Details for Patent: 5,360,800

Summary for Patent: 5,360,800

Title:	Tetrahydro-1H-pyrido[4,3-b]indol-1-one derivatives
Abstract:	The invention relates to tricyclic lactams of the general formula (I) ##STR1## wherein Im represents an imidazolyl group of the formula: ##STR2## and R1 represents a hydrogen atom or a group selected from C1-6 alkyl, C3-6 alkenyl, C3-10 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkylC1-4 alkyl, phenyl, phenyl C1-3 alkyl, phenylmethoxymethyl, phenoxyethyl or phenoxymethyl,one of the groups represented by R2, R3 and R4 is a hydrogen atom or a C1-6 alkyl, C3-7 cycloalkyl, C3-6 alkenyl, phenyl or phenyl C1-3 alkyl group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C1-6 alkhyl group;n represents 2 or 3; and physiologically acceptable salts and solvates thereof.The compounds are potent and selective antagonists of the effect of 5-HT at 5-HT3 receptors and are useful, for example, in the treatment of psychotic disorders, anxiety, and nausea and vomiting.
Inventor(s):	Ian H. Coates, Peter C. North, Alexander W. Oxford
Assignee:	Sebela International Ltd
Application Number:	US07/741,570
Patent Claim Types: see list of patent claims	Use; Composition; Dosage form;

US Drug Patent 5,360,800: Scope, Claims, Expiration, and Cilansetron Patent Landscape

US Patent No. 5,360,800 covers a broad class of pyrido[4,3-b]indol-1-one derivatives acting as 5-HT3 receptor antagonists, including cilansetron and its hydrochloride and maleate salts. The patent also claims pharmaceutical compositions and treatment methods for anxiety, schizophrenia, irritable bowel syndrome, dyspepsia, and reflux oesophagitis. The patent issued on November 29, 1994, and its enforceable US term expired on November 29, 2011, based on the pre-1995 patent-term rules applicable to the application. It is no longer an active barrier to US development, manufacture, or sale of products falling within its claims.[1][2]

What drug and chemical series does US Patent 5,360,800 cover?

The patent covers pyridoindolone compounds containing a substituted imidazolylmethyl group. The principal disclosed compound is cilansetron, also known as:

2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one.

Cilansetron is a selective 5-HT3 receptor antagonist developed principally for gastrointestinal disorders, particularly irritable bowel syndrome. The claimed structure contains:

Structural element	Claim scope
Core ring system	Pyrido[4,3-b]indol-1-one or related azepino analogue
Imidazole substituent	5-methyl-1H-imidazol-4-ylmethyl group within the principal claims
R1 substitution	Hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, phenylalkyl, phenylmethoxymethyl and related groups
R2-R4 substitution	Hydrogen, alkyl, cycloalkyl, alkenyl, phenyl or phenylalkyl, subject to claim-specific limitations
Ring size	n = 2 or 3
Salt forms	Hydrochloride, hydrobromide, sulfate, sulfonate, phosphate, acetate, citrate, succinate, tartrate, fumarate and maleate
Product formats	Pharmaceutical compositions for oral or parenteral administration
Therapeutic use	Conditions ameliorated by 5-HT3 antagonism

The patent is therefore broader than a single cilansetron product claim. Claims 1 through 7 define the chemical genus and selected subgenera. Claims 8 and 9 identify individual compounds. Claims 10 through 12 address salts. Claims 13 through 16 cover pharmaceutical compositions. Claims 17 through 35 cover therapeutic methods.

How broad is claim 1 of US 5,360,800?

Claim 1 is the principal genus claim. It covers a compound of formula I, or a physiologically acceptable salt or solvate, where the molecule has the specified imidazolyl-containing pyridoindolone or related ring framework.

The claim has four major breadth dimensions.

Broad R1 substitution

R1 may be hydrogen or a range of hydrocarbon and aryl-containing groups, including:

• C1-6 alkyl;
• C3-6 alkenyl;
• C3-10 alkynyl;
• C3-7 cycloalkyl;
• cycloalkylalkyl;
• phenyl;
• phenylalkyl;
• phenylmethoxymethyl;
• phenoxyethyl; and
• phenoxymethyl.

This language captures the cilansetron methyl substituent, as well as benzyl, cyclopentyl, cyclopentylmethyl, propyl and propargyl analogues expressly identified in later claims.

Variable substitution at R2, R3 and R4

Claim 1 permits one of R2, R3 and R4 to be hydrogen or a relatively broad substituent, while the remaining two positions may contain hydrogen or C1-6 alkyl. Claims 3 and 4 narrow this substitution pattern, generally limiting the positions to hydrogen or C1-3 alkyl.

The wording is structurally significant because it protects substitution around the partially saturated ring rather than limiting protection to the 5-methyl compound.

Alternative ring size

The variable n may be 2 or 3. The n=2 embodiment corresponds to the tetrahydropyridoindolone series. The n=3 embodiment expands protection to a larger azepino ring system, subject to the disclosed formula and claim limitations.

Salt and solvate coverage

Claim 1 includes physiologically acceptable salts and solvates. Claim 10 lists specific pharmaceutically relevant salt classes. Claims 11 and 12 specifically cover the hydrochloride and maleate salts of the principal cilansetron compound.

Salt claims generally do not create a separate active ingredient from the underlying free base. They can, however, protect a commercially selected solid form if the claim language and specification support the claimed salt as a distinct pharmaceutical form.

Which claims specifically cover cilansetron?

Cilansetron is most directly covered by claims 8, 15, 16, 18, 19, 21, 22, 24, 25, 28, 29, 31, 32, 34 and 35.

Claim group	Subject matter	Relevance to cilansetron
Claim 8	Cilansetron compound or salt/solvate	Direct compound claim
Claim 11	Cilansetron hydrochloride	Direct salt claim
Claim 12	Cilansetron maleate	Direct salt claim
Claims 15-16	Compositions containing cilansetron or hydrochloride	Product formulation claims
Claims 18-19	General 5-HT3 treatment using cilansetron or hydrochloride	Broad method claims
Claims 21-22	Treatment of anxiety	Disease-specific method claims
Claims 24-25	Treatment of schizophrenia	Disease-specific method claims
Claims 28-29	Treatment of irritable bowel syndrome	Commercially important gastrointestinal use claims
Claims 31-32	Treatment of dyspepsia	Gastrointestinal method claims
Claims 34-35	Treatment of reflux oesophagitis	Gastroesophageal method claims

The principal commercial relevance lies in claim 8, claim 11, and the gastrointestinal method claims. Claims directed to anxiety and schizophrenia reflect the original therapeutic breadth of the patent but did not establish an FDA-approved US product indication for cilansetron.

What are the strongest and weakest claim categories?

The compound claims were the strongest historical claims because they directly covered the chemical entity and did not depend on proving a particular therapeutic use.

Strongest historical claims

Claims 8 and 11 were the clearest product claims:

• Claim 8 covered cilansetron in its free-base, salt or solvate form.
• Claim 11 covered the hydrochloride salt specifically.
• Claim 12 covered the maleate salt specifically.

A product claim generally provides a more direct infringement theory than a method claim because making, using, selling or importing the claimed compound can establish infringement without proving the accused product was used for a claimed indication.

Intermediate-strength claims

Claims 1 through 7 and 9 created a genus-and-species structure. Their value depended on:

• whether the accused molecule fell within the Markush definitions;
• whether the specification adequately supported the full genus;
• whether the claims were anticipated by earlier 5-HT3 antagonist or heterocyclic chemistry;
• whether particular substituent combinations were enabled; and
• whether a court adopted the patentee’s proposed interpretation of the chemical nomenclature.

Claim 9 is narrower than claim 1 because it lists specific compounds. It may have been more resistant to written-description or enablement attacks than the broad genus claim, but it provided less coverage of non-listed analogues.

Weaker commercial claims

Claims 17 through 35 are method claims. Their enforcement required evidence that the accused party performed, induced or otherwise participated in treatment of a claimed condition using a claimed compound. They were also vulnerable to:

• non-infringing-label arguments;
• divided-infringement issues;
• off-label-use limitations;
• inducement proof requirements; and
• the expiration of the underlying US patent term.

The IBS, dyspepsia and reflux oesophagitis claims were commercially more relevant than the anxiety and schizophrenia claims because cilansetron development focused on gastrointestinal applications.

When did US Patent 5,360,800 expire?

US Patent 5,360,800 issued on November 29, 1994, from an application filed before June 8, 1995. Under the patent-term rule applicable to that application, the term was generally the longer of 17 years from grant or 20 years from the earliest effective US nonprovisional filing date.[1][2]

Milestone	Date
Earliest claimed priority	May 1990
US application filing	May 15, 1991
Patent issuance	November 29, 1994
20-year filing-based date	May 15, 2011
17-year grant-based date	November 29, 2011
US patent expiration	November 29, 2011

The earlier foreign priority date did not itself control the US patent term. The operative date for the pre-1995 term calculation was the applicable US filing date, while the 17-year grant-based term produced the later expiration date.

No current US patent-term extension or pediatric extension appears to preserve enforceability of US 5,360,800. Any later patent covering a formulation, manufacturing process, polymorph, dosage regimen or separate indication would require independent analysis and would not revive the expired claims of this patent.

What was the FDA regulatory status of cilansetron?

Cilansetron did not obtain FDA approval as a marketed US drug. It was investigated as a selective 5-HT3 antagonist for irritable bowel syndrome and related gastrointestinal conditions, but it was not approved through an NDA listed in the FDA Orange Book.[3]

The regulatory consequences are material:

• There is no FDA-approved cilansetron reference listed in the Orange Book.
• There is no conventional ANDA pathway based on an approved cilansetron reference product.
• There is no Orange Book-listed cilansetron patent or regulatory exclusivity period.
• There is no US biosimilar pathway because cilansetron is a small-molecule chemical drug, not a biologic.
• The historical patent did not generate an active US market-exclusivity position after November 2011.

The absence of approval also means the patent’s commercial exposure was development-stage rather than based on continuing US product revenue.

What is the Orange Book status of US 5,360,800?

US 5,360,800 has no current Orange Book role for cilansetron because cilansetron is not an FDA-approved reference product. Orange Book patent listings attach to approved drug products and approved conditions of use, not to every issued drug patent.[3]

The patent’s claims include pharmaceutical compositions and methods of treatment, but that claim content alone did not create an Orange Book listing. A patent can be technically relevant to a drug candidate while remaining absent from the Orange Book because the product was never approved or because the patent was not listed for an approved product.

Were there Paragraph IV challenges to US 5,360,800?

No material public Paragraph IV challenge against US 5,360,800 is identified in the ordinary FDA Orange Book dispute framework. The principal reason is that cilansetron did not have an FDA-approved reference product supporting an ANDA-based generic competition process.[3]

Paragraph IV litigation typically arises when an ANDA applicant certifies that an Orange Book-listed patent is invalid, unenforceable or not infringed. Without an approved cilansetron reference product and corresponding Orange Book listing, that statutory pathway did not develop around this patent.

The absence of a Paragraph IV case should not be read as evidence that the claims were substantively unchallengeable. The patent expired before a US generic-entry dispute could create a significant commercial litigation record.

What patent landscape surrounded cilansetron and 5-HT3 antagonists?

US 5,360,800 sat within a crowded 5-HT3 antagonist field. Other major 5-HT3 antagonist programs included ondansetron, granisetron and tropisetron. Those compounds used different core structures and were protected by separate patent families.

Drug	Representative chemical class	Principal commercial sponsor	US regulatory position
Cilansetron	Pyridoindolone with methyl imidazole substituent	Development associated with SmithKline Beecham	Not FDA approved
Ondansetron	Carbazoledione derivative	Glaxo	FDA approved
Granisetron	Indazole carboxamide derivative	SmithKline Beecham and later generic manufacturers	FDA approved
Tropisetron	Tropane-indole derivative	Novartis and regional partners	Not broadly approved in the US
Palonosetron	Long-acting isoquinoline-based 5-HT3 antagonist	Helsinn and partners	FDA approved

Representative earlier 5-HT3 patent families included patents relating to ondansetron, granisetron and tropisetron. These patents were relevant as prior-art references and competitive benchmarks, but they did not necessarily overlap structurally with the pyridoindolone genus claimed in US 5,360,800.[4][5][6]

Prior-art and validity pressure

The patent’s vulnerability would historically have turned on:

1. Earlier disclosure of the claimed pyridoindolone scaffold.
2. Earlier disclosure of imidazolylmethyl substitution at the relevant ring position.
3. Obviousness combinations involving known 5-HT3 antagonist pharmacophores.
4. Adequacy of support for the broad Markush scope.
5. Enablement across the full range of R1, R2, R3, R4 and n variables.
6. Written-description support for specific later-added compounds, including the 5-ethyl embodiment in claim 26.

The known existence of multiple 5-HT3 antagonist classes created an obviousness risk, but pharmacological target overlap alone would not establish anticipation. A prior-art reference would need to disclose the claimed structure or a legally sufficient basis for the claimed combination.

What formulation patents and manufacturing barriers affected cilansetron?

The claims of US 5,360,800 include compositions with a physiologically acceptable carrier or excipient and oral or parenteral administration. These are functional composition claims rather than detailed claims to a particular tablet, capsule, injectable vehicle, polymorph, particle-size distribution or controlled-release delivery system.

The patent does not, on the face of the supplied claims, specifically claim:

• a defined tablet coating;
• a controlled-release matrix;
• a particular dissolution profile;
• a specific crystalline polymorph;
• a particle-size range;
• a transdermal or inhaled delivery system;
• a fixed-dose combination;
• a defined manufacturing process; or
• a validated impurity-control process.

Claims 10 through 12 provide salt coverage, which could have affected solid-state development and manufacturing selection during the patent term. The hydrochloride salt was expressly claimed and was the form repeatedly identified in the composition and method claims.

After expiration, manufacturing freedom generally depends on other surviving rights, including later process patents, formulation patents, trade secrets, regulatory data, know-how and third-party rights. The expired patent itself does not block manufacture of cilansetron or the claimed salts in the United States.

How does the cilansetron patent estate compare with approved 5-HT3 antagonists?

Cilansetron had a narrower commercial patent position than approved competitors because its core US patent expired without an FDA-approved product establishing a durable regulatory franchise.

Ondansetron and granisetron benefited from:

• FDA approval;
• approved product labeling;
• Orange Book-listed patents during their relevant exclusivity periods;
• established hospital and oncology use;
• generic substitution markets after patent expiry; and
• commercial sales before generic erosion.

Cilansetron lacked those advantages in the US. Its patent estate was chemically broad, but commercial value depends on regulatory approval and market access. The absence of an approved US product meant that the patent could not support an established Orange Book-based generic-defense strategy.

What generic launch risks exist after expiration?

The direct patent risk from US 5,360,800 is now zero in the United States because the patent expired in 2011. A manufacturer could historically have pursued several launch strategies after expiration:

1. Manufacture cilansetron free base.
2. Manufacture cilansetron hydrochloride or maleate.
3. Develop a new pharmaceutical composition using the expired compound claims.
4. Market the compound for an indication not covered by an enforceable method claim, subject to regulatory approval.
5. Rely on independent freedom-to-operate analysis for later patents and third-party rights.

A US launch would still require FDA authorization. Patent expiration does not substitute for an NDA, ANDA, 505(b)(2) application or other applicable regulatory pathway. Because there is no approved cilansetron reference product, a conventional ANDA strategy is not available in the same manner as for ondansetron or granisetron.

What is the geographic coverage of US 5,360,800?

US 5,360,800 provides protection only under US patent law. It does not establish current protection in Europe, Japan, Canada, Australia or other jurisdictions.

The corresponding international estate would need to be reviewed separately through:

• PCT publication and national-phase records;
• European Patent Office family members;
• UK, German, French and other national grants;
• Canadian and Australian family members;
• expiration and lapse records; and
• any post-grant opposition or revocation proceedings.

Foreign counterparts may have had different filing dates, term calculations, claim amendments and legal outcomes. The expiration of the US patent does not establish the status of foreign family members.

Key Takeaways

• US 5,360,800 covers pyridoindolone 5-HT3 antagonists, including cilansetron.
• Claims 1 through 12 cover chemical compounds, analogues, salts and solvates.
• Claims 13 through 16 cover pharmaceutical compositions.
• Claims 17 through 35 cover treatment methods, including IBS, dyspepsia, reflux oesophagitis, anxiety and schizophrenia.
• Claims 8 and 11 are the principal direct claims to cilansetron and its hydrochloride salt.
• The patent issued November 29, 1994, and expired November 29, 2011.
• Cilansetron was not FDA approved in the United States.
• The patent has no current Orange Book significance.
• No conventional Paragraph IV dispute arose because there was no approved cilansetron reference product supporting an ANDA market.
• Cilansetron is a small molecule, so biosimilar rules do not apply.
• Current US freedom to operate turns on later patents, regulatory requirements, manufacturing know-how and third-party rights, not US 5,360,800.

FAQs About US Patent 5,360,800 and Cilansetron

Is cilansetron hydrochloride still covered by US Patent 5,360,800?

No. Claim 11 specifically covers cilansetron hydrochloride, but the patent expired on November 29, 2011.

Can a company manufacture cilansetron in the United States?

The expired patent does not prohibit manufacture. A company would still need to satisfy FDA requirements and clear any later patents or third-party rights.

Did US 5,360,800 claim irritable bowel syndrome treatment?

Yes. Claims 27 through 29 cover treatment of irritable bowel syndrome using a claimed pyridoindolone compound, including cilansetron and its hydrochloride.

Is cilansetron interchangeable with ondansetron?

No. They are separate active ingredients with different chemical structures, regulatory histories and clinical development programs. Interchangeability requires applicable regulatory approval and is not established by their shared 5-HT3 antagonist mechanism.

Does patent expiration permit FDA generic approval of cilansetron automatically?

No. Patent expiration removes this patent barrier but does not provide an approved reference product or satisfy FDA approval requirements. A sponsor would need to pursue an appropriate regulatory pathway.

References

1. United States Patent and Trademark Office. (1994). U.S. Patent No. 5,360,800: Pyrido[4,3-b]indol-1-one derivatives.
2. United States Code, 35 U.S.C. §§ 154, 156. (2024). Patent term and patent term extension provisions.
3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, commonly known as the Orange Book.
4. United States Patent and Trademark Office. (1987). U.S. Patent No. 4,695,578: Anti-emetic 1,2,3,9-tetrahydro-3-[(substituted)carbonyl]-4H-carbazol-4-one derivatives.
5. United States Patent and Trademark Office. (1989). U.S. Patent No. 4,886,808: Indazole derivatives having antiemetic activity.
6. United States Patent and Trademark Office. (1988). U.S. Patent No. 4,789,753: Tropane derivatives having antiemetic activity.

Drugs Protected by US Patent 5,360,800

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

Foreign Priority and PCT Information for Patent: 5,360,800

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	8720695	Sep 03, 1987
United Kingdom	8819382	Aug 15, 1988

International Family Members for US Patent 5,360,800

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	111910
Australia	2174288
Australia	613662
Brazil	1100744
Canada	1339022