United States Patent 4,053,628: Scope, Claims, Expiration, and Cromolyn Sodium Patent Landscape

United States Patent 4,053,628 covers the therapeutic use of cromoglycic acid, also known as cromoglicic acid or cromolyn, for allergic or immune-mediated conditions of the eye and nose. Its strongest protection was directed to low-metal, sterile aqueous ophthalmic or nasal solutions containing cromoglycic acid or a pharmaceutically acceptable salt. The patent issued on October 11, 1977, and its 17-year term expired on October 11, 1994. It presents no current U.S. patent barrier to generic cromolyn ophthalmic or nasal products.

The patent is important historically because it moved beyond the cromoglycic acid molecule itself and claimed product-quality controls intended to preserve solution clarity and stability. Those formulation limitations materially narrowed the enforceable scope of claims 2 and 3.

What drug does United States Patent 4,053,628 cover?

The active ingredient is 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol, generally called cromoglycic acid, cromoglicic acid, or cromolyn. The marketed pharmaceutical form is commonly cromolyn sodium, the disodium salt of cromoglycic acid.

Attribute	Patent 4,053,628
Active ingredient	Cromoglycic acid or a pharmaceutically acceptable salt
Common U.S. name	Cromolyn sodium
Therapeutic area	Ophthalmology and allergy
Dosage forms addressed	Topical sterile aqueous solutions; sub-conjunctival administration
Claimed sites	Eye and nose
U.S. patent number	4,053,628
Issue date	October 11, 1977
Patent term	17 years from grant under the pre-Uruguay Round regime
Expiration date	October 11, 1994
Current status	Expired

The claims do not cover every use of cromolyn. They are limited to specified administration routes and conditions in which allergy or immune reactions contribute to the disease.

What does claim 1 protect?

Claim 1 is the broadest claim. It covers:

Treatment of an eye or nose condition;
The condition must involve allergy or an immune reaction as a contributing factor;
The active agent must be cromoglycic acid or a pharmaceutically acceptable salt; and
Administration must be topical or by sub-conjunctival injection.

The claim does not require:

A particular concentration;
A sterile aqueous solution;
A chelating agent;
A metal-ion limit;
A specific disease;
A particular dosage frequency; or
A particular salt, provided the salt is pharmaceutically acceptable.

A product or treatment would fall outside claim 1 if it used a different active ingredient, treated a condition unrelated to allergy or immune response, or used an administration route outside topical delivery and sub-conjunctival injection.

Claim 1 construction issues

The phrase “in which conditions allergy or immune reactions play a contributory part” is functional and potentially broad. It reaches conditions where allergy or immune response is not necessarily the sole cause. The claim therefore extends beyond classic allergic rhinitis and conjunctivitis, at least as a matter of claim language.

The route limitation remains important. Inhaled cromolyn for asthma, oral cromolyn for mast-cell disorders, and other non-ocular or non-nasal uses are outside the literal scope of claim 1.

What formulations are protected by claims 2 and 3?

Claims 2 and 3 are formulation-specific method claims. Both require administration of a sterile aqueous composition containing cromoglycic acid or its salt at a concentration of 0.1% to 10% weight/volume.

Claim 2: ultra-low-metal sterile aqueous solution

Claim 2 requires:

A sterile aqueous solution;
Cromoglycic acid or a pharmaceutically acceptable salt;
Active ingredient concentration of 0.1% to 10% w/v;
Less than approximately 0.40 ppm of specified metal ions;
Topical or sub-conjunctival administration; and
A substantially clear solution.

The listed metals include ions from Groups IIa, Ib, IIb and IVb of the periodic table, together with transition metals. The drafting is chemically dated, but the practical limitation is clear: the formulation must have an exceptionally low concentration of metal contaminants capable of affecting cromoglycic acid stability, color, precipitation, or clarity.

A competing product would need to satisfy every limitation to infringe claim 2. A solution with 0.40 ppm or more of a relevant metal ion would not meet the literal “less than about 0.40 ppm” limitation, subject to claim-construction issues concerning the word “about.”

Claim 3: chelator-containing formulation

Claim 3 covers a somewhat less stringent metal specification combined with a chelating or sequestering agent. It requires:

A sterile aqueous solution;
Cromoglycic acid or a pharmaceutically acceptable salt;
Active ingredient concentration of 0.1% to 10% w/v;
Less than approximately 20 ppm of the specified metal ions;
Approximately 0.05% to 0.1% w/v of a pharmaceutically acceptable chelating or sequestering agent;
A substantially clear solution; and
Topical or sub-conjunctival administration.

The relationship between claims 2 and 3 is commercially significant. Claim 2 protects a very high-purity, low-metal approach. Claim 3 permits a higher metal-ion level but requires a chelator. Likely chelating agents would include compounds such as edetate salts, although the claim language supplied does not name a particular chelator.

Formulation claim comparison

Limitation	Claim 2	Claim 3
Cromoglycic acid or salt	Required	Required
Sterile aqueous solution	Required	Required
Concentration	0.1%-10% w/v	0.1%-10% w/v
Metal-ion limit	Less than about 0.40 ppm	Less than about 20 ppm
Chelator	Not required	0.05%-0.1% w/v required
Clear solution	Required	Required
Administration	Topical or sub-conjunctival	Topical or sub-conjunctival

What diseases are covered by claims 4, 5, and 6?

Claim 4 narrows claim 1 to listed eye conditions. The list includes:

Vernal catarrh;
Marginal corneal ulceration or infiltration;
Ocular effects of hay fever;
Non-specific conjunctivitis;
Herpes simplex keratitis and conjunctivitis;
Herpes zoster keratitis and conjunctivitis;
Adenovirus infections;
Phlyctenular conjunctivitis;
Corneal homograft rejection;
Trachoma;
Anterior uveitis; and
Drug sensitivity.

Claim 5 covers nasal conditions, including:

Seasonal rhinitis;
Perennial rhinitis;
Nasal polyps; and
Allergic manifestations of the nasopharynx.

Claim 6 narrows claim 4 by specifying an ocular dose of 0.66 to 1.32 mg administered to the affected eye two to four times daily.

The disease lists should not be treated as modern FDA labeling. A patent claim can describe a proposed therapeutic use without establishing that the FDA approved the use. In particular, the infectious, inflammatory, transplant-related and uveitic conditions listed in claim 4 should be separated from approved cromolyn indications.

When did United States Patent 4,053,628 lose exclusivity?

The patent expired on October 11, 1994.

The patent predates the 20-year-from-earliest-effective-filing-date term created by the Uruguay Round Agreements Act. Under the then-applicable U.S. rule, the patent term was generally 17 years from issuance. Patent 4,053,628 issued on October 11, 1977, placing the end of its enforceable term on October 11, 1994. No patent-term extension or patent-term adjustment would revive the expired patent. [1][2]

Event	Date
U.S. patent issued	October 11, 1977
Patent term under historical rule	17 years from issue
Expiration	October 11, 1994
Current enforceability	None

Expiration eliminates infringement liability under this patent. It does not eliminate separate regulatory requirements for marketing a cromolyn product.

What is the Orange Book status of cromolyn sodium?

Patent 4,053,628 should not create an Orange Book barrier today because it expired nearly three decades ago. Orange Book patent listings are relevant to listed drugs and approved conditions, but an expired patent cannot block approval through an active period of patent protection.

Cromolyn sodium products have included ophthalmic solutions, nasal sprays and inhalation products. The marketed products commonly associated with the compound include:

Cromolyn sodium ophthalmic solution, historically marketed for allergic conjunctivitis;
NasalCrom, a nonprescription cromolyn sodium nasal spray; and
Intal, an inhaled cromolyn sodium product historically used for asthma prophylaxis.

The FDA has separately classified certain cromolyn products by dosage form and regulatory status. A product’s discontinued, prescription, over-the-counter or unapproved status is distinct from the expired patent status. [3][4]

Are there Paragraph IV challenges to this patent?

No current Paragraph IV challenge can have commercial effect against Patent 4,053,628 because the patent expired on October 11, 1994.

Paragraph IV certifications are relevant when an ANDA applicant challenges a listed patent as invalid, unenforceable or not infringed before expiration. Once the patent term ended, an applicant no longer needed to delay launch on account of this patent. Historical ANDA activity may have involved other cromolyn patents or regulatory exclusivities, but Patent 4,053,628 is not a current Paragraph IV obstacle.

What patent litigation affects cromolyn sodium?

Patent 4,053,628 does not present ongoing U.S. litigation risk. Any infringement action based solely on this patent would be barred by expiration.

The commercial dispute risk for cromolyn products is therefore more likely to arise from:

Product-specific patents filed after the original patent;
Trade-secret claims involving manufacturing;
Trademark disputes;
FDA compliance issues;
Drug-quality or sterility issues;
State-law competition claims; or
Contract disputes involving distribution or licensing.

No settlement agreement tied to an enforceable term of Patent 4,053,628 remains commercially operative after expiration.

How strong was the patent estate for cromoglycic acid?

The patent was technically meaningful but commercially narrow in its formulation claims.

Strong elements

Claim 1 had broad therapeutic-use language. It did not require a particular concentration or excipient. Claims 4 and 5 gave the patentee specific fallback positions covering named ocular and nasal conditions.

Claims 2 and 3 addressed a real formulation problem: cromoglycic acid solutions could be sensitive to trace metal contamination and could develop instability or loss of clarity. The low-metal and chelation limitations could have distinguished ordinary aqueous formulations.

Weak elements

The patent did not protect the cromoglycic acid molecule as a composition of matter. It also did not cover all routes of administration or all therapeutic uses. Claims 2 and 3 required proof of several technical parameters, including:

Sterility;
Aqueous composition;
Concentration;
Metal-ion content;
Solution clarity;
Chelator concentration for claim 3; and
A covered route and condition.

Those elements create substantial non-infringement opportunities. A manufacturer using a nonaqueous formulation, a different concentration, a different administration route, or a formulation outside the metal and chelator ranges would not necessarily fall within the formulation claims.

How does this patent compare with later cromolyn products?

Issue	Patent 4,053,628	Later cromolyn products
Active ingredient	Cromoglycic acid or salt	Usually cromolyn sodium
Eye treatment	Covered	Common historical use
Nasal treatment	Covered	Common OTC use
Inhalation	Not covered by these claims	Major historical use
Formulation	Sterile aqueous solutions in claims 2 and 3	Product-specific formulations
Metal control	Expressly claimed	May be controlled by manufacturing specifications
Chelator	Required only by claim 3	Product-dependent
Current patent barrier	None	Must be assessed against later patents, if any
FDA approval	Not established by patent	Determined by product-specific FDA status

The patent’s scope should not be conflated with the full cromolyn patent landscape. Earlier patents may have addressed the compound or broader pharmaceutical uses. Later patents could have addressed containers, preservatives, delivery devices, manufacturing processes or new formulations. Patent 4,053,628 itself, however, is expired.

What generic launch risks exist?

The patent-related launch risk is low because the patent has expired. A generic or authorized manufacturer can rely on the absence of enforceable rights under Patent 4,053,628.

Remaining launch risks are primarily regulatory and technical:

Demonstrating sterility for ophthalmic products;
Establishing container-closure integrity;
Controlling metal impurities;
Demonstrating solution clarity and stability;
Matching the reference product’s concentration and dosage form;
Complying with FDA monograph or ANDA requirements;
Establishing preservative performance where applicable; and
Confirming that no later, product-specific patent remains enforceable.

The formulation limitations in claims 2 and 3 may still have technical relevance as manufacturing targets, but they do not create legal exclusivity after expiration.

Does the patent create biosimilar risk?

No. Cromolyn sodium is a chemically synthesized small molecule, not a biologic. Biosimilar approval under the Public Health Service Act is not the relevant pathway. Competition would proceed through an NDA, ANDA, OTC monograph pathway or another applicable FDA route depending on dosage form and product classification. [3][5]

What licensing deals are connected to the patent?

The patent was associated with the historical cromoglycic acid development program and its original pharmaceutical commercialization. No current license is needed to practice the expired patent.

A historical commercial license or assignment could remain relevant to ownership history, royalty accounting or archival diligence, but it would not restore exclusivity against third parties. The key commercial rights after expiration concern trademarks, regulatory approvals, manufacturing know-how and distribution arrangements rather than the patent claims.

Key Takeaways

U.S. Patent 4,053,628 covers cromoglycic acid, commonly marketed as cromolyn sodium, for certain allergic or immune-mediated eye and nose conditions.
Claim 1 is the broadest claim and covers topical or sub-conjunctival treatment.
Claims 2 and 3 protect sterile, substantially clear aqueous formulations with specific concentration, metal-ion and chelator limitations.
Claims 4 and 5 list specific ocular and nasal conditions.
Claim 6 specifies an ocular dose of 0.66 to 1.32 mg two to four times daily.
The patent issued on October 11, 1977, and expired on October 11, 1994.
It is not a current Orange Book, Paragraph IV or patent-litigation barrier.
Cromolyn sodium is a small molecule, so biosimilar analysis does not apply.
Current commercial risk is regulatory, manufacturing and product-specific rather than based on Patent 4,053,628.

FAQs

Can a generic company market cromolyn sodium without a license to Patent 4,053,628?

Yes. The patent expired on October 11, 1994. A license under that patent is no longer required.

Does Patent 4,053,628 cover cromolyn inhalers?

No. The supplied claims are limited to eye and nose conditions and topical or sub-conjunctival administration. They do not cover inhaled cromolyn products.

Does claim 3 require a specific chelating agent?

No specific agent is named in the claim language supplied. The agent must be pharmaceutically acceptable, function as a chelating or sequestering agent, and be present at approximately 0.05% to 0.1% w/v.

Can a nasal cromolyn spray infringe claim 2?

Not today, because the patent is expired. Before expiration, infringement would have required satisfaction of every claim limitation, including the sterile aqueous solution, concentration, low-metal level, substantially clear appearance and covered administration.

Is cromolyn sodium subject to biosimilar competition?

No. Cromolyn sodium is a small-molecule drug. Generic-drug and OTC regulatory pathways, rather than biosimilar approval, govern competition.

References

U.S. Patent and Trademark Office. (1977). United States Patent No. 4,053,628.
U.S. Patent and Trademark Office. (2024). Manual of Patent Examining Procedure, Chapter 2700: Patent term and adjustment.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations.
U.S. Food and Drug Administration. (2024). Drug approval package and labeling resources for cromolyn sodium products.
U.S. Food and Drug Administration. (2024). Biosimilar and interchangeable biosimilar products.

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

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

Details for Patent: 4,053,628

Summary for Patent: 4,053,628