United States Drug Patent 5,559,111: Claim Scope, Expiration, and Endothelin-Antagonist Patent Landscape

U.S. Patent No. 5,559,111 is a broad compound patent covering substituted δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amides, pharmaceutical compositions containing them, and therapeutic use in cardiovascular, renal, ophthalmic and anxiety-related disorders. The claim set is characteristic of an endothelin-receptor antagonist research program. The patent issued on September 24, 1996, and its enforceable U.S. term has expired under the ordinary pre-Uruguay Round transition rules and the later 20-year-from-filing framework, subject to any patent-term adjustment or terminal disclaimer recorded in the official file. The patent does not, from the claims supplied, identify an FDA-approved active ingredient, an Orange Book-listed product, or a marketed drug.

What does U.S. Patent 5,559,111 cover?

The patent covers a chemically defined genus of peptidomimetic compounds. The central structure contains:

A δ-amino-γ-hydroxy alkanoic-acid backbone.
An omega-position aryl group.
An amide at the carboxylic-acid terminus.
A methylene linker designated as X.
Multiple stereochemical configurations, including the configuration defined in claim 5.
Optional pharmaceutically acceptable salts.

The most commercially relevant structural pattern appears in claims 3, 4 and 6 through 24:

Structural element	Representative limitation
Core	5-amino-4-hydroxy substituted octanoic-acid amide
C-2 substituent	Methyl or isopropyl
C-7 substituent	Isopropyl or related branched alkyl
Aromatic group	Substituted phenyl, frequently 4-methoxy-3-(3-methoxypropyloxy)phenyl
Terminal amide	Butylamide, morpholinoethylamide, morpholinopropylamide, carbamoylalkylamide and related groups
Stereochemistry	Predominantly 4(S), 5(S), 7(S), with variable C-2 and amide-side-chain stereochemistry
Ionic form	Free compound or pharmaceutically acceptable salt

The claims are directed primarily to compounds rather than a single active pharmaceutical ingredient. This distinction is important. A generic manufacturer would not infringe merely by making a chemically unrelated endothelin antagonist. Infringement would require the accused compound to satisfy each limitation of at least one asserted claim.

How broad is independent claim 1?

Claim 1 is a Markush genus claim. It defines a large family of compounds through eight variables, R1 through R8, rather than naming one molecule.

The claim has several narrowing structural constraints:

The molecule must have the claimed δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amide framework.
X must be methylene.
R5 must be lower alkyl or cycloalkyl.
R6 must be an amino-derived substituent.
R7 must be lower alkyl, lower alkenyl, cycloalkyl or aryl-lower alkyl.
R8 must fall within an extensive list of alkyl, heterocyclic, amino, carboxyl, cyano, sulfonyl, sulfamoyl or heteroaryl substituents.
The compound may be claimed as a salt.

The breadth is concentrated in R2, R3 and R8. These variables allow substantial variation in:

Ether and polyether substituents.
Alkylthio and sulfone groups.
Pyridyl, pyrimidinyl, thiazolyl and imidazolyl groups.
Piperidine, pyrrolidine, piperazine, morpholine and thiomorpholine groups.
Carboxamides, carbamates and sulfonamides.
N-substituted terminal amides.
Heteroaryl-containing side chains.

The claim is therefore broad in chemical diversity but narrower in scaffold identity. The backbone and stereochemical architecture provide the principal genus-defining limitations.

What do dependent claims 2 through 5 add?

Claims 2 and 3 reduce the large Markush lists to preferred substituent classes. They focus on substituents that appear repeatedly in the examples, including:

Alkoxyalkyl and alkoxyalkoxy groups.
Phenylalkoxy and substituted phenylalkoxy groups.
Pyridylalkoxy groups.
Alkylthioalkoxy and alkylsulfonylalkoxy groups.
Aminoalkyl, morpholinoalkyl and piperidinoalkyl groups.
Carboxyalkyl and carbamoylalkyl groups.
Heteroarylalkyl groups.

Claim 4 narrows the molecule substantially:

R1 and R4 are hydrogen.
R2 is C1-C4 alkoxy-C1-C4 alkoxy or alkoxyalkyl.
R3 is C1-C4 alkyl or alkoxy.
R6 is amino.
R5 and R7 are branched C1-C4 alkyl.
R8 is a carbamoylalkyl, morpholinoalkyl, thiomorpholinoalkyl, acylpiperidylalkyl or oxopyrrolidinylalkyl group.

Claim 5 focuses on stereochemistry. It is significant because endothelin-antagonist activity in this class is likely sensitive to stereochemical configuration. A compound with the same connectivity but a different configuration may fall outside claim 5 while remaining within claim 1, provided all other limitations are met.

Which claims are most relevant to a freedom-to-operate review?

Claims 10 through 24 are the most readily searchable because they identify specific compounds. They are narrower than claims 1 through 5 but can present a direct infringement risk if a development candidate matches the named substitution pattern.

The recurring high-value motif is:

5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)phenyl]octanoic acid amide

The terminal amide varies across the claims. Examples include:

Morpholinoethylamide.
Morpholinopropylamide.
N-2-thiomorpholinoethylamide.
Carbamoylalkylamides.
N-methylcarbamoyl and N,N-dimethylcarbamoyl derivatives.
Acetylpiperidinylalkylamide.
Oxopyrrolidinyl and oxopiperidinyl derivatives.

A candidate containing the same core and aryl substitution pattern should be screened against claims 1, 4, 6, 7 and 10 through 24, even if the terminal amide differs from the specifically named compounds.

What therapeutic uses are protected?

Claim 9 is a method-of-treatment claim covering administration of a claimed compound for:

Hypertension.
Congestive heart failure.
Cardiac hypertrophy.
Cardiac fibrosis.
Post-infarction cardiomyopathy.
Nephropathy.
Vasculopathy.
Neuropathy.
Restenosis following angioplasty.
Raised intra-ocular pressure.
Glaucoma.
Abnormal vascular growth.
Hyperaldosteronism.
Anxiety states.

The method claim requires both a covered compound and treatment of a listed condition. It does not independently cover treatment with any endothelin antagonist. It also does not extend to a compound outside the structural scope of claim 1.

Because claim 9 is a pre-United States Supreme Court Eli Lilly v. Teva style method claim and the patent is expired, it has no current exclusionary value. Its historical significance is that it shows the intended pharmacological field and supports classification of the compounds as endothelin-pathway agents.

What pharmaceutical compositions are protected?

Claim 8 covers a pharmaceutical composition containing a claim 1 compound in free or pharmaceutically acceptable salt form together with customary pharmaceutical excipients.

The claim does not require:

A particular dosage form.
A particular release profile.
A specific excipient.
A defined dose.
A particular route of administration.
A particular ratio of active ingredient to excipient.

The composition claim is broad but derivative. It depends on the active compound satisfying claim 1. It does not create an independent formulation estate comparable to a later patent directed to tablets, controlled release, injectable formulations, particle size or solid-state forms.

Are formulation patents present in this patent?

No separate formulation technology is apparent from the supplied claims. Claim 8 is a conventional composition claim. It does not expressly protect:

Crystalline polymorphs.
Amorphous solid dispersions.
Specific hydrates or solvates.
Nanoparticles.
Liposomes.
Transdermal systems.
Sustained-release matrices.
Enteric coatings.
Specific tablet or capsule compositions.

Any later product-specific formulation would require a separate patent family. Claim 8 could cover the formulation only if the active ingredient itself falls within claim 1.

Is there an Orange Book listing or FDA exclusivity?

The claims supplied do not identify an approved drug, an NDA number or a reference-listed product. The patent therefore cannot be treated as an Orange Book patent merely because it claims pharmaceutical compounds or treatment methods.

The FDA Orange Book generally lists patents submitted for approved drug products under the applicable patent-listing provisions. A patent directed to a development-stage compound, without an approved product and NDA linkage, does not independently create Orange Book-listed exclusivity. FDA small-molecule regulatory exclusivity also depends on approval history, not on issuance of the patent alone (U.S. Food and Drug Administration, 2024).

No biologic claim is present. Biosimilar litigation and the Biologics Price Competition and Innovation Act are not relevant to this patent. Any competitive threat would arise through small-molecule generic development or a non-infringing chemical alternative.

When did U.S. Patent 5,559,111 lose exclusivity?

The patent issued September 24, 1996. For a pre-June 8, 1995 application, the term generally ran for the longer of 17 years from grant or 20 years from the earliest effective U.S. nonprovisional filing, subject to transition rules. For later applications, the ordinary term is 20 years from the earliest effective nonprovisional filing, with possible patent-term adjustment under 35 U.S.C. § 154 (35 U.S.C. §§ 154, 156).

On either ordinary calculation, a 1996-issued compound patent of this type would have expired no later than the early-to-mid 2010s unless a recorded term extension or unusual procedural adjustment applied. The supplied information does not establish an FDA patent-term extension. Because the patent is now outside its ordinary term, it presents no current U.S. patent barrier to generic launch.

Event	Date or status
U.S. patent issuance	September 24, 1996
Patent type	Chemical compound, composition and treatment claims
Ordinary term status	Expired
Current enforceability	No ordinary enforceable term remaining
FDA regulatory exclusivity	Not established by the claims
Orange Book status	No product linkage shown in the supplied record
Paragraph IV relevance	Historical only, absent an unexpired listed patent

What would a Paragraph IV challenge have involved?

A Paragraph IV certification would have been relevant only if this patent had been listed for an approved reference drug and remained unexpired. A generic applicant could have challenged it by asserting that the patent was invalid, unenforceable or not infringed.

The principal historical challenge theories would have included:

Lack of written description across the extensive Markush genus.
Enablement of the full breadth of R2, R3 and R8.
Anticipation by earlier peptidomimetic or endothelin-antagonist disclosures.
Obviousness based on known endothelin receptor antagonists and conventional side-chain modifications.
Indefiniteness arising from OCR-like or chemically ambiguous terminology.
Non-infringement based on stereochemistry or a terminal amide outside the claimed alternatives.

The strongest validity pressure would likely have focused on the breadth of claim 1 rather than the narrowly identified compounds in claims 10 through 24. Narrow species claims are generally more difficult to defeat through a single anticipation reference, although obviousness and enablement remain fact-intensive.

How strong is the patent estate?

The patent has strong historical genus coverage but weak current commercial force because it has expired.

Dimension	Assessment
Scaffold coverage	Broad
Substituent coverage	Very broad, especially R2, R3 and R8
Species coverage	Extensive named compounds
Stereochemical coverage	Material and commercially relevant
Composition coverage	Conventional and broad
Method-of-use coverage	Broad disease list, but compound-dependent
Formulation coverage	Limited
Manufacturing coverage	Not shown in supplied claims
Current U.S. exclusivity	None under ordinary patent term
Generic vulnerability during term	Moderate to high for broad genus; lower for exact species
Biosimilar relevance	None

The claims do not disclose manufacturing-process protection. They may be difficult to practice at commercial scale because the compounds contain multiple stereocenters, polyfunctional side chains and diverse amide substituents. That is a process-development issue, not an independent patent barrier. A later process patent, chiral-resolution patent or solid-state patent could have created separate protection, but no such rights can be attributed to U.S. Patent 5,559,111 from the supplied claims.

Which companies challenged or licensed the patent?

The supplied material does not identify an approved product, license agreement, litigation docket, settlement or Paragraph IV filing associated with U.S. Patent 5,559,111. No such event can be reliably attributed to the patent from the claim text alone.

The patent appears to belong to an older pharmaceutical discovery program involving endothelin-receptor antagonist chemistry. The commercial landscape for this mechanism later included compounds such as bosentan, ambrisentan and macitentan, but those products are not interchangeable with the claimed compounds and are not shown by the supplied claims to be covered by this patent. Their patent estates must be analyzed separately by active ingredient, formulation, method of use and jurisdiction.

How does this patent compare with later endothelin-antagonist patents?

U.S. Patent 5,559,111 is an early scaffold and genus patent. Later endothelin-antagonist portfolios commonly shifted toward:

More selective ETA or dual ETA/ETB receptor profiles.
Optimized oral pharmacokinetics.
Defined crystalline forms and salts.
Drug-specific formulations.
Pulmonary arterial hypertension indications.
Combination treatment with PDE-5 inhibitors, prostacyclin analogues or soluble guanylate cyclase stimulators.
Manufacturing routes suitable for commercial production.

The practical difference is that the 5,559,111 claims are structurally expansive but product-unspecific. Later portfolios are often narrower but more directly connected to an approved active ingredient and therefore more commercially relevant.

Key Takeaways

U.S. Patent 5,559,111 claims a broad genus of δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amides, including endothelin-antagonist-like peptidomimetics.
Claims 1 through 4 provide broad Markush coverage; claim 5 adds stereochemical protection.
Claims 6 through 7 and 10 through 24 identify numerous preferred species, including compounds with the 4-methoxy-3-(3-methoxypropyloxy)phenyl motif.
Claim 8 covers conventional pharmaceutical compositions, not a specialized formulation platform.
Claim 9 covers treatment of cardiovascular, renal, ophthalmic and anxiety-related conditions with a covered compound.
The patent does not, from the supplied record, establish an FDA-approved product, Orange Book listing, regulatory exclusivity period or biosimilar issue.
The patent’s ordinary U.S. term has expired. It is not a current barrier to generic or competing small-molecule development.
Any live risk would have to come from related continuation, divisional, formulation, process, polymorph or drug-specific patents, not from the expired patent itself.

FAQs

Does U.S. Patent 5,559,111 cover bosentan?

The supplied claims do not identify bosentan by name or establish that bosentan falls within the claimed Markush structure. Bosentan requires a separate structure-specific claim analysis.

Can a generic manufacturer launch a compound covered by claim 1?

The patent itself is expired under the ordinary U.S. patent term. A launch assessment must still screen related patents, regulatory exclusivity and non-U.S. rights.

Does claim 9 create exclusivity for treating pulmonary hypertension?

No. Claim 9 lists hypertension and related diseases but does not expressly recite pulmonary arterial hypertension. It is also compound-dependent and expired.

Are salts independently protected by this patent?

Yes, the claims repeatedly include the compounds in salt form, including pharmaceutically acceptable salts. Salt coverage is derivative of the underlying claimed compound.

Does the patent protect a manufacturing process?

No process claim appears in the supplied claims. The patent primarily covers compounds, compositions and therapeutic use.

References

U.S. Patent No. 5,559,111, Novel δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amides. (1996, September 24). United States Patent and Trademark Office.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. U.S. Department of Health and Human Services.
35 U.S.C. § 154. Patent term.
35 U.S.C. § 156. Extension of patent term.
21 U.S.C. § 355. New drug applications and patent certifications.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Switzerland	1169/94	Apr 18, 1994

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0678503	⤷ Start Trial	CA 2007 00049	Denmark	⤷ Start Trial
European Patent Office	0678503	⤷ Start Trial	91373	Luxembourg	⤷ Start Trial
European Patent Office	0678503	⤷ Start Trial	300296	Netherlands	⤷ Start Trial
European Patent Office	0678503	⤷ Start Trial	SPC041/2007	Ireland	⤷ Start Trial
European Patent Office	0678503	⤷ Start Trial	C00678503/01	Switzerland	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,559,111

Summary for Patent: 5,559,111