United States Drug Patent 5,231,095: Scope, Claims, Expiration, and Patent Landscape for S-Timolol Hemihydrate

US Patent 5,231,095 protects a specific crystalline and stereochemical form of timolol: S-(-)-timolol hemihydrate. Its two claims cover the compound itself and pharmaceutical compositions containing it. The patent does not broadly cover racemic timolol, timolol maleate, every S-timolol salt, or all timolol formulations.

The patent issued on July 27, 1993. Applying the pre-Uruguay Round patent-term rule generally applicable to applications filed before June 8, 1995, its 17-year term from issue would have ended on July 27, 2010, absent a term adjustment or other unusual term event. The patent is therefore expired and does not create a current US barrier to generic manufacture or commercialization. [1, 2]

What compound does US Patent 5,231,095 protect?

Claim 1 covers S-(-)-3-morpholino-4-(3-tert-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole hemihydrate, identified in the patent as S-timolol hemihydrate.

The protected subject matter has four defining characteristics:

Limiting characteristic	Scope
Timolol chemical structure	3-morpholino-4-substituted-1,2,5-thiadiazole core
Stereochemistry	S-(-) enantiomer
Hydration state	Hemihydrate, generally represented as approximately 0.5 water molecule per molecule of timolol
Product form	The compound itself, independent of a particular dosage form

The underlying timolol base is commonly represented as C13H24N4O3S. The claimed hemihydrate is represented as C13H24N4O3S·0.5H2O.

Claim 1 is a product claim. A product falling within the claim could infringe regardless of whether it is sold as an ophthalmic solution, tablet, gel, injectable preparation, or another pharmaceutical form. The claim does not require a particular indication, dose, excipient, manufacturing process, or route of administration.

How does Claim 1 differ from ordinary timolol and timolol maleate?

Claim 1 is narrower than a claim to timolol generally.

S-timolol versus racemic timolol

Timolol can exist as enantiomers. The claim is limited to the S-(-) enantiomer. A racemic mixture containing both enantiomers would not necessarily satisfy the stereochemical limitation of Claim 1, although infringement analysis could depend on the actual composition and claim construction.

A product containing only R-timolol would fall outside Claim 1 based on stereochemistry. A product containing S-timolol in a form other than the claimed hemihydrate would raise a separate hydration-state issue.

S-timolol hemihydrate versus S-timolol base

Claim 1 requires the hemihydrate. An anhydrous S-timolol product is not literally the claimed compound if the anhydrous and hemihydrate forms are analytically distinguishable. The patent therefore does not automatically cover every solid form of S-timolol.

S-timolol hemihydrate versus timolol maleate

Timolol maleate is a salt formed with maleic acid. It is chemically distinct from S-timolol hemihydrate. A product containing timolol maleate would not ordinarily fall within Claim 1 because it does not contain the claimed hemihydrate compound as its active pharmaceutical ingredient.

This distinction is commercially important. Most established generic timolol ophthalmic products have historically relied on timolol maleate or related approved forms rather than on S-timolol hemihydrate.

What does Claim 2 cover?

Claim 2 covers a pharmaceutical composition comprising S-(-)-timolol hemihydrate together with pharmaceutically acceptable adjuvants.

The claim has two principal limitations:

The active agent must be the specific S-timolol hemihydrate identified in Claim 1.
The product must be a pharmaceutical composition containing that agent and acceptable adjuvants.

The term “comprising” is open-ended. A composition may contain additional active or inactive ingredients, provided that it contains the claimed S-timolol hemihydrate and otherwise satisfies the claim.

The claim does not specify:

Ophthalmic administration
A particular concentration
A particular pH
A preservative
A buffer
A viscosity modifier
A tablet, capsule, solution, suspension, gel, or implant
A method of treating glaucoma or ocular hypertension
A particular release profile

“Pharmaceutically acceptable adjuvants” is broad and could include excipients such as water, buffers, preservatives, tonicity agents, stabilizers, carriers, solubilizers, and viscosity-enhancing agents. The active-agent limitation remains controlling.

What patents protect timolol and related products?

The patent landscape separates into foundational compound patents, stereochemical or solid-form patents, formulation patents, and regulatory exclusivity.

Patent category	Relevant subject matter	Relationship to US 5,231,095
Foundational timolol patents	Timolol chemical structures and beta-blocker compounds	Earlier patents may have covered timolol or broader chemical genera
Enantiomer patents	S- or R-timolol	US 5,231,095 narrows protection to S-timolol
Solid-form patents	Hydrates, polymorphs, salts, and crystalline forms	US 5,231,095 specifically claims the hemihydrate
Formulation patents	Ophthalmic solutions, gels, sustained-release systems, preservatives, and delivery systems	Claim 2 is composition-focused but does not require a particular formulation
Method-of-use patents	Treatment of glaucoma, ocular hypertension, or related conditions	US 5,231,095 does not contain an express method-of-use claim
Manufacturing patents	Resolution, crystallization, hydration, purification, or synthesis	The two supplied claims do not claim a manufacturing process
Regulatory patents	Patents listed in the FDA Orange Book for approved products	Current listing status must be evaluated product by product

The patent is best characterized as a stereochemical and solid-state patent rather than a broad timolol platform patent.

When did US Patent 5,231,095 expire?

US Patent 5,231,095 issued on July 27, 1993. For a US application subject to the pre-June 8, 1995 term rule, the ordinary term was 17 years from issuance. On that basis, the expected expiration date was July 27, 2010. [1, 2]

Event	Date
US patent issued	July 27, 1993
Ordinary pre-1995 patent term	17 years from issue
Expected expiration	July 27, 2010
Current status	Expired

The patent is not a current exclusivity obstacle in the United States. Patent expiration eliminates the right to exclude based on the patent, although it does not eliminate separate rights that might arise from later patents, trade secrets, regulatory exclusivity, trademarks, or contractual restrictions.

What is the Orange Book status of US 5,231,095?

US Patent 5,231,095 should not be treated as a current Orange Book barrier merely because it concerns an FDA-regulated drug substance.

The Orange Book lists patents submitted by an approved NDA holder for a specific approved drug product. Listing depends on the NDA, the product, and the patent’s relationship to the approved indication or formulation. A patent may be historically associated with a product without creating a current listed-patent barrier.

For an ANDA applicant, the relevant questions are:

Whether the reference listed drug has a current patent listing
Whether the listed patent has expired
Whether the applicant must make a Paragraph III or Paragraph IV certification
Whether any 30-month stay remains possible
Whether later formulation or method-of-use patents remain enforceable

Because US 5,231,095 expired in 2010, it cannot support a present Paragraph IV enforcement action or a new 30-month stay. FDA Orange Book records remain the controlling source for product-specific listing information. [3]

When would a Paragraph IV challenge have mattered?

During the patent’s enforceable term, an ANDA applicant seeking approval of a product that arguably contained the claimed S-timolol hemihydrate could have made a Paragraph IV certification asserting that the patent was invalid, unenforceable, or would not be infringed. [4]

The patent’s narrow claim structure would have created several potential challenge theories:

Claim construction challenges

An applicant could argue that its product did not contain the claimed hemihydrate or did not contain the S-(-) enantiomer.

Validity challenges

Potential validity issues could have included:

Anticipation by an earlier disclosure of S-timolol hemihydrate
Obviousness based on known timolol enantiomers and known hydrate formation
Written-description or enablement issues
Indefiniteness relating to the claimed hydrate or stereochemical identity

Infringement defenses

A proposed product could have been designed around the claims by using:

Racemic timolol
Timolol maleate
An anhydrous S-timolol form
Another salt
A formulation that did not contain the claimed compound

Those strategies would have required technical confirmation. Hydrate status and stereochemical composition are generally established through analytical methods such as X-ray powder diffraction, thermogravimetric analysis, Karl Fischer water determination, solid-state spectroscopy, and chiral chromatography.

What formulations are protected by Claim 2?

Claim 2 potentially covers any pharmaceutical composition containing S-timolol hemihydrate and acceptable adjuvants. Its language is broad as to dosage form but narrow as to the active agent.

Potentially covered products could include:

Preserved ophthalmic solutions
Preservative-free ophthalmic solutions
Ophthalmic suspensions
Ophthalmic gels
Oral tablets or capsules
Injectable compositions
Topical ocular delivery systems
Sustained-release compositions

The claim does not independently claim a formulation technology. It does not require a specific combination of excipients, a particular concentration, or a particular delivery mechanism. A later patent directed to a specialized gel, nanoparticle system, preservative-free container, or sustained-release formulation could have had a separate and potentially broader or narrower scope.

Does US 5,231,095 cover method-of-use patents?

No. The supplied claims are directed to:

The S-timolol hemihydrate compound; and
A pharmaceutical composition containing that compound.

They do not expressly claim treatment of glaucoma, ocular hypertension, cardiac disease, or any other condition. A method-of-use patent could have existed separately, but it would not be identified from the two claims supplied.

The absence of a method claim reduces the patent’s direct scope against a party using the compound. The compound and composition claims could still have supported infringement allegations against manufacture, importation, sale, or use of products containing the claimed material during the patent term.

Which companies challenged or licensed the patent?

The supplied patent claims do not establish a Paragraph IV challenger, licensee, settlement agreement, or litigation outcome. The patent appears to belong to the Merck timolol patent family, consistent with Merck’s historical development and commercialization of timolol products. [1]

No current licensing leverage remains from US 5,231,095 because the patent has expired. Historical licenses or settlements could still be relevant to ownership history or damages analysis, but they would not restore patent exclusivity after expiration.

What biosimilar risk applies to S-timolol?

Biosimilar risk is not the correct regulatory framework. Timolol is a chemically synthesized small-molecule drug, not a biologic subject to the abbreviated biologics license application pathway under the Public Health Service Act.

A competitor would ordinarily pursue an ANDA for a therapeutically equivalent small-molecule product, where an approved reference listed drug and applicable FDA requirements exist. The relevant competitive risks are generic substitution, formulation differentiation, supply-chain entry, and potential patent or regulatory barriers. [3, 5]

How strong is the patent estate for S-timolol hemihydrate?

The expired patent was technically narrow but potentially strong against an exact-match product during its term.

Factor	Assessment
Compound specificity	Strong, because the claim identifies a defined enantiomer and hydrate
Stereochemical coverage	Narrow; excludes or may not reach racemic and R-isomer products
Solid-form coverage	Narrow; limited to hemihydrate
Formulation coverage	Broad in Claim 2 as to dosage form, but limited to the claimed active
Method-of-use coverage	None in the supplied claims
Manufacturing coverage	None in the supplied claims
Current enforceability	None; patent expired
Generic design-around potential	Material, using another salt, stereoisomeric composition, or solid form
Present commercial leverage	Low for this patent alone

What generic launch scenarios exist today?

Because US 5,231,095 expired, a company could evaluate several entry paths without facing this patent:

Develop an approved product containing a non-claimed timolol form.
Develop an S-timolol product using a form other than the claimed hemihydrate.
Develop a product containing the claimed hemihydrate, subject to FDA requirements and any other unexpired patents.
Pursue an ophthalmic formulation with differentiated preservative, container, concentration, or release characteristics.
Rely on existing timolol regulatory pathways where an applicable reference product is available.

The principal remaining risks would arise from other patents, FDA approval requirements, chemistry and manufacturing controls, bioequivalence, product quality, and commercial competition rather than from US 5,231,095.

Key Takeaways

US Patent 5,231,095 claims S-(-)-timolol hemihydrate and pharmaceutical compositions containing it.
Claim 1 is limited by both stereochemistry and hydration state.
Claim 2 is open-ended as to excipients and dosage form but requires the specific claimed active agent.
The patent does not broadly cover racemic timolol, timolol maleate, every S-timolol form, manufacturing methods, or treatment methods.
The patent issued July 27, 1993 and ordinarily expired July 27, 2010.
It cannot support a current Paragraph IV lawsuit or 30-month stay.
Timolol is a small molecule, so biosimilar analysis is inapplicable.
Current entry analysis must focus on later Orange Book-listed patents, FDA requirements, formulation patents, and manufacturing barriers.

FAQs

Is S-timolol hemihydrate the same as timolol maleate?

No. S-timolol hemihydrate is a defined enantiomeric hydrate. Timolol maleate is a maleate salt and is chemically distinct.

Does the patent cover all ophthalmic timolol products?

No. It covers ophthalmic products only if they contain the specifically claimed S-(-)-timolol hemihydrate and satisfy Claim 2.

Can a generic company make S-timolol after the patent expired?

Yes, subject to FDA approval, applicable drug-product requirements, and any other unexpired patents or regulatory restrictions.

Does the patent cover anhydrous S-timolol?

Not expressly. Claim 1 identifies the hemihydrate. An anhydrous form may fall outside the claim if it is analytically distinct and does not otherwise meet the claim limitations.

Was a biosimilar application required for S-timolol?

No. Timolol is a small-molecule drug. The relevant abbreviated pathway is generally the ANDA pathway, not the biosimilar pathway.

References

United States Patent and Trademark Office. (1993). U.S. Patent No. 5,231,095: S-(-)-3-morpholino-4-(3-tert-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole hemihydrate.
United States Code, 35 U.S.C. § 154. Patent term provisions.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. Center for Drug Evaluation and Research.
United States Code, 21 U.S.C. § 355(j). Abbreviated new drug applications and patent certifications.
U.S. Food and Drug Administration. (2018). ANDAs for certain highly purified synthetic peptide drug products that refer to listed drugs of rDNA origin: Guidance for industry.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Finland	884838	Oct 20, 1988

PCT Information
PCT Filed	October 13, 1989	PCT Application Number:	PCT/FI89/00196
PCT Publication Date:	May 03, 1990	PCT Publication Number:	WO90/04592

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	112277	⤷ Start Trial
Austria	154513	⤷ Start Trial
Australia	4329693	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,231,095

Summary for Patent: 5,231,095