Manufacturing quality systems
Sterility and endotoxin controls
Labeling and intended-use restrictions
Later formulation or delivery patents

What patent landscape surrounds trypan blue membrane staining?

The patent landscape separates into five technical groups.

Patent category	Typical protected subject matter	Relevance to 6,372,449
Intraocular staining methods	Using dye to visualize membranes or structures	Closest conceptual category
Formulation patents	Concentration, pH, osmolarity, excipients, sterility, stability	Potential later blocking rights
Delivery-system patents	Cannulas, injectors, dual-chamber systems, controlled delivery	Product and procedure risk
Combination-staining patents	Trypan blue with other dyes or surgical agents	May create differentiated products
Manufacturing patents	Purification, sterile filling, container closure, quality control	Commercial supply-chain barriers

The expired patent is strongest as a historical foundational method patent. It is no longer a blocking right. A current freedom-to-operate review should focus on later patents with claims directed to:

A finished ophthalmic trypan blue composition
A defined concentration near commercial product levels
A preservative-free sterile formulation
A particular pH or osmolality
A dual-dye or sequential-staining method
A retinal membrane peeling method using a specified dye
A delivery device or cannula
A prefilled ophthalmic surgical product

How strong was the patent estate for the claimed invention?

The patent had meaningful breadth during its active term because claim 1 omitted the concentration, retinal membrane, pathology, and surgical-treatment limitations found in the dependent claims.

Its strength can be assessed as follows:

Factor	Assessment
Claim breadth	High for the use of trypan blue to visually identify intraocular membranes
Chemical scope	Narrow to trypan blue; no broader dye genus
Formulation scope	Limited; no detailed formulation claim in the supplied claims
Procedure scope	Broad under claim 1, narrower under claims 6 and 7
Retinal specificity	Limited in claim 1; explicit in claim 3
Commercial relevance	High for membrane-staining products used during ophthalmic surgery
Current enforceability	None because the patent has expired
Design-around potential during term	Possible through a different dye, a non-visual identification method, or a use outside the claimed purpose
Present business value	Historical prior-art and landscape significance, not exclusionary value

The broadest vulnerability would have concerned the relationship between the claim language and earlier disclosure of trypan blue staining in ophthalmic surgery. The patent’s practical value depended on whether the claimed use was novel and nonobvious over prior use of trypan blue for anterior capsule staining or other ocular visualization.

What litigation and settlement issues affect this patent?

The patent cannot support new enforcement litigation after expiration. Any historical litigation would need to be evaluated based on the filing date, asserted claims, accused products, and the patent’s then-current status.

No settlement agreement can be inferred from ownership, commercialization, or FDA authorization alone. A commercial product using trypan blue does not establish that the manufacturer licensed U.S. Patent 6,372,449. Patent licenses are often private and may not appear in the patent file.

For diligence purposes, the relevant historical questions are:

Whether the patent was asserted against a trypan blue manufacturer
Whether any defendant raised anticipation or obviousness defenses
Whether a court construed “instilling into the eye”
Whether the patent owner asserted claim 1 independently of claims 3 through 7
Whether any settlement included a launch date or field-of-use restriction
Whether the patent was assigned before expiration
Whether any terminal disclaimer or reexamination affected the term

The expired status eliminates the need to negotiate a license solely for future practice of the claimed method.

Which companies are exposed to this patent today?

No company has current patent exposure solely from U.S. Patent 6,372,449 because the patent is expired.

Companies selling trypan blue products may still face separate exposure from:

Active formulation patents
Device patents
Labeling or regulatory claims
Trade-secret claims
Contract restrictions
Manufacturing agreements
Trademark rights
Product-liability obligations

Potential commercial participants include branded ophthalmic surgical-aid manufacturers, generic sterile ophthalmic manufacturers, compounding pharmacies, contract manufacturers, and suppliers of vitreoretinal surgical products. The identity of a product manufacturer does not establish infringement of any active patent.

How does this patent compare with formulation and product patents?

U.S. Patent 6,372,449 is a method patent. A formulation patent generally claims the product itself and can create broader supply-chain control because manufacture, sale, or use may infringe without proof that the product was used for the claimed surgical purpose.

Issue	U.S. Patent 6,372,449	Formulation patent
Claim type	Method of use	Composition or product
Required proof	Use in the claimed manner	Making, selling, or using claimed composition
Concentration	Only dependent claim 2	Often central to the claim
Label relevance	Important for induced infringement analysis	Often less dependent on label
Manufacturing exposure	Usually indirect	Often direct
Current status	Expired	Must be reviewed patent by patent
Design-around	Alternative dye or use	Change concentration, excipients, container, or process if claims permit

What are the likely generic launch scenarios?

Because the patent is expired, three launch scenarios are commercially relevant:

Immediate launch of a non-infringing product

A manufacturer can launch a trypan blue product without waiting for U.S. Patent 6,372,449, subject to FDA authorization, quality requirements, and any other active patents.

Launch under an anterior-segment indication

A manufacturer may pursue an indication focused on anterior capsule staining. This could reduce exposure to retinal method-of-use claims, although the expired patent does not currently create that exposure in any event.

Launch for retinal membrane visualization

A product intended for internal limiting membrane or epiretinal membrane staining may be commercially attractive but must be reviewed against later patents and FDA labeling requirements. The expired patent is relevant as prior art and historical market context, not as a present barrier.

What geographic rights did U.S. Patent 6,372,449 provide?

The patent provided rights only in the United States. It did not directly control use, manufacture, or sale outside the United States.

Foreign counterparts, if any, required separate examination. Patent families may include applications in Europe, Canada, Australia, Japan, or other jurisdictions, but expiration dates and claim scope could differ because of:

Different filing dates
National-phase prosecution
Patent-term adjustments
Supplementary protection systems
Local examination amendments
Abandonment or lapse
Maintenance-fee failures

A U.S. expiration finding should not be extended automatically to foreign jurisdictions. The U.S. patent number alone does not establish the status of a global patent family.

What manufacturing and intellectual-property barriers remain?

The principal current barriers are regulatory and operational rather than the expired method claim.

A commercial trypan blue product may require:

Sterile manufacturing
Validated filtration or aseptic processing
Endotoxin control
Stability data
Container-closure integrity
Particulate controls
Consistent dye identity and purity
Appropriate ophthalmic labeling
FDA authorization under the applicable pathway
Controlled distribution for surgical use

Manufacturing know-how may remain protected as trade secrets even after patent expiration. A competitor can practice the expired method but may not lawfully acquire confidential production procedures, supplier specifications, or proprietary quality-control protocols.

Key Takeaways

U.S. Patent 6,372,449 claims the use of trypan blue to visually identify intraocular membranes and structures.
Claim 1 is the broadest claim and does not require a specific concentration or surgical treatment.
Claim 2 covers 0.05% w/w to 3% w/w trypan blue.
Claims 3 through 5 focus on epiretinal, internal limiting, pathological, and proliferative-vitreoretinopathy membranes.
Claims 6 and 7 cover subsequent surgical treatment, including membrane removal, lifting, repositioning, and size reduction.
The patent expired no later than April 16, 2019, based on its April 16, 2002 issue date.
The patent is not a current barrier to generic or branded trypan blue launch.
Trypan blue is not a biosimilar issue, and products regulated as ophthalmic surgical aids may not appear in the Orange Book.
Current freedom-to-operate risk must be assessed against later formulation, delivery-device, manufacturing, and product patents.
A license cannot be presumed from commercialization or FDA authorization.

FAQs About U.S. Patent 6,372,449

Can a company use trypan blue for internal limiting membrane staining without licensing this patent?

Yes. U.S. Patent 6,372,449 has expired, so it does not require a current license for that use. Later active patents must be assessed separately.

Does a trypan blue product at 0.06% infringe claim 2?

The concentration falls within claim 2’s numerical range, but the patent is expired. During the patent term, infringement would also have required practice of the limitations incorporated from claim 1.

Does the patent claim VisionBlue by name?

No. The supplied claims do not identify a brand, manufacturer, container, or commercial product. They claim a method using trypan blue.

Is posterior-segment use covered by FDA approval for anterior capsule staining?

Not automatically. FDA authorization depends on the approved or cleared intended use. Authorization for anterior capsule staining does not establish approval for retinal membrane visualization.

Can the expired patent still matter in a patent dispute?

Yes, as historical prior art, ownership evidence, prosecution-history evidence, or part of a patent-family analysis. It cannot provide a new enforceable exclusionary right after expiration.

References

United States Patent and Trademark Office. (2002). U.S. Patent No. 6,372,449, Method for identification of intraocular membranes and structures.
35 U.S.C. § 154. Patent term.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
U.S. Food and Drug Administration. (2004). VisionBlue ophthalmic surgical aid, PMA P040020.
21 U.S.C. § 355(j). Abbreviated applications and patent certifications.
Biologics Price Competition and Innovation Act of 2009, Pub. L. No. 111-148, §§ 7001-7003.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	5664000	⤷ Start Trial
Australia	715620	⤷ Start Trial
Australia	774292	⤷ Start Trial
Japan	2003504118	⤷ Start Trial
Japan	2007152130	⤷ Start Trial
Japan	2012236077	⤷ Start Trial
Japan	3953322	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 6,372,449