US Patent 4,657,900: Claim Scope, Expiration, Orange Book Status, and Mesalamine Patent Landscape

US Patent 4,657,900 protects an oxygen-controlled, bisulfite-stabilized 5-aminosalicylic acid, or mesalamine, rectal suspension packaged in a two-container system. The core commercial concept is a single-dose polyethylene enema bottle placed inside an oxygen-barrier pouch, typically incorporating aluminum foil. The patent’s pre-1995 17-year term expired in 2004, so the claims no longer create an enforceable patent barrier to generic mesalamine enemas.

What does US Patent 4,657,900 cover?

The patent covers a pharmaceutical article and associated storage method for preventing oxidation and discoloration of an aqueous mesalamine rectal suspension.

Its technical combination has five central elements:

Substantially pure pharmaceutical-grade 5-aminosalicylic acid.
An aqueous medium with a pH of about 3 to 5.
Dissolved bisulfite, generally at up to about 0.25% w/w.
A first container that stores the formulation with little or no oxygen.
A second oxygen-barrier container that prevents atmospheric oxygen from reaching the first container during prolonged storage.

The invention addresses a known formulation problem. Mesalamine can undergo oxidative degradation, producing discoloration and potentially reducing product quality. Bisulfite consumes residual oxygen, but the patent claims recognize that the bisulfite supply could be exhausted if oxygen continuously permeates through a plastic container. The outer oxygen-barrier pouch therefore forms part of the claimed product architecture.

What is the independent product claim?

Claim 1 is the principal article-of-manufacture claim. It requires:

Claim element	Scope
First sealed container	Container adapted for aqueous liquids and substantially free of atmospheric oxygen
Formulation	Stable suspension for rectal administration
Active ingredient	Substantially pure 5-aminosalicylic acid
Solution phase	Saturated, substantially colorless, substantially oxygen-free aqueous solution
pH	About 3 to 5
Stabilizer	Bisulfite at a concentration up to about 0.25% w/w
Function	Resistance to color formation and oxidative degradation
Second container	Sealed package containing the first container
Outer atmosphere	Substantially oxygen-free
Oxygen barrier	Prevents oxygen transmission sufficient to exhaust the bisulfite during storage

Claim 1 is narrower than a claim to mesalamine enemas generally. A product must satisfy both the formulation limitations and the dual-container packaging limitations.

A mesalamine enema in a high-barrier container could potentially avoid claim 1 if it lacks the specified first-container/second-container structure. Conversely, a two-package product could avoid infringement if its formulation lacks the claimed bisulfite, pH, oxygen-control, or suspension characteristics.

How do claims 2 through 15 narrow the patent?

Claims 2 through 15 add container, stabilizer, and rheology limitations.

Claim	Added limitation	Commercial significance
2	First container is a plastic bottle	Covers conventional polymer enema bottles
3	Single-dose disposable collapsible polyethylene enema bottle with dispensing tip	Closely tracks commercial rectal suspension packaging
4	Oxygen barrier includes aluminum foil	Targets foil-based barrier laminates
5	Second container is a sealed plastic pouch	Covers pouch packaging
6	Polyethylene enema bottle plus sealed plastic pouch	Defines the central commercial package combination
7	Pouch includes aluminum foil	Narrows claim 6 to foil-containing barrier packaging
8	Bisulfite concentration of about 0.1% to 0.2% w/w	Covers a narrower stabilizer range
9	Bisulfite is potassium metabisulfite	Identifies a specific bisulfite source
10	Flocculating agent prevents caking	Addresses redispersibility and physical stability
11	Flocculant is water-gellable polyacrylic acid	Narrows the rheology system
12	Thickener prevents settling	Addresses suspension uniformity
13	Thickener is xanthan gum	Identifies a specific excipient
14	1.5% to 10% mesalamine, up to 0.2% sodium bisulfite, flocculant, and thickener	Dense formulation and packaging combination
15	Claim 14 with an aluminum-foil-containing pouch	Narrowest commercial package formulation claim

Claims 3, 6, 7, 14, and 15 are particularly relevant to commercial mesalamine enemas. They require a single-dose polyethylene bottle and an outer pouch, with claims 14 and 15 adding concentration and excipient limitations.

What do claims 16 through 20 protect?

Claims 16 through 20 are method claims directed to storage and oxygen control rather than the packaged product alone.

Claim 16 requires a method of protecting an aqueous mesalamine solution by:

Maintaining bisulfite in the solution.
Using bisulfite only to address trace oxygen present before storage.
Storing the solution in a container with no more than trace atmospheric oxygen.
Protecting the solution from atmospheric oxygen during storage.

The unusual limitation is that the bisulfite must be effective against residual oxygen but ineffective against oxygen transmitted into the package during storage. The claim therefore separates two functions:

Bisulfite scavenges oxygen already present.
Packaging prevents continued oxygen ingress.

Claim 17 adds the disposable rectal enema bottle and undissolved mesalamine suspension.

Claim 18 addresses a relatively oxygen-permeable plastic bottle protected by a second container with a substantially lower oxygen transmission rate.

Claim 19 specifies a pouch made from a plastic laminate incorporating aluminum foil.

Claim 20 covers a single storage container made from a material with sufficiently low oxygen transmission to protect the solution without requiring the separate outer package structure described in claims 17 through 19.

What is the difference between the product and method claims?

The product claims focus on what is sold. The method claims focus on how the mesalamine formulation is stored.

Issue	Claims 1-15	Claims 16-20
Claim type	Article of manufacture and formulation	Storage and protection method
Required packaging	Generally two-container system under claim 1	May use a second package or a sufficiently low-transmission container
Key technical feature	Bisulfite-stabilized suspension and oxygen barrier	Controlled use of bisulfite and prevention of oxygen exposure
Infringement evidence	Product samples, specifications, packaging, formulation data	Manufacturing and storage procedures, package specifications, stability protocols
Commercial relevance	Directly targets finished product packaging	Could reach storage practices before distribution

What formulations are protected by US Patent 4,657,900?

The patent protects aqueous rectal suspensions containing undissolved mesalamine together with a saturated or substantially saturated dissolved mesalamine phase.

The claimed formulation characteristics include:

Mesalamine concentration of about 1.5% to 10% w/w under claim 14.
pH of about 3 to 5.
Bisulfite concentration up to about 0.25% w/w under claim 1.
A narrower bisulfite range of about 0.1% to 0.2% w/w under claim 8.
Potassium metabisulfite under claim 9.
Sodium bisulfite under claim 14.
A flocculating agent to prevent caking.
A thickener to prevent settling.
Water-gellable polyacrylic acid as a flocculant.
Xanthan gum as a thickener.

The claims do not cover every mesalamine dosage form. Oral tablets, capsules, granules, suppositories, delayed-release systems, and unbuffered solutions would generally fall outside the claim set unless they also satisfy the rectal-suspension and packaging limitations.

The claims also do not broadly cover mesalamine as an active ingredient. Their scope depends on the interaction among formulation chemistry, oxygen control, suspension stability, and packaging.

When did US Patent 4,657,900 expire?

US Patent 4,657,900 issued in 1987 and was governed by the pre-1995 patent term rule, which generally provided 17 years from issuance. On that basis, the patent expired in 2004, approximately 17 years after its issue date. The patent is therefore not an active exclusionary right today. [1]

Milestone	Date or period
Patent issue	1987
Governing term	17 years from issuance under pre-1995 law
Expected expiration	2004
Current enforceability	Expired
Current Paragraph IV exposure	None for this patent
Current freedom-to-operate relevance	Historical and technical, not an enforceable patent block

A patent expiration does not erase the patent’s technical disclosure. The formulation and package architecture can still be relevant to prior-art analysis, obviousness arguments, product development, and interpretation of later patents.

What is the Orange Book status of mesalamine enemas?

Mesalamine rectal suspension products, including Rowasa, were regulated as approved prescription drug products through the FDA’s NDA and ANDA systems. The product category is a small-molecule generic market rather than a biologic reference-product market. FDA labeling identifies mesalamine rectal suspension as a rectally administered product for ulcerative proctitis and related distal ulcerative colitis indications. [2]

The patent’s expiration means it cannot currently prevent an ANDA applicant from marketing a compliant mesalamine enema. Any historical Orange Book listing would have ceased to create a current patent-delayed approval risk once the patent expired.

Regulatory issue	Assessment
Product type	Small-molecule mesalamine rectal suspension
FDA pathway for generics	ANDA, subject to applicable reference-product requirements
Biosimilar pathway	Not applicable
Historical Orange Book relevance	Potential patent listing for the branded product
Current patent effect	No enforceable exclusivity from US 4,657,900
Current regulatory barriers	Chemistry, manufacturing, controls, bioequivalence, labeling, container closure, and stability requirements

FDA approval does not establish freedom from every patent. Later patents covering manufacturing, packaging, excipients, process controls, or specific labeling could have created separate issues. Those rights must be analyzed independently from US 4,657,900.

Which companies challenged the patent through Paragraph IV?

No current Paragraph IV challenge can be directed to US 4,657,900 because the patent expired in 2004. A historical Paragraph IV filing would have been relevant only during the patent’s enforceable term.

The likely competitive pathway for mesalamine rectal suspension was conventional generic substitution after the relevant branded exclusivity and patent barriers ended. The key commercial competitors include:

The branded Rowasa product and successor marketing entities.
Generic manufacturers offering mesalamine rectal suspension.
Contract manufacturers supplying polyethylene enema bottles and foil-barrier pouches.
Suppliers of mesalamine active pharmaceutical ingredient and suspension excipients.

Because the patent is expired, the decisive issues for current applicants are regulatory approval, product quality, manufacturing scale, supply continuity, and commercial contracting rather than Paragraph IV litigation against this patent.

What patent litigation affects US Patent 4,657,900?

The patent’s age and expiration materially reduce current litigation significance. No live infringement action can produce prospective exclusion based solely on an expired patent. Historical litigation, if any, would have focused on whether a marketed mesalamine enema used:

A polyethylene bottle.
A separate oxygen-barrier pouch.
Aluminum foil in the pouch laminate.
Bisulfite within the claimed concentration range.
The claimed pH.
Flocculants and thickeners corresponding to claims 10 through 15.

The most important litigation questions would have been claim construction and proof of the functional limitations. Terms such as “substantially oxygen-free,” “effective to stabilize,” “effective to prevent,” “substantially pure,” and “prolonged storage” require technical and factual analysis.

Potential defenses would have included:

Noninfringement based on a different container architecture.
A formulation outside the claimed bisulfite or pH range.
Absence of undissolved mesalamine.
No aluminum foil or no separate outer pouch.
Invalidity based on anticipation or obviousness.
Indefiniteness of functional or qualitative limitations.
Lack of enablement for the full breadth of the claimed storage conditions.

How strong was the patent estate for mesalamine enemas?

US Patent 4,657,900 had a focused but commercially meaningful estate. Its strength came from combining formulation and packaging limitations that were likely implemented together in the marketed product.

Strength factor	Assessment
Product specificity	High; claims target rectal suspension packaging
Formulation breadth	Moderate; claims require bisulfite, pH, oxygen control, and suspension characteristics
Packaging breadth	Moderate to high in claims 1 and 16; narrower claims specify polyethylene and foil
Design-around potential	Moderate; competitors could alter packaging, oxygen scavenging, excipients, or formulation
Evidence burden	High for oxygen transmission, dissolved oxygen, bisulfite levels, and stability
Duration	Limited by 2004 expiration
Present blocking value	None

The patent did not create a broad platform monopoly over mesalamine. It covered a particular stability solution for an oxygen-sensitive rectal suspension. Its commercial importance was strongest during the period when the branded product depended on this packaging configuration and generic substitution was constrained by patent term and regulatory exclusivity.

How does this patent compare with later mesalamine patent strategies?

Later mesalamine patent portfolios generally pursued different claim categories:

Patent strategy	Typical subject matter	Relationship to US 4,657,900
Formulation patents	Delayed release, coatings, buffers, polymers, particle size	Broader oral or targeted-delivery technologies
Method-of-use patents	Dosing, induction, maintenance, disease subgroups	Separate from package stability
Manufacturing patents	Crystallization, purification, granulation, coating	Process-focused rather than container-focused
Device patents	Applicators, delivery tips, dose-control systems	May overlap with rectal administration hardware
Packaging patents	Oxygen barriers, container closures, unit-dose systems	Closest technical successor category
Regulatory exclusivity	New indications or formulations	Separate from patent rights

US 4,657,900 is best understood as a packaging-enabled formulation patent. It is narrower than a compound patent and more product-specific than a conventional excipient patent.

What generic launch risks exist today?

For this patent, no patent-based generic launch risk remains because the patent expired. A current mesalamine enema applicant would instead face the following risks:

Failure to demonstrate pharmaceutical equivalence.
Inadequate stability against discoloration or oxidation.
Container-closure incompatibility.
Failure to reproduce suspension redispersibility.
Inconsistent delivered dose from the enema applicator.
Manufacturing variation in mesalamine particle size or settling behavior.
Labeling differences from the reference product.
Supply interruptions involving mesalamine API or specialized foil pouches.
Later, unrelated patents covering product-specific manufacturing or delivery features.

The expired patent remains useful as a design reference. A generic applicant could use a different oxygen-control strategy, such as a lower-transmission container, headspace management, oxygen scavenging, or a different stabilizer system, provided the resulting product meets FDA quality and equivalence requirements.

What geographic coverage did US Patent 4,657,900 provide?

The patent provided rights only in the United States. Any corresponding foreign patent applications or grants would require separate family-level review. A US patent does not establish protection in Canada, Europe, Japan, or other markets.

For international commercialization, the relevant analysis would include:

Patent-family members.
National-phase filings.
Foreign expiration dates.
Local patent-term adjustments.
Supplementary protection certificates, if applicable.
Local Orange Book or patent-register rules.
Market-specific regulatory exclusivity.

The US patent’s 2004 expiration does not establish the expiration status of any foreign counterpart.

What manufacturing and intellectual-property barriers remain?

US 4,657,900 no longer blocks manufacture, but its disclosure identifies several manufacturing controls that remain commercially important:

Low-oxygen filling and sealing.
Control of dissolved oxygen.
Selection of polymer bottle materials.
Qualification of foil-containing pouch laminates.
Bisulfite assay and uniformity.
Mesalamine particle-size control.
Suspension viscosity and settling performance.
Resistance to caking.
Container-closure integrity.
Long-term and accelerated stability testing.

These controls can create practical barriers even without enforceable patent rights. They are quality and scale-up issues rather than continuing exclusivity rights.

Key Takeaways

US Patent 4,657,900 covers a bisulfite-stabilized aqueous mesalamine rectal suspension packaged to limit oxygen exposure.
Claim 1 requires a first oxygen-controlled container inside a second oxygen-barrier container.
Claims 3, 6, 7, 14, and 15 most closely track a commercial single-dose polyethylene enema bottle in a foil-containing pouch.
Claims 16 through 20 protect oxygen-controlled storage methods.
The patent’s pre-1995 17-year term ended in 2004.
No current Paragraph IV or biosimilar issue arises from this patent.
The patent does not broadly cover mesalamine, oral formulations, or all rectal dosage forms.
Current generic competition is governed primarily by FDA approval, formulation performance, container-closure qualification, manufacturing scale, and any later unexpired patents.
The patent remains relevant as technical prior art and as a historical reference for mesalamine suspension stability and oxygen-barrier packaging.

FAQs About US Patent 4,657,900

Does US Patent 4,657,900 still block generic mesalamine enemas?

No. Its patent term expired in 2004, so it no longer provides an enforceable exclusionary right.

Does the patent cover Rowasa by name?

The claims do not depend on the Rowasa trademark. They cover technical characteristics of a mesalamine rectal suspension and its oxygen-controlled packaging.

Can a product infringe if it uses only one container?

A product using only one container would generally not satisfy the two-container requirement of claim 1, although claim 20 describes a low-oxygen-transmission single-container storage approach under its separate method claim.

Are aluminum-foil pouches required for every claim?

No. Aluminum foil is required only by narrower claims such as claims 4, 7, 15, and 19. Claim 1 requires an effective oxygen barrier but does not expressly require aluminum foil.

Is a mesalamine biosimilar relevant to this patent?

No. Mesalamine is a chemically synthesized small molecule. Generic drug approval, usually through an ANDA, is the relevant pathway rather than biosimilar approval.

References

U.S. Patent and Trademark Office. (1987). United States Patent No. 4,657,900.
U.S. Food and Drug Administration. (n.d.). Mesalamine rectal suspension prescribing information and approved drug products.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations.
Drug Price Competition and Patent Term Restoration Act, 21 U.S.C. §§ 355, 156; 35 U.S.C. § 154.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Germany	3773657	⤷ Start Trial
European Patent Office	0279093	⤷ Start Trial
Spain	2026179	⤷ Start Trial
Israel	81799	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,657,900

Summary for Patent: 4,657,900