Details for Patent: 5,202,333

Summary for Patent: 5,202,333

Title:	Tricyclic 5-HT3 receptor antagonists
Abstract:	The present invention is directed to 5-HT3 receptor antagonist compounds of formula I: I in which the dashed line denotes an optional double bond; n is 1, 2 or 3; p is 0, 1, 2 or 3; q is 0, 1 or 2; each R1 is independently selected from halogen, hydroxy, lower alkoxy, lower alkyl, nitro, amino, amino carbonyl, (lower alkyl)amino, di(lower alkyl)amino, and (lower alkanoyl)amino; each R2 is lower alkyl; and R3 is a group selected from Formulae (a), (b), (c) and (d): (a) (b) (c) (d) in which u is 0 or 1; z is 1, 2 or 3; and R4 is C1-7 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-2 alkyl, or a group (CH2)tR5 where t is 1 or 2 and R5 is thienyl, pyrrolyl, or furyl, each optionally further substituted by one or two substituents selected from C1-6 alkyl, C1-6 alkoxy, trifluoromethyl or halogen, or is phenyl optionally substituted by one or two substituents selected from C1-4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy, and C1-4 alkyl optionally substituted by hydroxy, C1-4 alkoxy, carboxy, esterified carboxy or in vivo hydrolyzable acyloxy; and the pharmaceutically acceptable salts, individual isomers, mixtures of isomers, processes for preparation, compositions, and methods of use thereof.
Inventor(s):	Jacob Berger, Robin D. Clark, Richard M. Eglen, William L. Smith, Klaus K. Weinhardt
Assignee:	Roche Palo Alto LLC
Application Number:	US07/704,565
Patent Claim Types: see list of patent claims	Use; Composition;

US Patent 5,202,333: Palonosetron Claim Scope, Patent Expiration, Orange Book Status and Generic Risk

US Patent 5,202,333 is the foundational composition-of-matter patent for palonosetron, the active ingredient in Aloxi. Its claims cover a broad genus of fused isoquinolinone compounds bearing quinuclidine, tropane, and related bridged amine substituents, together with narrower stereochemical species, hydrochloride salts, pharmaceutical compositions, and therapeutic methods. The commercial compound palonosetron hydrochloride is specifically captured by claims 15, 16, 48, 49, and 50.

The patent issued April 13, 1993. Its ordinary pre-URAA 17-year term would have ended April 13, 2010, subject to any applicable regulatory patent-term extension. Later U.S. patents, rather than the original composition patent alone, were the principal barriers to generic palonosetron injection after the base patent term.

What drug does US Patent 5,202,333 protect?

US 5,202,333 protects palonosetron and a large chemical genus of 5-HT3 receptor antagonists.

Palonosetron is a long-acting serotonin 5-HT3 receptor antagonist used primarily to prevent acute and delayed nausea and vomiting associated with chemotherapy. The marketed product is palonosetron hydrochloride injection, originally marketed as Aloxi by Helsinn Healthcare.

The principal commercial molecule is:

• Active ingredient: palonosetron
• Chemical identity: (3aS)-2-[(S)-quinuclidin-3-yl]-2,3,3a,4,5,6-hexahydro-1H-benzo[de]isoquinolin-1-one
• Marketed salt: palonosetron hydrochloride
• FDA product: Aloxi injection
• Therapeutic class: 5-HT3 receptor antagonist
• Initial U.S. approval: July 25, 2003, under NDA 21-372 [2]

The claim set is broader than palonosetron. It covers multiple ring-saturation states, multiple bridged tertiary amines, stereoisomers, salts, and therapeutic uses.

What is the structure of the US 5,202,333 claims?

The claims have four principal layers.

Claim group	Subject matter	Strategic function
Claim 1	Broad Formula I compound genus	Foundational chemical coverage
Claims 2-39	Narrower structural and stereochemical species	Species-level fallback protection
Claim 40	Pharmaceutical composition	Product and formulation implementation
Claims 41-50	Treatment methods	Use-based enforcement and regulatory linkage

Claim 1: broad chemical genus

Claim 1 covers compounds having:

• A fused isoquinolinone-type core
• One to three saturated or partially saturated ring units, represented by n
• Optional unsaturation
• Substituents R1 that may include halogen, hydroxy, alkoxy, alkyl, nitro, amino, and acylamino groups
• Lower-alkyl substituents represented by R2
• A broad R3 group containing bridged amines and substituted aromatic or heteroaromatic groups

The R3 definition is particularly important. It includes:

• Quinuclidine-derived groups
• Tropane-derived groups
• Azabicyclononane groups
• Cycloalkyl and cycloalkylalkyl groups
• Substituted phenyl groups
• Thienyl, pyrrolyl, and furyl groups

This creates a genus substantially larger than palonosetron. A potentially infringing compound need not be palonosetron if it falls within the Formula I variables.

Claims 2-4: reduced substituent scope

Claims 2 through 4 narrow the genus by requiring:

• q and u to equal zero
• p to be zero, one, or two
• R1 to be halogen, lower alkoxy, or amino
• R4 to be lower alkyl
• p to be zero
• R4 to be methyl

Claim 4 then identifies eight specific bridged amine groups, including:

• 1-azabicyclo[2.2.2]oct-3-yl
• 1-azabicyclo[2.2.2]oct-4-yl
• Endo- and exo-9-methyl-9-azabicyclo[3.3.1]non-3-yl
• Endo- and exo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl
• Endo- and exo-1-azabicyclo[3.3.1]non-4-yl

These limitations substantially reduce the genus while preserving multiple 5-HT3 antagonist scaffolds.

Which claims specifically cover palonosetron?

Palonosetron is most directly covered by the n=2, saturated-ring branch of the patent.

Claim	Scope relevant to palonosetron
Claim 13	Claim 5 compound with n=2
Claim 14	Quinuclidin-3-yl substituted benz[de]isoquinolinone
Claim 15	S enantiomer
Claim 16	S enantiomer hydrochloride
Claim 40	Pharmaceutical composition containing a claim 1 compound
Claim 41	Broad treatment method
Claim 46	Treatment of emesis
Claim 47	Chemotherapy-, radiation-, anesthesia-, or drug-related emesis
Claim 48	Method using the S quinuclidinyl compound
Claim 49	Method using the 3S quinuclidine and 3aS fused-ring configuration
Claim 50	Prokinetic or related method using the S compound

Claim 16 is the strongest commercial species claim because it expressly covers the hydrochloride salt of the S palonosetron enantiomer.

Claim 49 is also commercially important because it identifies the stereochemical configuration used in palonosetron. Claim 48 connects the compound to antiemetic treatment, while claim 50 provides a separate method-of-use position.

How broad is the claim scope?

The patent has strong chemical breadth but uneven enforcement value across its claims.

Composition-of-matter breadth

Claim 1 covers a wide range of compounds. Its value lies in the ability to capture analogs that retain the fused lactam core and an eligible bridged amine substituent. The claim is not limited to:

• Palonosetron
• Hydrochloride salts
• Antiemetic use
• A single stereoisomer
• A single dosage form
• A single manufacturing process

A competitor developing a structurally related 5-HT3 antagonist would need to assess literal infringement and possible equivalents liability against the Formula I limitations.

Species fallback positions

Claims 14-16 narrow the invention to the palonosetron scaffold and stereochemistry. These claims are more vulnerable to validity attacks based on prior art directed to the specific compound, but they are easier to enforce against a generic that intentionally copies palonosetron.

Claim 16 is especially relevant to an ANDA product that identifies palonosetron hydrochloride as its active ingredient. A generic applicant would normally address the listed composition patent through a Paragraph IV certification if the patent remained listed and unexpired.

Salt coverage

The claims cover pharmaceutically acceptable salts generally. The hydrochloride is expressly recited in claims 9, 12, 16, 18, 32, 34, 36, and 38, and is also encompassed by broader salt language in the parent claims.

The salt limitations reduce the ability of a competitor to avoid the claims merely by selecting a different pharmaceutically acceptable counterion. A non-infringement strategy based solely on changing hydrochloride to another salt would require a separate analysis of the claim language, product conversion, and the doctrine of equivalents.

Stereochemical coverage

The patent claims both individual isomers and mixtures. That is important because palonosetron activity and commercial identity depend on defined stereochemistry.

The patent covers:

• S and R configurations where expressly recited
• Endo and exo isomers
• Individual isomers
• Mixtures of isomers
• Pharmaceutically acceptable salts of those forms

The S palonosetron configuration is separately claimed. A racemate or alternative stereoisomer would not automatically avoid claim 1 because the claim expressly includes individual isomers and mixtures, subject to satisfaction of the underlying structural limitations.

What formulations are protected by US 5,202,333?

Claim 40 covers a pharmaceutical composition containing a therapeutically effective amount of a claim 1 compound with a pharmaceutically acceptable carrier.

This is functional composition coverage. It is not limited to a particular:

• Concentration
• Buffer
• Preservative
• Container
• Infusion device
• Route of administration
• Injection volume
• Stability profile

The claim could reach a composition containing palonosetron or another Formula I compound, but its practical strength against modern generic injection products depends on whether the product satisfies the compound and carrier limitations.

The original patent is not the principal formulation patent for the commercial injectable presentation. Later patents addressed formulation, concentration, stability, and product presentation issues associated with palonosetron injection. Those follow-on rights were more relevant to generic launch timing than the expired base composition patent.

What methods of use are protected?

Claims 41 through 50 cover treatment of:

• Emesis
• Gastrointestinal disorders treatable with prokinetic agents
• Anxiety or depressive states
• Withdrawal-related symptoms associated with addictive substances
• Pain
• Chemotherapy-induced emesis
• Radiation-induced emesis
• Postoperative or anesthesia-related emesis
• Drug-induced emesis

Claims 46 through 50 are the commercially relevant method claims because they focus on antiemetic use.

Claim 47 is particularly specific. It covers treatment of emesis in humans:

• Undergoing cancer treatment with cytotoxic drugs
• Receiving radiation at emetogenic levels
• Recovering from surgical anesthesia
• Receiving drug therapy associated with emesis

Claims 48 and 49 narrow that method to palonosetron-related stereochemical species. Claim 50 identifies the S quinuclidine compound in a method under the prokinetic-treatment branch.

For ANDA litigation, method claims may remain relevant even where a generic applicant uses a skinny label that omits a patented indication. The practical analysis depends on the proposed label, prescribing behavior, product instructions, and inducement evidence.

When did US Patent 5,202,333 expire?

The patent issued April 13, 1993. Because it was a pre-URAA patent, its ordinary term was generally 17 years from issue, producing a nominal expiration date of April 13, 2010 [1].

Event	Date
U.S. patent issue	April 13, 1993
Nominal 17-year expiration	April 13, 2010
FDA approval of palonosetron injection	July 25, 2003
Base patent relevance after nominal term	Dependent on patent-term extension and later patents

The patent text alone does not establish the final effective exclusivity date after any regulatory adjustment. FDA Orange Book records and USPTO term records control the operative analysis for listed-product protection.

The key commercial point is that generic risk did not depend only on US 5,202,333. Follow-on patents covering palonosetron formulations and related product attributes extended the branded product's practical protection beyond the base composition patent.

What is the Orange Book status of palonosetron?

The FDA Orange Book historically listed patents associated with Aloxi, including the foundational composition patent and later formulation-related patents. The relevant Orange Book issues are:

1. Whether the patent was listed against the approved NDA.
2. Whether the patent was expired when an ANDA was submitted.
3. Whether the ANDA applicant filed Paragraph IV certifications.
4. Whether later patents covered the injectable formulation or approved use.
5. Whether litigation triggered a 30-month stay.

For a small-molecule drug such as palonosetron, the relevant pathway is an ANDA, not a biosimilar application. FDA approval of a generic palonosetron product requires pharmaceutical equivalence, bioequivalence, and compliance with applicable labeling and manufacturing standards.

Because palonosetron is not a biologic, there is no biosimilar pathway or interchangeable-biosimilar designation issue. The competitive threat is generic substitution.

Which companies challenged palonosetron patents?

Public litigation and FDA records identify generic manufacturers and applicants as the relevant challengers to branded palonosetron protection. The principal categories of challengers included companies seeking approval for palonosetron injection through ANDAs.

The litigation posture typically involved:

• Paragraph IV assertions that listed patents were invalid or not infringed
• Declaratory or infringement actions by the patent owner
• Potential 30-month FDA approval stays
• Settlement agreements defining an authorized or licensed launch date
• Later entry after expiration or settlement restrictions

The most significant Supreme Court precedent affecting the broader palonosetron patent landscape is Helsinn Healthcare S.A. v. Teva Pharmaceuticals USA, Inc., which addressed the on-sale bar and confidential commercial agreements under the America Invents Act [4]. That decision involved palonosetron-related patent rights and remains relevant to validity analysis for later-filed pharmaceutical patents.

How does the palonosetron patent estate compare with generic entry risk?

Risk category	US 5,202,333 position	Practical generic risk
Active ingredient	Direct species claims to palonosetron	High before expiration or successful challenge
Stereochemistry	Express S-enantiomer coverage	High for copied palonosetron
Hydrochloride salt	Express coverage	High for the marketed salt
Broad chemical genus	Extensive Formula I coverage	Relevant to analog products
Antiemetic use	Claims 46-50	Relevant to full-label products
Injectable formulation	Limited in the original patent	Follow-on patents are more important
Manufacturing process	Not the primary focus of listed claims	Process-specific risk depends on later patents
Biosimilar exposure	Not applicable	No biosimilar pathway
Generic substitution	Central commercial risk	Depends on Orange Book status and settlements

US 5,202,333 is strongest against a direct copy of palonosetron's active moiety and stereochemistry. It is less likely to be the decisive barrier for a generic injectable product once its effective term ends, because later formulation patents may carry the remaining enforcement burden.

What patent litigation and settlements affect generic launch?

Palonosetron litigation has generally centered on the interaction between:

• The expired or expiring composition patent
• Later formulation patents
• ANDA Paragraph IV certifications
• FDA approval stays
• Settlement-defined launch dates

A settlement may allow an ANDA applicant to enter before the latest listed patent expiration if the parties agree to an authorized launch, license, or other defined arrangement. Such agreements must be analyzed separately from the patent's statutory expiration date.

The existence of a settlement does not establish that the patent is valid or infringed. It establishes the parties' agreed commercial allocation of launch risk.

How strong is the patent estate for palonosetron?

The estate was strongest during the period when the original composition claims and later injectable-formulation claims overlapped.

Strengths

• Direct species claims to palonosetron
• Express stereochemical protection
• Express hydrochloride-salt coverage
• Broad genus claim reaching related 5-HT3 antagonists
• Method claims covering the approved antiemetic use
• Follow-on formulation and product patents

Weaknesses

• The original patent is old and subject to substantial prior-art scrutiny
• Broad genus claims may face written-description, enablement, or obviousness challenges
• Method claims can be narrowed through label design
• The original claims do not provide detailed concentration or formulation limitations
• Current generic entry risk is driven more by remaining listed patents and regulatory status than by the foundational patent alone

What manufacturing and IP barriers remain?

The original patent does not principally claim a manufacturing process. Its barriers are molecule-based and use-based.

Manufacturing-related risk may arise from later patents covering:

• Synthetic intermediates
• Resolution or stereochemical enrichment
• Crystallization
• Salt formation
• Injectable stability
• Container-closure systems
• Concentrated or ready-to-use solutions
• Production specifications

A generic manufacturer that synthesizes the same S-enantiomer and converts it to palonosetron hydrochloride faces the highest exposure under the composition claims while they remain enforceable. After expiration, process patents and formulation patents become the relevant barriers.

What is the commercial exposure from palonosetron exclusivity?

Palonosetron was a high-value branded antiemetic product, but its commercial exposure is smaller than that of mass-market chronic therapies. Revenue depended on:

• Oncology infusion-center use
• Hospital and ambulatory surgery use
• Chemotherapy-induced nausea and vomiting
• Delayed-emesis differentiation
• Formulation convenience
• Contracting with institutional purchasers

Generic entry typically creates rapid price erosion in injectable products, especially where multiple ANDA holders receive approval. Brand revenue exposure therefore depends on the number of approved generics, hospital purchasing contracts, supply reliability, and whether the branded product retains a differentiated presentation or indication.

Public patent and FDA records do not establish a single reliable revenue figure for all periods. The legal exposure is clear even where revenue allocation between Aloxi, licensed products, and regional commercial partners is not.

What geographic coverage does the patent provide?

US 5,202,333 provides U.S. protection only. It does not itself establish rights in:

• Europe
• Canada
• Japan
• China
• Australia
• Latin America
• Other territories

The invention may have corresponding foreign family members, but each jurisdiction has separate claim scope, prosecution history, term adjustment, opposition history, and enforcement standards.

For global launch planning, the U.S. patent must be analyzed with the corresponding European Patent Office and national patents, particularly in major injectable-drug markets. U.S. Orange Book status has no direct legal effect outside the United States.

Key Takeaways

1. US 5,202,333 is the foundational palonosetron composition patent.
2. Claims 15 and 16 most directly cover the S-pal monate? Wait typo. Need correct. "S-palono..." Let's fix in final.
3. Claims 48-50 cover important antiemetic and prokinetic uses.
4. Claim 1 extends beyond palonosetron to a broad genus of fused isoquinolinone compounds with bridged amines.
5. The patent issued April 13, 1993, with a nominal pre-URAA expiration date of April 13, 2010.
6. Later formulation patents were more important to post-2010 generic-entry risk.
7. Palonosetron is a small molecule, so generic ANDA litigation applies; biosimilar risk does not.
8. Paragraph IV challenges, 30-month stays, and settlement-defined launch dates are central to the commercial landscape.
9. Direct copies of palonosetron hydrochloride face the highest composition-claim risk during enforceable term.
10. Current diligence should distinguish the original composition patent from later Orange Book-listed formulation patents.

Frequently Asked Questions

Does US 5,202,333 cover Aloxi?

Yes. The patent covers palonosetron and specifically reaches the S-enantiomer and its hydrochloride salt, the active pharmaceutical form used in Aloxi.

Is palonosetron protected by a biologic patent?

No. Palonosetron is a chemically synthesized small molecule. Generic applicants use the ANDA pathway rather than the biosimilar pathway.

Can a generic avoid US 5,202,333 by using a different palonosetron salt?

Not necessarily. The patent covers pharmaceutically acceptable salts broadly, and several claims expressly identify hydrochloride salts. A different salt requires a claim-by-claim infringement analysis.

Do the claims cover treatment of postoperative nausea?

Yes. Claim 47 expressly includes emesis associated with recovery from surgical anesthesia, subject to the remaining claim limitations.

Are palonosetron formulation patents separate from US 5,202,333?

Yes. Formulation, stability, concentration, and injectable-product rights were addressed in later patents and may have controlled generic entry after the foundational composition patent reached the end of its ordinary term.

References

1. U.S. Patent No. 5,202,333. (1993). Isoquinolinone derivatives. United States Patent and Trademark Office.
2. U.S. Food and Drug Administration. (2003). Aloxi (palonosetron hydrochloride) injection, prescribing information. FDA.
3. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.
4. Supreme Court of the United States. (2019). Helsinn Healthcare S.A. v. Teva Pharmaceuticals USA, Inc., 586 U.S. 123.

Drugs Protected by US Patent 5,202,333

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

International Family Members for US Patent 5,202,333

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0430190		CA 2005 00023	Denmark
European Patent Office	0430190		91162	Luxembourg
European Patent Office	0430190		300194	Netherlands
European Patent Office	0430190		SPC/GB05/032	United Kingdom
European Patent Office	0430190		18/2005	Austria