United States Patent 4,404,193: Methyldopa Oral Suspension Claims, Scope, Expiration, and Patent Landscape

U.S. Patent 4,404,193 protects a specific aqueous oral suspension of methyldopa containing approximately 50 mg/mL methyldopa and 500 mg/mL sucrose, together with narrower formulation and bioequivalence limitations. The patent issued on September 13, 1983, and its ordinary 17-year patent term expired in September 2000. It therefore does not create a current U.S. barrier to generic manufacture, formulation, or sale. Its historical importance was concentrated in the liquid formulation of methyldopa rather than in methyldopa as an active ingredient.

What does U.S. Patent 4,404,193 protect?

The patent claims an oral aqueous suspension for treating hypertension. Its principal technical elements are:

Element	Claimed requirement
Active ingredient	Methyldopa
Dosage form	Aqueous oral suspension
Methyldopa concentration	About 50 mg/mL
Sucrose concentration	About 500 mg/mL
Methyldopa-to-sucrose ratio	About 1:10 by weight
Intended use	Oral treatment of hypertension
Additional limitation in dependent claims	Bioequivalence equal or superior to an equivalent methyldopa tablet
Narrow formulation	Methyldopa anhydrous, Avicel RC-591, ethanol, disodium edetate, sodium bisulfite, citric acid, polysorbate 80, preservatives, sucrose, and purified water

The patent does not claim methyldopa generally, the use of methyldopa for hypertension generally, or all liquid methyldopa products. Its enforceable subject matter was directed to a particular pharmaceutical composition and, in narrower claims, a specified excipient system.

How broad is independent claim 1?

Claim 1 is the core composition claim. It uses the transitional term “comprising,” which generally permits the presence of additional ingredients unless another limitation excludes them. A product could therefore fall within claim 1 even if it contains excipients not expressly identified in the claim.

The claim requires all of the following:

A pharmaceutical composition.
An aqueous suspension.
Methyldopa for oral hypertension treatment.
Approximately 50 mg of methyldopa per milliliter.
Approximately 500 mg of sucrose per milliliter.
An approximately 1:10 methyldopa-to-sucrose weight ratio.

The concentration and ratio limitations are closely related. At 50 mg/mL methyldopa and 500 mg/mL sucrose, the stated ratio is mathematically 1:10. A product that contains methyldopa at materially lower or higher concentration, or that uses a substantially different sucrose level, would have a stronger noninfringement position.

The word “about” introduces numerical latitude, but it does not eliminate the need for a product to remain reasonably close to the claimed concentrations and ratio. The scope would depend on intrinsic claim construction, the specification, prosecution history, and technical evidence concerning what a skilled person would understand “about” to mean.

Claim 1 and alternative sweeteners

Claim 1 requires sucrose. A suspension using sorbitol, glucose, fructose, maltitol, or another sweetener would not literally satisfy the sucrose limitation. An equivalence theory would face technical and prosecution-history questions, particularly because sucrose is a central compositional feature rather than an incidental excipient.

Claim 1 and methyldopa salts

The supplied claim refers to methyldopa and the narrower formulation specifies methyldopa anhydrous. A product using a chemically different methyldopa salt or derivative would require separate analysis. It would not automatically fall within the literal language of the claim.

Claim 1 and solutions

The claim requires an aqueous suspension, not merely an aqueous solution. A fully dissolved methyldopa product would present a substantial noninfringement argument because a suspension contains dispersed insoluble particles, while a solution does not.

What formulation is protected by claim 3?

Claim 3 narrows claim 1 to a formulation consisting essentially of the following composition per milliliter:

Ingredient	Claimed amount
Methyldopa anhydrous	50 mg
Avicel RC-591	10 mg
Ethyl alcohol, 95%	0.011 mL
Disodium edetate	0.5 mg
Sodium bisulfite	2 mg
Citric acid	1 mg
Polysorbate 80	0.2 mg
Preservatives	1-1.4 mg
Sucrose	500 mg
Purified water	Quantity sufficient to 1 mL

“Consists essentially of” is narrower than “comprising” but broader than “consisting of.” It generally permits unlisted components that do not materially alter the basic and novel characteristics of the claimed composition. The likely technical characteristics include suspension stability, preservation, chemical stability, redispersibility, palatability, and oral bioavailability.

A product that reproduces every listed ingredient and amount would face the highest historical infringement exposure under claim 3. A product with a different suspending agent, preservative system, antioxidant, sweetener, or concentration would require separate analysis under literal infringement and the doctrine of equivalents.

Avicel RC-591

Avicel RC-591 is a microcrystalline cellulose and carboxymethylcellulose-based suspending aid. Its presence indicates that the invention was directed to maintaining methyldopa in a stable, redispersible oral suspension rather than simply dissolving the active ingredient in water.

A formulation using xanthan gum, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, or another suspending system would not literally meet the Avicel RC-591 limitation. Equivalence would depend on the role of the substitute and the patent’s prosecution history.

Stability ingredients

Disodium edetate, sodium bisulfite, citric acid, and polysorbate 80 address formulation stability and physical performance. Their inclusion narrows claim 3 materially. The narrower claim would be easier to design around than claim 1, although claim 1 could still present a historical issue if a redesigned product retained the claimed methyldopa and sucrose concentrations.

What do claims 2 and 4 add?

Claims 2 and 4 add bioequivalence limitations:

Claim 2 requires a composition with bioequivalence equal to or superior to a tablet containing an equivalent amount of methyldopa.
Claim 4 applies the same concept to the specific formulation of claim 3.

These limitations are unusual. Bioequivalence is ordinarily expressed as equivalence within predefined pharmacokinetic acceptance criteria rather than as a product being “superior” to a tablet. The language may create questions concerning:

The applicable bioequivalence metric.
Whether the comparison is based on area under the curve, maximum concentration, or both.
The identity and dose of the reference tablet.
The meaning of “superior.”
Whether the limitation is structural, functional, or merely an intended result.
Whether the claim provides an objective testing standard.

A patentee would likely need comparative pharmacokinetic evidence to enforce these claims. A defendant could challenge the claims on claim-construction, indefiniteness, written-description, enablement, or proof-of-infringement grounds, depending on the patent record and the evidence available.

Claims 2 and 4 do not expand the composition scope. They narrow the claims by requiring the additional bioequivalence characteristic.

When did U.S. Patent 4,404,193 lose exclusivity?

The patent issued on September 13, 1983. For a U.S. utility patent issued from an application filed before June 8, 1995, the ordinary term was 17 years from grant, subject to terminal disclaimers and other adjustments. On that basis, the ordinary expiration date was September 13, 2000. [1, 2]

Event	Date
Patent grant	September 13, 1983
Ordinary statutory term	17 years from grant
Ordinary expiration	September 13, 2000
Current status	Expired
Current blocking effect	None from this patent alone

The patent’s expiration means that no current U.S. product needs a license from the historical patent owner to practice the claimed methyldopa suspension technology. Expiration also removes the patent as a basis for a current injunction, damages claim, or Paragraph IV dispute.

The expiration analysis should be distinguished from regulatory exclusivity. Any FDA exclusivity associated with an original methyldopa product would have expired decades earlier and would not revive this patent.

What is the Orange Book status of Patent 4,404,193?

U.S. Patent 4,404,193 should not be treated as a current Orange Book barrier. Orange Book-listed patents are relevant to approved drug products and abbreviated new drug application certification procedures. A patent that expired in 2000 cannot provide a current period of patent protection against an ANDA applicant. [3, 4]

The patent also appears directed to a formulation that is distinct from the principal modern generic market for methyldopa tablets. Orange Book status must be evaluated product by product because a patent may be listed for one approved dosage form and not another. Patent 4,404,193 itself does not establish that a current methyldopa tablet or liquid product has a live listed patent.

FDA regulatory significance

The patent does not establish FDA approval. Patent rights and FDA approval are separate systems.

A sponsor seeking to market a new methyldopa oral suspension would generally need an FDA-approved regulatory pathway, such as:

An ANDA, if a suitable reference-listed drug and applicable requirements support abbreviated approval.
An NDA, if the product cannot rely on an approved reference product or requires a full clinical and regulatory submission.
A 505(b)(2) application, where permitted by the product’s regulatory facts and reliance strategy.

The expired patent would not prevent any of these pathways. FDA review would still address quality, identity, strength, purity, stability, microbial control, dose uniformity, bioavailability or bioequivalence, labeling, and manufacturing controls. [3]

Are there Paragraph IV challenges to this patent?

A current Paragraph IV challenge to U.S. Patent 4,404,193 would have no practical commercial purpose because the patent expired in 2000. Paragraph IV certification is directed to patents an ANDA applicant asserts are invalid, unenforceable, or not infringed. An expired patent cannot delay approval through the Hatch-Waxman patent-challenge framework.

Historically, an ANDA applicant could have challenged the patent if it had been listed against a relevant reference product while still in force. Potential theories would have included:

Noninfringement based on different methyldopa or sucrose concentrations.
Use of a solution rather than a suspension.
Use of a different suspending agent.
Failure to meet the stated bioequivalence limitation.
Invalidity based on anticipation or obviousness.
Indefiniteness of “about,” “equal or superior,” or “bioequivalence.”
Lack of written description or enablement for the full scope of claim 1.

No current Paragraph IV exposure remains from this patent.

What patent landscape surrounds methyldopa oral suspensions?

The relevant landscape has four layers: the active ingredient, the liquid formulation, regulatory exclusivity, and manufacturing know-how.

Active-ingredient patents

Methyldopa is an old small-molecule antihypertensive. Patent 4,404,193 does not create exclusivity over methyldopa, its use in hypertension, or conventional methyldopa tablets. Those areas became commercially open long before the patent expired.

Formulation patents

The patent’s historical value was concentrated in:

Aqueous suspension technology.
The 50 mg/mL methyldopa concentration.
The 500 mg/mL sucrose concentration.
The 1:10 active-to-sucrose ratio.
Suspension stability and redispersibility.
Preservation and oxidation control.
Comparative tablet bioequivalence.

Those features could once have differentiated a liquid product from tablets and extemporaneously compounded preparations. They no longer provide live U.S. patent protection.

Method-of-use claims

The supplied claims do not claim a new hypertension treatment regimen, patient population, dosing schedule, or clinical use distinct from oral methyldopa treatment. The method-of-use content is primarily an intended-use limitation associated with the composition.

Manufacturing and process barriers

The expired patent does not prevent manufacturing. A current developer may still encounter practical barriers involving:

Suspension uniformity during storage.
Sedimentation and redispersion.
Methyldopa oxidation.
Preservative effectiveness.
Container compatibility.
Dose measurement by an oral syringe.
Content uniformity throughout shelf life.
Taste masking at high sucrose concentration.
Stability after opening.

These are formulation-development and regulatory barriers, not surviving patent barriers attributable to Patent 4,404,193.

Are biosimilar or generic risks relevant?

Biosimilar risk is not relevant because methyldopa is a conventional small-molecule drug, not a biologic licensed under the Public Health Service Act. The competitive pathway is generic-drug entry, not biosimilar interchangeability.

Generic competition is strongest for tablets and other established dosage forms. A methyldopa suspension could face a different regulatory and commercial analysis because an approved reference product, dosage-form equivalence, and suitable labeling may not align with the tablet market.

Potential product categories include:

Product category	Patent risk from 4,404,193	Primary commercial issue
Methyldopa tablets	None	Low-price generic competition
Methyldopa oral solution	No literal suspension claim if fully dissolved	FDA pathway and stability
Methyldopa oral suspension	No current patent barrier	Approval, formulation performance, market size
Extemporaneous suspension	No current patent barrier	Pharmacy practice and quality control
Modified-release methyldopa	Not covered by supplied claims	Separate formulation and regulatory analysis

Which companies are challenging the patent?

No current challenger can obtain a meaningful commercial advantage by challenging Patent 4,404,193 because the patent expired more than two decades ago. Current generic manufacturers compete in the methyldopa market under the ordinary abbreviated-drug-approval framework rather than through a live dispute over this patent.

The supplied information does not identify a historical assignee, licensee, litigation docket, or settlement agreement. Those matters cannot be attributed to a specific company from the claim text alone.

What licensing deals or settlements affect the patent?

Patent 4,404,193 does not create a current licensing requirement. No licensing deal or settlement is reflected in the supplied claims. Any historical agreement would need to be established from assignment records, SEC filings, court dockets, or regulatory submissions rather than from the patent claims.

Because the patent expired in 2000, a historical settlement would have no continuing exclusionary effect unless it contained separate contractual restrictions unrelated to the patent. Such contractual terms would not extend the patent term.

How strong was the patent estate?

The patent estate appears narrow in breadth but commercially coherent for its intended product.

Issue	Assessment
Active ingredient coverage	Narrow; no general methyldopa exclusivity
Dosage-form coverage	Focused on aqueous suspensions
Concentration coverage	Specific to approximately 50 mg/mL
Sweetener coverage	Specific to approximately 500 mg/mL sucrose
Formulation detail	Claim 3 is highly specific
Functional limitations	Claims 2 and 4 may raise proof and definiteness issues
Design-around potential	Meaningful, particularly through concentration, sweetener, or suspending-agent changes
Current enforceability	None because the patent expired
Regulatory relevance today	Historical only

The strongest historical claim was likely claim 1 because it covered a broader class of aqueous suspensions than claim 3. Claim 3 offered more detailed formulation protection but was easier to avoid through excipient substitution. Claims 2 and 4 potentially added commercial differentiation but also introduced evidentiary and claim-construction complications.

Key Takeaways

U.S. Patent 4,404,193 covers an aqueous methyldopa suspension, not methyldopa generally.
Claim 1 centers on approximately 50 mg/mL methyldopa, 500 mg/mL sucrose, and a 1:10 weight ratio.
Claim 3 narrows protection to a defined excipient and preservative system.
Claims 2 and 4 add bioequivalence limitations that could create proof and definiteness issues.
The patent issued September 13, 1983, and ordinarily expired September 13, 2000.
The patent has no current Orange Book blocking effect and cannot support a current Paragraph IV delay.
Biosimilar analysis is irrelevant because methyldopa is a small molecule.
Current commercial barriers involve FDA approval, formulation stability, manufacturing quality, and market economics rather than this expired patent.
No licensing deal, settlement, assignee, or litigation history is established by the supplied claim text.

FAQs

Does Patent 4,404,193 cover methyldopa syrup?

Not broadly. It covers an aqueous suspension meeting the claimed methyldopa and sucrose concentrations. A liquid product marketed as a syrup could avoid the claims if it is a solution rather than a suspension or does not meet the concentration and ratio limitations.

Can a company use Avicel RC-591 in a methyldopa suspension?

Yes, the expired patent does not prevent current use of Avicel RC-591. Separate third-party rights concerning the excipient, supplier, trademark, or manufacturing process would require independent review.

Is a 1:10 methyldopa-to-sucrose ratio still patent-protected?

No, not under U.S. Patent 4,404,193. The relevant claims expired in 2000.

Would a 25 mg/mL methyldopa suspension infringe claim 1?

It would not literally meet the stated approximately 50 mg/mL limitation. Since the patent has expired, the question has no current infringement consequence in the United States.

Does the patent cover pediatric methyldopa dosing?

The supplied claims do not claim a pediatric population or a particular pediatric dosing regimen. They claim a composition for oral treatment of hypertension.

References

United States Patent No. 4,404,193. (1983). Pharmaceutical composition containing methyldopa. United States Patent and Trademark Office.
United States Code, 35 U.S.C. § 154. (2024). Contents and term of patent; provisional rights.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.
United States Code, 21 U.S.C. § 355. (2024). New drugs.
U.S. Patent and Trademark Office. (2024). Manual of Patent Examining Procedure, §§ 2111, 2111.03, 2714. USPTO.

Details for Patent: 4,404,193

Summary for Patent: 4,404,193