US Patent 3,975,536: Scope, Claims, Expiration, and Cromolyn Sodium Patent Landscape

US Patent 3,975,536 protects sterile aqueous formulations of cromolyn, also known as cromoglycic acid or cromoglicic acid, principally through control of trace-metal ions, preservatives, chelating agents, and solution clarity. The patent is a formulation patent, not a basic compound patent. Its US term expired decades ago, so it does not create a current US exclusivity barrier for cromolyn sodium products.

What drug and formulation does US Patent 3,975,536 cover?

The active ingredient identified in the claims is:

1,3-bis(2-carboxy-chromon-5-yloxy)-propan-2-ol

This is the chemical entity commonly known as cromolyn, cromoglycic acid, or cromoglicic acid. Pharmaceutical products generally use the disodium salt, sodium cromoglycate or cromolyn sodium.

The patent targets sterile aqueous solutions in which cromolyn is vulnerable to degradation, discoloration, precipitation, or loss of clarity caused by trace-metal contamination. The formulation strategy is based on one of two approaches:

Extremely low concentrations of specified metal ions; or
A higher permitted metal-ion concentration combined with a chelating or sequestering agent.

The claimed products are therefore defined by formulation quality attributes rather than by a new therapeutic use for cromolyn.

What are the independent claims of US 3,975,536?

Claims 1 and 6 are the two independent composition claims.

Claim	Core formulation	Metal-ion limit	Additional limitation
1	Sterile aqueous cromolyn solution	Less than about 0.40 ppm	Substantially clear solution
6	Sterile aqueous cromolyn solution	Less than about 20 ppm	0.05-0.1% w/v chelating or sequestering agent; substantially clear

Both independent claims require cromolyn or a pharmaceutically acceptable salt at 0.1-10% w/v.

Claim 1: low-metal formulation

Claim 1 requires all of the following:

A pharmaceutical composition;
A sterile aqueous solution;
Cromolyn or a pharmaceutically acceptable salt;
Cromolyn concentration of 0.1-10% w/v;
Less than about 0.40 ppm of specified metal ions;
A substantially clear solution.

The specified metals include ions of metals in:

Group IIa;
Group Ib;
Group IIb;
Group IVb; and
The transition-metal groups identified by the claim.

The claim does not expressly require a preservative or chelating agent. A product can potentially fall within claim 1 through control of raw materials, water, equipment, containers, processing conditions, or filtration, provided the final solution satisfies the metal threshold and other limitations.

Claim 6: chelator-assisted formulation

Claim 6 provides a different formulation route. It permits less stringent metal control, up to about 20 ppm, but requires:

A chelating or sequestering agent at about 0.05-0.1% w/v; and
A substantially clear aqueous solution.

The claim expressly identifies EDTA or an EDTA salt as an example through dependent claim 7.

Claim 6 is potentially broader than claim 1 with respect to metal concentration but narrower because it requires the chelator concentration. A formulation containing EDTA outside the claimed 0.05-0.1% w/v range would not satisfy claim 6 solely because it uses EDTA.

What formulations are protected by the dependent claims?

Preservative-containing formulations

Claims 2 and 8 cover formulations containing a preservative at 0.001-0.10% w/v. They also recite a preparation sequence:

Prepare an aqueous solution containing cromolyn, or cromolyn and the chelating agent;
Mix it with an aqueous preservative solution; and
Filter the resulting admixture.

This language gives the claims a product-by-process character. The legal significance depends on whether the preparation steps impose a limitation on the finished composition under the applicable infringement analysis. The claims are not limited merely to the presence of cromolyn and a preservative; they also recite the mixing and filtration process.

Sodium ethylmercurithiosalicylate

Claim 3 specifies sodium 2-(ethyl mercuriothio)benzoate, commonly known as thiomersal or thimerosal, at 0.001-0.5% w/v.

Because claim 3 depends on claim 2, the practical concentration range is constrained by claim 2's 0.001-0.10% w/v range. The dependent claim should therefore be read as adding the specified preservative while remaining subject to the narrower preservative range inherited from claim 2.

Alkyl-substituted preservative compounds

Claim 4 covers a class of preservatives represented by the formula reproduced in the patent, where R is C8H17 to C18H37 alkyl, or a mixture of those compounds. The formula image is not included in the supplied claim text, so the exact chemical identity of the preservative class cannot be established from the text alone.

Claim 5 narrows claim 4 to a preservative concentration of 0.005-0.10% w/v.

How should the claims be construed technically?

The patent has five principal technical limitations.

1. The active ingredient must be cromolyn

The claims do not cover all chromone derivatives, mast-cell stabilizers, or ophthalmic and inhaled antiallergic agents. They are directed to the specified bis-chromonyl compound and its pharmaceutically acceptable salts.

A product containing ketotifen, nedocromil, lodoxamide, or another unrelated cromone would not meet the active-ingredient limitation.

2. The dosage form must be aqueous and sterile

The claims require a sterile aqueous solution. They do not expressly cover:

Dry powders;
Suspensions;
Non-aqueous solutions;
Ointments;
Tablets;
Capsules;
Nebulizer formulations that are not solutions; or
Solid dosage forms later reconstituted by a user, unless the reconstituted product satisfies the claim.

3. Cromolyn concentration is material

The concentration range is 0.1-10% w/v. A formulation below 0.1% or above 10% would fall outside the express concentration limitation, subject to ordinary claim-construction principles concerning approximation and equivalents.

4. Metal-ion content is a central limitation

Claim 1 is commercially difficult to practice unintentionally because it requires less than about 0.40 ppm of specified ions. The relevant measurement is the concentration in the composition, not merely the concentration in one raw material.

Potential sources of relevant metals include:

Process water;
Stainless-steel manufacturing equipment;
Glass containers;
Elastomeric closures;
Excipients;
Preservatives;
Active-ingredient raw materials; and
Cleaning and sterilization systems.

Claim 6 provides a materially different control strategy by allowing approximately 20 ppm while requiring a chelator.

5. The solution must be substantially clear

"Substantially clear" is a functional and visual limitation. It supports the patent's technical objective of preventing visible precipitation, haze, or discoloration. A formulation that satisfies the numerical composition limits but is visibly turbid could present a claim-scope issue.

When did US Patent 3,975,536 lose exclusivity?

US Patent 3,975,536 is an issued US patent from the pre-1995 patent-term regime. Its term was governed by the 17-year period from grant rather than the current 20-year period measured from the earliest effective nonprovisional filing date.

The patent issued in 1976. Its ordinary US patent term therefore ended in approximately 1993. No current US patent exclusivity remains under this patent. The historical patent term also predates modern Hatch-Waxman patent-listing practice and cannot provide a present-day Paragraph IV barrier.

Event	Approximate date
US patent grant	1976
Applicable term regime	17 years from grant
Ordinary US expiration	Approximately 1993
Current enforceability	Expired
Current Orange Book exclusivity value	None

The patent's expiration does not determine whether later patents, regulatory exclusivity, or product-specific patents exist for a particular cromolyn product. It does establish that this patent itself cannot block current US manufacture, sale, or filing activity.

What is the Orange Book status of cromolyn sodium?

The Orange Book lists patents submitted by sponsors for approved products when the statutory listing requirements are met. A decades-old expired formulation patent such as US 3,975,536 does not create current Orange Book exclusivity.

Cromolyn products have historically been marketed in several dosage forms, including inhalation, ophthalmic, nasal, and other topical or mucosal products. Orange Book relevance depends on the individual approved product, NDA, dosage form, and sponsor-submitted patent information. The presence of cromolyn sodium in an approved product does not mean that US 3,975,536 remains listed or enforceable.

FDA approval status and patent status are separate issues:

FDA approval concerns safety, efficacy, quality, labeling, and manufacturing;
Orange Book listing concerns submitted patent information for an approved drug;
Patent expiration concerns the enforceability of the patent right; and
OTC status may place a product outside the ordinary ANDA patent-certification pathway.

For a current product-specific assessment, the relevant records are the FDA Orange Book, Drugs@FDA, product labeling, and any applicable OTC monograph or abbreviated application record. The expired patent does not independently support a current Paragraph IV challenge.

Are there biosimilar risks for cromolyn sodium?

No conventional biosimilar risk exists. Cromolyn sodium is a small-molecule drug, not a biologic. Competitors would generally use generic-drug, abbreviated application, OTC, or other small-molecule regulatory pathways rather than the biosimilar pathway under the Public Health Service Act.

The competitive risks are therefore:

Generic or authorized-generic entry;
Reformulation;
OTC substitution;
Private-label products;
Compounded products, where legally permitted;
Alternative mast-cell stabilizers; and
Substitution by antihistamine or corticosteroid products.

Which companies are challenging the patent?

US 3,975,536 is expired. There is no current Paragraph IV litigation or live patent challenge directed to this patent that would affect US market entry.

Historical litigation, if any, would have been relevant only during the patent's enforceable term. A current competitor would not need to invalidate or design around the patent because an expired patent cannot support an injunction or damages claim for new activity.

What manufacturing and intellectual-property barriers remain?

The patent's formulation concepts can still have technical value even though its legal rights have expired. Cromolyn solutions may require control of trace metals and compatibility between the active ingredient, preservative, container, and manufacturing system.

Potential current barriers include:

Developing a stable sterile aqueous solution;
Controlling elemental impurities;
Demonstrating preservative effectiveness;
Establishing container-closure compatibility;
Meeting sterility assurance requirements;
Avoiding precipitation or haze;
Validating filtration and sterilization;
Demonstrating shelf life; and
Complying with current elemental-impurity standards.

These are regulatory and manufacturing barriers, not barriers created by US 3,975,536.

A modern product may avoid the historical claim architecture by using:

A nonaqueous dosage form;
A dry powder;
A different preservative system;
A metal concentration outside the claimed range;
A chelator concentration outside the claimed range; or
A different delivery system.

Because the patent is expired, such changes are generally driven by stability, safety, quality, and commercial strategy rather than infringement avoidance.

How strong is the patent estate for cromolyn sodium?

The estate represented by US 3,975,536 is legally weak today because the patent has expired. Historically, it was technically focused and potentially meaningful for sterile aqueous products.

Estate characteristic	Assessment
Basic compound protection	Not provided by this patent
Composition protection	Narrow, formulation-specific
Metal-control limitation	Strong numerical limitation
Chelator pathway	Defined by concentration and clarity
Preservative pathway	Narrowly specified
Manufacturing-process limitation	Present in claims 2 and 8
Current US enforceability	None
Biosimilar relevance	None
Current generic-entry barrier	None from this patent

The principal historical value was in protecting a formulation solution to cromolyn instability. The principal current value is informational: the patent identifies metal contamination, chelation, preservation, and filtration as critical development variables.

How does US 3,975,536 compare with compound, method-of-use, and formulation patents?

Patent category	Typical protected subject matter	Relevance of US 3,975,536
Compound patent	Cromolyn chemical structure and salts	Not the subject of these claims
Formulation patent	Sterile aqueous solution, metal limits, chelator, preservative	Primary category
Method-of-use patent	Treatment of asthma, rhinitis, conjunctivitis, or allergy	Not claimed
Manufacturing patent	Synthesis, purification, or crystallization	Not claimed in the supplied claims
Device patent	Inhaler, nebulizer, pump, or dispenser	Not claimed
Regulatory exclusivity	FDA exclusivity period	Not created by this patent

Key Takeaways

US Patent 3,975,536 covers sterile aqueous cromolyn formulations.
Claim 1 requires 0.1-10% w/v cromolyn, less than about 0.40 ppm of specified metal ions, and a substantially clear solution.
Claim 6 permits about 20 ppm of those metal ions but requires 0.05-0.1% w/v of a chelating or sequestering agent.
Dependent claims address preservatives, thimerosal, a C8-C18 alkyl preservative class, EDTA, mixing, and filtration.
The patent is a formulation patent, not a basic cromolyn compound or therapeutic-use patent.
Its pre-1995 US patent term expired approximately in 1993.
It creates no current US patent, Orange Book, Paragraph IV, generic-entry, or biosimilar barrier.
Cromolyn sodium is a small molecule and is not subject to biosimilar competition.
The patent remains technically relevant to trace-metal control, solution clarity, preservative compatibility, and sterile manufacturing.

FAQs

Does US Patent 3,975,536 cover cromolyn sodium itself?

No. It covers specified sterile aqueous compositions containing cromolyn or a pharmaceutically acceptable salt. It does not claim the underlying cromolyn molecule as such.

Can a modern cromolyn product infringe an expired patent?

An expired patent cannot support an infringement action for current commercial activity. The claim language may still be relevant for historical analysis, freedom-to-operate records, and formulation development.

Does adding EDTA automatically place a cromolyn formulation within claim 6?

No. Claim 6 requires EDTA or another qualifying chelator at approximately 0.05-0.1% w/v, along with the specified cromolyn concentration, metal-ion ceiling, aqueous sterile solution, and substantial clarity.

Is thimerosal concentration in claim 3 broader than claim 2?

The text of claim 3 recites 0.001-0.5% w/v, but claim 3 depends on claim 2, which limits the preservative to 0.001-0.10% w/v. The narrower inherited range is the relevant practical range.

Does the patent protect inhalers or nebulizer devices?

No. The supplied claims protect the aqueous composition and, in certain dependent claims, the mixing and filtration process. They do not claim an inhaler, nebulizer, pump, dispenser, or other delivery device.

References

United States Patent and Trademark Office. (1976). U.S. Patent No. 3,975,536.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
U.S. Food and Drug Administration. (n.d.). Drugs@FDA: FDA-approved drugs.
U.S. Food and Drug Administration. (2018). Q3D elemental impurities: Guidance for industry.
U.S. Food and Drug Administration. (n.d.). Cromolyn sodium product labeling and regulatory records.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
	14529/71	May 12, 1971
	57169/71	Dec 9, 1971
	25237/73	May 25, 1973
	25238/73	May 25, 1973
	26649/73	Jun 5, 1973

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	4208072	⤷ Start Trial
Australia	465305	⤷ Start Trial
Belgium	782981	⤷ Start Trial
Canada	1000201	⤷ Start Trial
Cyprus	955	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 3,975,536

Summary for Patent: 3,975,536