United States Patent 5,104,888: Claim Scope, Expiration, Orange Book Status, and Patent Landscape

US Patent 5,104,888 is an expired small-molecule patent covering a broad genus of chroman-linked thiazolidinedione derivatives, narrower chemical subgenera, specified individual compounds, and pharmaceutical compositions for hyperlipidemia or hyperglycemia. The patent issued on April 14, 1992, under the pre-URAA 17-year patent term regime and therefore expired no later than April 14, 2009, absent an unusual term adjustment or disclaimer. It does not create a current US exclusivity barrier.

The claims are chemically broad but structurally disciplined. They require a chroman or related aromatic system connected through an alkoxybenzyl linker to a thiazolidine-2,4-dione or related ring system. The patent is relevant to the historical development of thiazolidinedione insulin-sensitizing and lipid-modifying compounds, but it is not a current basis for generic-launch blocking, Paragraph IV litigation, or biosimilar risk.

What compounds does US Patent 5,104,888 cover?

The patent covers compounds built around four principal structural elements:

A substituted chroman, aromatic, or heteroaromatic moiety.
An oxygen-containing linker, generally represented by (CH2)n-O-Ar.
A benzyl or heteroaryl connection to a thiazolidine-2,4-dione ring.
Optional oxidation, oxime, ester, ether, acyl, alkyl, carboxylate, and amino-substituent variations.

The central claim architecture is:

substituted chroman or aromatic group - linker - aromatic ring - benzyl-thiazolidinedione

The claim set also permits substantial variation in the oxidation state and substitution pattern of the chroman-side chain. W may be methylene, carbonyl, hydroxy-substituted methine, or an oxime-type group. U may be methylene, or may combine with W to form an unsaturated linkage.

Core structural limitations

Claim variable	Principal scope
R1	Hydrogen, C1-C10 alkyl, or C7-C13 aralkyl
R2	Hydrogen or C1-C5 alkyl
R3	Hydrogen, acyl, sulfo, alkyl, ester-containing alkyl, aromatic acyl, or heterocyclic acyl
R4/R5	Hydrogen, alkyl, or alkoxy substituents
R6/R7	Hydrogen, alkyl, substituted alkyl, ester-containing alkyl, hydroxyalkyl, or amino-carbonyl-substituted alkyl
Ar	Carbocyclic aromatic or selected heteroaromatic divalent group
W	Methylene, carbonyl, hydroxy-substituted methine, or oxime
U	Methylene, or part of an alkene with W
n	One to three
Ring system	Thiazolidine-2,4-dione and related substituted thiazolidinedione structures

The claim language is written as a Markush framework. A Markush claim covers a defined class of alternatives, but each commercial or investigational compound must satisfy every limitation and proviso applicable to the selected substituents.

How many patents and claims cover the invention?

US 5,104,888 contains 37 claims in the claim text supplied.

Claim group	Claims	Subject matter
Broad compound genus	1	Formula I compounds and salts
Narrow compound subgenera	2-15	Progressively restricted substituent combinations
Named compounds	16-21	Six specifically identified compounds or compound classes
Broad composition genus	22	Pharmaceutical composition for hyperlipidemia or hyperglycemia
Narrow composition subgenera	23-36	Composition claims corresponding to compound claims 2-15
Named composition species	37	Composition containing one of six listed active compounds

Claims 1 and 22 are the commercial center of gravity. Claim 1 covers compounds. Claim 22 covers pharmaceutical compositions containing compounds within the same broad genus. Claims 16-21 and 37 provide the clearest protection for specific named structures.

What is the scope of independent claim 1?

Claim 1 is a large compound genus with extensive nested definitions. Its scope depends on both the positive structural limitations and provisos alpha and beta.

Positive limitations

A compound generally must contain:

A defined substituted aromatic or heteroaromatic group.
A linker with one to three methylene units.
A thiazolidine ring system.
A permitted W/U arrangement.
Substituents within the enumerated carbon-number and functional-group ranges.
A pharmaceutically acceptable salt if the claimed subject is a salt rather than the neutral compound.

Proviso alpha

Proviso alpha prevents certain relatively unsubstituted para-phenylene compounds from falling within the claim unless the hydrophobic substitution is placed in a specified position.

Where R3 and R6/R7 are relatively limited, and Ar is para-phenylene, the claim requires either:

R1 to be a longer C6-C10 alkyl group when R4 is small; or
R4 to be a longer C6-C10 alkyl group or R1 to be a C7-C13 aralkyl group when R4 is small.

This proviso narrows the most generic para-phenylene embodiments and preserves a required hydrophobic substituent.

Proviso beta

Proviso beta addresses compounds in which R1, R2, R4, and R5 are all relatively small and Ar is para-phenylene. In that configuration, at least one of R3, R6, or R7 must be an alkyl or substituted alkyl group.

The provisos are important in infringement analysis. A molecule may satisfy the broad variable definitions but fall outside claim 1 because it fails alpha or beta.

What do claims 2 through 15 add?

Claims 2-15 progressively narrow the genus by limiting the substituents and ring systems.

Claims 2-4

These claims focus on:

C1-C10 alkyl groups at selected positions.
Ortho-, meta-, and para-phenylene groups.
Certain pyridine-diyl groups.
Defined acyl, hydroxyalkyl, ester, carbamate, and heterocyclic substituents.
Oxime and oxime-ester variants.

Claims 2-4 are still broad subgenera. They cover many more structures than the six compounds expressly named in claims 16-21.

Claims 5-7

These claims impose more specific alkyl lists, including methyl, isobutyl, hexyl, heptyl, octyl, nonyl, and 3,7-dimethyloctyl. They also narrow the aromatic group to phenylene or specified pyridinediyl arrangements.

Claims 5-7 are stronger as structural search targets because the enumerated substituent lists reduce ambiguity.

Claims 8-10

These claims concentrate on:

Selected alkyl groups at R1 and R4.
Para- or meta-phenylene systems.
Specific pyridine-diyl connectivity.
Oxime derivatives, including hydroxyimino, carboxyalkoxyimino, and acyloxyimino forms.
Dicarboxylate and substituted alkyl ester side chains.

These claims reach several medicinal-chemistry series rather than a single marketed molecule.

Claims 11-15

Claims 11-15 narrow the invention toward:

Ester-substituted alkyl groups.
Specific long-chain R1 and R4 substituents.
Oxime, carbonyl, and methylene variants.
Compounds with one or two methylene units in the linker.
The -CH2-COO(C1-C5 alkyl) side chain in claim 15.

Claims 14 and 15 are among the narrower chemical subgenera and would generally require a compound-by-compound element comparison.

Which named compounds are protected by claims 16 through 21?

The patent expressly identifies six compounds or compound classes.

Claim	Named compound or class
16	5-[4-(6-Hydroxy-5,7,8-trimethyl-2-octylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione
17	Hydroxyimino tetramethylchroman derivative
18	Acetoxy and acetoxyimino tetramethylchroman derivative
19	Carboxymethoxy tetramethylchroman-4-one derivative with an N-acetic acid thiazolidinedione substituent
20	Carboxymethoxy hydroxyimino tetramethylchroman derivative with an N-acetic acid thiazolidinedione substituent
21	The corresponding N,N'-diacetic acid or 3,5-diyl diacetic acid derivative

The named-compound claims are narrower than claim 1 but have practical value in historical structure-based searches. They can remain relevant to patent-family analysis even after the parent patent expires because corresponding foreign patents, continuation applications, divisional applications, or later formulation patents may have different terms.

Does the patent cover troglitazone?

The supplied claims do not identify troglitazone by its standard chemical name. Troglitazone is generally described as a tetramethylchroman-linked thiazolidinedione with a 6-hydroxy substituent and a benzyl-thiazolidinedione connection.

Claim 16 is structurally similar to this class but recites a 5,7,8-trimethyl-2-octylchroman structure rather than the standard tetramethylchroman structure associated with troglitazone. A definitive infringement or identity determination requires normalization of the patent structure drawing and comparison against the exact stereochemical and substitution pattern of the candidate compound.

The patent should therefore be treated as a related chroman-thiazolidinedione patent, not automatically as the core patent for troglitazone. The principal historical troglitazone patent landscape includes separate Sankyo patent families and regulatory records.

When did US Patent 5,104,888 lose exclusivity?

The patent issued on April 14, 1992. Patents filed before June 8, 1995 generally receive a term of 17 years from grant under the transition rules of the Uruguay Round Agreements Act. On that basis, the patent term ended on April 14, 2009. The USPTO patent record identifies the patent as an issued US patent in this pre-URAA period. [1]

Event	Date
US patent grant	April 14, 1992
Statutory term basis	17 years from grant
Projected expiration	April 14, 2009
Current enforceability	Expired
Current Paragraph IV relevance	None for this patent
Biosimilar relevance	None

The expiration date eliminates current exclusionary rights under this patent. It does not eliminate the possibility that a later patent family covers a particular formulation, salt, polymorph, manufacturing process, or method of treatment.

What is the Orange Book status of US Patent 5,104,888?

US Patent 5,104,888 is not a current Orange Book barrier for an approved drug product. The patent is expired, and its claims are directed primarily to compounds and compositions rather than a currently enforceable listed drug patent.

The FDA Orange Book distinguishes active ingredient, formulation, method-of-use, and product-by-process patents. A patent must be submitted and accepted for listing against an approved application to appear in the Orange Book. Patent expiration alone does not prove whether a historical patent was once listed, but it removes the patent from any current exclusivity analysis. [2]

The patent also does not create a biosimilar issue. Its claimed products are chemically synthesized small molecules, not biological products regulated under the Public Health Service Act.

Were there Paragraph IV challenges or generic litigation?

No current Paragraph IV risk attaches to US Patent 5,104,888 because the patent expired in 2009. A Paragraph IV certification is directed to a listed patent that has not expired or otherwise ceased to present a relevant patent barrier.

The supplied information does not identify a US infringement action, ANDA challenge, or settlement agreement directed specifically to Patent 5,104,888. Because the patent is expired, any historical litigation would have no continuing exclusionary effect unless it involved damages, validity, ownership, or another collateral issue.

Settlement agreements

There is no continuing settlement value in an agreement that merely delayed generic entry until expiration of this patent. Any commercial settlement analysis must instead focus on later patents covering a specific approved product, formulation, salt, polymorph, or manufacturing process.

What formulation patents are protected?

Claim 22 and claims 23-37 cover pharmaceutical compositions containing the claimed chemical compounds with a pharmaceutically acceptable carrier or diluent. These are composition-of-matter-plus-carrier claims, not detailed dosage-form claims.

The patent does not, based on the supplied claims, expressly claim:

A particular tablet coating.
A controlled-release matrix.
A specific particle-size distribution.
A defined crystalline polymorph.
A fixed-dose combination.
A specific dissolution profile.
A particular capsule, suspension, or transdermal system.
A manufacturing process.

The composition claims could cover conventional pharmaceutical preparations containing a qualifying active compound, but they do not establish a distinct modern formulation estate comparable to a later extended-release or amorphous-solid-dispersion patent.

How strong is the patent estate?

The patent was historically broad but is now commercially weak because it is expired.

Dimension	Assessment
Chemical breadth	High
Number of claim layers	High
Named-compound coverage	Present
Composition coverage	Present
Formulation specificity	Low to moderate
Manufacturing-process coverage	Not apparent from supplied claims
Current patent term	None
Current generic blocking power	None
Historical design-around difficulty	Moderate
Current litigation leverage	None

The broad Markush claim creates substantial historical coverage across chroman, oxime, ester, acyl, and thiazolidinedione variants. Its strength would have depended on written-description support, enablement, claim construction, prosecution amendments, and prior art. The supplied claim text alone cannot establish validity.

The long list of functional alternatives also creates prosecution and validity pressure. A challenger could examine whether the specification enabled the full breadth of the genus, whether the claims were supported across all listed substituent combinations, and whether earlier thiazolidinedione, chroman, vitamin E, or lipid-regulating disclosures anticipated or rendered obvious the claimed combinations.

How does this patent compare with competing thiazolidinedione patents?

US 5,104,888 sits within the broader thiazolidinedione landscape but is not equivalent to the principal patent estate for every thiazolidinedione drug.

Patent area	Typical subject matter	Relationship to US 5,104,888
Early thiazolidinediones	Core insulin-sensitizing ring systems	Prior-art and competitive chemical context
Pioglitazone patents	Distinct pyridyl- or phenyl-linked thiazolidinedione structures	Usually separate chemical families
Rosiglitazone patents	Distinct substituted pyridyl thiazolidinedione structures	Separate compound and use claims
Troglitazone patents	Chroman-linked thiazolidinedione structures	Closest historical technical neighborhood
Later patents	Salts, polymorphs, formulations, combinations, and methods	Potentially independent of the expired patent

A freedom-to-operate review for a commercial product should not stop with US 5,104,888. It should identify the exact active ingredient, salt, solid form, dosage form, manufacturing route, indication, and jurisdiction, then map those features against later patent families.

What generic launch scenarios exist?

For the patent itself, generic launch is unrestricted from a patent-term perspective.

Scenario 1: Compound-only launch

A manufacturer can produce a compound falling within an expired claim without infringing US 5,104,888. Other active patents, regulatory exclusivities, controlled-substance rules, or non-patent regulatory requirements may still apply.

Scenario 2: Formulation launch

A generic formulation is not blocked by the expired composition claims. The relevant risk would come from later formulation patents, if any, and from the reference product's regulatory status.

Scenario 3: New indication

A later method-of-use patent could affect a specific indication even though the compound patent has expired. That risk must be assessed separately from the expired compound claims.

Scenario 4: Manufacturing route

A process patent could restrict production even where the product patent has expired. The supplied patent claims do not identify a live manufacturing barrier.

What geographic coverage remains?

US Patent 5,104,888 has no current US exclusionary term. Foreign counterparts may have had different filing dates, national-phase dates, term adjustments, prosecution histories, and expiration dates. Foreign patent status cannot be inferred from the US grant date.

A global landscape should separately review:

European Patent Office family members.
Japanese priority and national patents.
United Kingdom and German validations.
Canadian and Australian counterparts.
Patent term extensions or supplementary protection certificates.
National maintenance and lapse records.
Later continuation, divisional, or improvement applications.

The US patent number alone does not establish current rights outside the United States.

What licensing or commercial deals are associated with this patent?

The supplied record does not identify a license, assignment, co-development agreement, or settlement specifically tied to US 5,104,888. The patent's applicant or owner history should be checked through USPTO assignment records before relying on ownership or licensing assumptions. [3]

A commercial review should distinguish:

Assignment of patent ownership.
License of the chroman-thiazolidinedione platform.
Development agreements for a specific candidate.
Product commercialization rights.
Settlements involving later patents.

A platform license may continue to have contractual value after patent expiration, but expiration removes the patent's statutory exclusivity.

What is the revenue exposure?

US 5,104,888 has no direct current revenue-protection value because it expired. Its historical revenue relevance would have depended on whether a commercial product practiced claims 1, 16-21, or 22-37 and whether the patent was paired with regulatory exclusivity or later patents.

Current revenue exposure should be assigned to later rights covering:

Approved active ingredients.
Drug product formulations.
Salt or polymorph forms.
Combination products.
Pediatric or orphan exclusivity.
Method-of-use claims.
Manufacturing processes.

No product sales, approval record, or revenue attribution can be reliably assigned to this patent from the claim text alone.

Key Takeaways

US Patent 5,104,888 claims a broad family of chroman-linked thiazolidinedione compounds and pharmaceutical compositions.
The patent contains 37 claims: 21 compound claims and 16 composition claims.
Claim 1 is the principal broad compound genus; claim 22 is the corresponding composition genus.
Claims 16-21 identify six specific compounds or compound classes.
Claims 1 and 22 are narrowed by detailed alpha and beta provisos.
The patent issued on April 14, 1992, and expired no later than April 14, 2009, under the pre-URAA 17-year term.
It presents no current US generic-launch, Paragraph IV, Orange Book, or biosimilar barrier.
The claims do not establish a detailed modern formulation or manufacturing estate.
Any current freedom-to-operate risk must come from later patents, not this expired patent.
Foreign counterparts and later patent families require separate jurisdiction-by-jurisdiction review.

FAQs

Does US Patent 5,104,888 still prevent manufacture of its claimed compounds?

No. The US patent term expired in 2009. Later patents covering a particular product or process could still be relevant.

Is US Patent 5,104,888 a patent for a biologic drug?

No. It covers chemically synthesized small molecules. Biosimilar regulations do not apply.

Can a company challenge US Patent 5,104,888 with a Paragraph IV certification?

Not as a current patent barrier. Paragraph IV certifications address unexpired listed patents. This patent is expired.

Do claims 22 through 37 protect a specific tablet formulation?

No. They broadly cover pharmaceutical compositions containing qualifying active compounds with a pharmaceutically acceptable carrier or diluent. They do not recite a detailed tablet technology.

Does the patent automatically cover every thiazolidinedione antidiabetic drug?

No. Coverage depends on the complete structural limitations, substituent definitions, provisos, and claim construction. Structurally distinct thiazolidinediones may fall outside the claims.

References

United States Patent and Trademark Office. (1992). US Patent No. 5,104,888.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, commonly known as the Orange Book.
United States Patent and Trademark Office. (2024). Patent assignment search.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	60-35324	Feb 26, 1985
Japan	60-35325	Feb 26, 1985

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	56448	⤷ Start Trial
Australia	5412286	⤷ Start Trial
Australia	588857	⤷ Start Trial
Canada	1256106	⤷ Start Trial
Germany	3674089	⤷ Start Trial
Denmark	173350	⤷ Start Trial
Denmark	87886	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 5,104,888