Details for Patent: 4,824,860

Summary for Patent: 4,824,860

Title:	Treatment of Parkinsons disease
Abstract:	Compounds of structure (I) in which each group R is hydrogen or C1-4alkyl; R<1> and R<2> are hydrogen or C1-4alkyl; R<3> is hydrogen or hydroxy; and n is 1 to 3, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for the treatment of Parkinsons Disease.
Inventor(s):	David A. A. Owen
Assignee:	Smith Kline and French Laboratories Ltd
Application Number:	US07/196,653
Patent Claim Types: see list of patent claims	Use;

United States Patent 4,824,860: Ropinirole Parkinson’s Treatment Claims and Patent Landscape

U.S. Patent 4,824,860 protects the use of ropinirole and related 4-substituted indolone compounds to treat Parkinson’s disease. Its narrowest claims specifically cover ropinirole, chemically identified as 4-(2-di-n-propylaminoethyl)-2-(3H)-indolone, and ropinirole hydrochloride. The patent issued on April 25, 1989, and its ordinary pre-URAA patent term expired on April 25, 2006. The patent is no longer an enforceable barrier to generic ropinirole products.[1]

The patent was a method-of-use patent. It did not claim ropinirole as a new chemical entity in the broad composition-of-matter format used under modern patent practice. The practical commercial importance of the patent came from its use claims covering administration of ropinirole for Parkinson’s disease.

What drug does U.S. Patent 4,824,860 protect?

The patent protects ropinirole-related compounds used in Parkinson’s disease treatment. The key commercial compound is ropinirole hydrochloride, marketed originally by SmithKline Beecham and later GlaxoSmithKline as Requip.

Item	Details
Patent	U.S. Patent 4,824,860
Patent title	Indolone derivatives
Issued	April 25, 1989
Commercial active ingredient	Ropinirole
Common pharmaceutical form	Ropinirole hydrochloride
Original product	Requip
Therapeutic use	Parkinson’s disease
Patent type	Method-of-treatment patent
Ordinary expiration	April 25, 2006
Current status	Expired
FDA product category	Small-molecule prescription drug
Biosimilar pathway	Not applicable

Ropinirole is a non-ergoline dopamine agonist. It acts primarily through dopamine D2-family receptors and is used for Parkinson’s disease and, in other approved products, restless legs syndrome. The claims in Patent 4,824,860 are directed only to Parkinson’s disease treatment.

What does claim 1 of Patent 4,824,860 cover?

Claim 1 is a genus method claim. It covers administering an effective, non-toxic amount of a defined class of substituted indolone compounds, or a pharmaceutically acceptable salt of those compounds, to a patient with Parkinson’s disease.

The claim contains four principal structural variables:

1. The amino substituents designated R may be hydrogen or C1-C4 alkyl.
2. R1 and R2 may independently be hydrogen or C1-C4 alkyl.
3. R3 may be hydrogen or hydroxy.
4. The variable n may be 1, 2, or 3.

The claim therefore extends beyond ropinirole itself. It covers a structural genus that includes compounds with different alkyl substitution patterns, chain lengths, and ring hydroxy substitution.

The legal subject matter is the treatment method, not merely possession of the chemical. A claimant would need to establish that a defendant administered, or induced administration of, an embraced compound for Parkinson’s disease. A product that merely contains a covered chemical would not necessarily infringe the claim without the required treatment-use element.

Scope of the Markush structure

Claim 1 uses a Markush-style definition. The claim does not cover every dopamine agonist or every indolone derivative. It covers only compounds matching the specified scaffold and substituent limitations.

The structural limits are material:

• The indolone nucleus must be present.
• The aminoethyl side chain must occupy the claimed position on the indolone ring.
• The nitrogen substituents must fall within hydrogen or C1-C4 alkyl categories.
• The terminal substituent pattern must satisfy the R1/R2 limitations.
• The side-chain length must fall within n=1 to n=3.
• The claimed compound must be used to treat Parkinson’s disease.

A compound outside the indolone scaffold, outside the permitted alkyl ranges, or having a different side-chain arrangement would not fall within the literal scope of claim 1. It could still raise an equivalents issue under historical infringement law, but the expired status of the patent makes that issue commercially immaterial today.

What do claims 2 and 3 specifically protect?

Claims 2 and 3 are narrower species claims.

Claim	Covered subject matter	Scope
1	Defined class of substituted indolones and salts used for Parkinson’s disease	Broadest claim
2	4-(2-di-n-propylaminoethyl)-2-(3H)-indolone used for Parkinson’s disease	Specific free base
3	Hydrochloride salt of that compound used for Parkinson’s disease	Specific ropinirole hydrochloride treatment

Claim 2 covers the free-base form of ropinirole. Claim 3 covers ropinirole hydrochloride, the commercially important salt used in Requip and generic ropinirole tablets.

Claim 3 does not claim every pharmaceutical formulation containing ropinirole hydrochloride. It claims administration of the hydrochloride salt for Parkinson’s disease. A conventional tablet, capsule, or other dosage form could have been relevant to infringement only because it administered the claimed compound for the claimed indication.

When did Patent 4,824,860 lose exclusivity?

The patent’s ordinary term expired on April 25, 2006, 17 years after issuance. The patent issued before the Uruguay Round Agreements Act changed U.S. patent term calculation to 20 years from the earliest effective nonprovisional filing date. Pre-URAA patents generally retained a term of 17 years from grant.[1]

Milestone	Date
Patent issued	April 25, 1989
Ordinary 17-year term	April 25, 2006
Generic market opportunity	After expiration, subject to FDA approval
Current enforceability	None

The patent did not create a current exclusivity barrier. Any historical regulatory exclusivity, pediatric exclusivity, or patent-term extension would have ended long ago and would not affect present generic entry.

What was the Orange Book status of ropinirole?

The FDA Orange Book listed Patent 4,824,860 in connection with Requip, the immediate-release ropinirole product approved under NDA 020658. The listing related to the approved Parkinson’s disease indication and reflected the method-of-use nature of the patent.[2]

Patent listings do not extend patent life. They provide the FDA and ANDA applicants with notice of patents that the NDA holder identified as relevant to the approved product. Once the listed patent expired, it ceased to block approval or commercial launch of an ANDA.

The Orange Book status of the original Requip product must be distinguished from later extended-release products. Requip XL used different formulation and delivery technology and was evaluated under a separate NDA. Patents directed to extended-release delivery, tablet architecture, or release-control materials were separate from Patent 4,824,860.

Were there Paragraph IV challenges to Patent 4,824,860?

Generic applicants could have addressed the patent through an ANDA certification under the Hatch-Waxman framework. The relevant options included:

• Paragraph I: no patent information was listed.
• Paragraph II: the listed patent had expired.
• Paragraph III: the applicant would wait until patent expiration.
• Paragraph IV: the listed patent was invalid, unenforceable, or not infringed.

For ropinirole, the practical post-expiration route was a Paragraph II or Paragraph III certification rather than a commercially meaningful Paragraph IV challenge. FDA-approved generic ropinirole products entered after the 2006 patent expiration period.[3]

A Paragraph IV certification filed before expiration could have triggered patent litigation under 35 U.S.C. §271(e)(2), potentially creating a 30-month stay of FDA approval. After expiration, the patent no longer supplied a credible basis for blocking launch.

Publicly significant current litigation cannot arise from Patent 4,824,860 because the patent is expired. Any historical ANDA litigation connected to ropinirole would have ended through judgment, dismissal, settlement, or expiration-driven mootness.

What formulation patents protected Requip and Requip XL?

Patent 4,824,860 did not materially protect extended-release formulation technology. The patent’s claims are centered on the compound and its administration for Parkinson’s disease.

Later patent activity around ropinirole focused on commercial product differentiation, including:

• Extended-release tablets.
• Controlled release of ropinirole hydrochloride.
• Tablet matrices and release profiles.
• Dosing regimens designed for once-daily administration.
• Formulations intended to reduce peak-to-trough concentration variation.

Requip XL was approved by the FDA in 2007 as an extended-release formulation of ropinirole hydrochloride.[4] Any later formulation patents had separate claim scope and separate expiration dates. Expiration of Patent 4,824,860 did not automatically invalidate or eliminate formulation patents covering Requip XL.

Immediate-release versus extended-release protection

Product category	Primary patent issue
Requip immediate release	Compound and Parkinson’s treatment claims, including Patent 4,824,860
Generic immediate-release ropinirole	Patent 4,824,860 expired; formulation and regulatory requirements remained
Requip XL	Extended-release formulation and dosing patents
Generic extended-release ropinirole	Potential formulation, release-profile, and regulatory patent issues

A generic manufacturer could launch immediate-release ropinirole after the relevant patent expiration without necessarily being free to copy every extended-release formulation.

Did Patent 4,824,860 cover restless legs syndrome?

No. The issued claims expressly recite treatment of Parkinson’s disease. They do not claim treatment of restless legs syndrome.

Ropinirole later received FDA approval for moderate-to-severe primary restless legs syndrome under a separate regulatory application and labeling history.[5] That indication could have been protected through separate method-of-use patents or regulatory exclusivity, but Patent 4,824,860 itself is limited to Parkinson’s disease treatment.

This distinction matters for Orange Book analysis. A patent directed to Parkinson’s disease may not block approval for a different indication if the generic applicant properly carves out the patented use from its labeling. Conversely, a separate RLS method patent could create a distinct skinny-label issue.

How strong was the patent estate for ropinirole?

The estate was strong during the commercial life of the original drug because claim 3 directly covered ropinirole hydrochloride administered for Parkinson’s disease. The estate was less comprehensive than a modern estate built around a composition-of-matter patent because Patent 4,824,860 did not claim the molecule as a standalone product in the broadest possible form.

Strength factor	Assessment
Direct coverage of commercial salt	Strong
Coverage of free base	Strong through claim 2
Broader chemical genus	Moderate to strong, subject to construction
Standalone composition claim	Not the principal protection shown in the quoted claims
Parkinson’s disease use	Directly covered
Extended-release formulation	Not covered by the quoted claims
Restless legs syndrome use	Not covered by the quoted claims
Current blocking value	None because expired

The patent’s commercial value came from the combination of a direct species claim and a clinically important indication. Its principal weakness was term expiration before the extended-release product’s full commercial life.

Which companies challenged or competed with ropinirole?

The main competitive pressure came from established Parkinson’s treatments rather than direct chemical equivalents alone.

Drug	Company or originator	Pharmacologic class	Competitive position
Ropinirole	SmithKline Beecham, later GSK	Non-ergoline dopamine agonist	Requip and generic ropinirole
Pramipexole	Boehringer Ingelheim	Non-ergoline dopamine agonist	Mirapex and generic pramipexole
Rotigotine	Schwarz Pharma, later UCB	Dopamine agonist patch	Neupro transdermal system
Levodopa/carbidopa	Multiple originators and generic manufacturers	Dopamine precursor plus decarboxylase inhibitor	Core Parkinson’s therapy
Bromocriptine	Multiple companies	Ergot dopamine agonist	Older comparator

Generic manufacturers of ropinirole hydrochloride included major ANDA sponsors such as Teva, Mylan, Watson/Actavis and Sandoz, depending on strength, dosage form and approval timing. The competitive market after patent expiration was primarily a conventional generic market for immediate-release tablets.

What generic launch risks remained after patent expiration?

Patent expiration removed the principal compound-use barrier, but generic manufacturers still faced several practical requirements:

1. FDA ANDA approval and therapeutic-equivalence findings.
2. Bioequivalence across the relevant tablet strengths.
3. Compliance with manufacturing and quality requirements.
4. Labeling alignment with the reference listed drug.
5. Avoidance of unexpired extended-release formulation patents.
6. Proper treatment of any patented indications through labeling carve-outs.
7. Supply-chain and active pharmaceutical ingredient qualification.

The risk profile differed by product:

• Immediate-release generic ropinirole had low patent risk after 2006.
• Extended-release products had higher formulation and delivery-system risk.
• A product labeled for restless legs syndrome required separate analysis of any indication-specific patents.
• Manufacturing patents could create a residual process risk even where the finished-dose product was unpatented.

Were licensing deals or settlement agreements material?

The public commercial history identifies SmithKline Beecham and GlaxoSmithKline as the principal originator interests associated with ropinirole and Requip. Patent 4,824,860 itself did not create a continuing licensing requirement after expiration.

No current license can preserve an expired patent right against generic entry. Historical settlements involving generic applicants, if any, would have been limited by the patent’s April 2006 expiration and would not support present-day exclusivity.

What is the current patent landscape for ropinirole?

The current landscape is segmented by product type rather than dominated by Patent 4,824,860.

Patent category	Relevance today
Original ropinirole Parkinson’s method patent	Expired
Immediate-release tablet patents	Generally no material barrier from Patent 4,824,860
Extended-release formulation patents	Must be assessed separately
Restless legs syndrome use patents	Separate indication analysis
Manufacturing patents	Potentially relevant by supplier and process
Regulatory exclusivity	Expired for the original product
Biosimilar exclusivity	Not applicable

Ropinirole is a synthetic small molecule, not a biologic. Biosimilar concepts under the Public Health Service Act do not apply. Competition proceeds through the ANDA pathway rather than the 351(k) biosimilar pathway.[6]

Key Takeaways

• U.S. Patent 4,824,860 covers Parkinson’s disease treatment with ropinirole-related indolone compounds.
• Claim 1 is a broad genus method claim with structural limits on the indolone, alkyl substituents and side-chain length.
• Claim 2 specifically covers ropinirole free base.
• Claim 3 specifically covers ropinirole hydrochloride, the commercial salt in Requip.
• The patent issued April 25, 1989, and ordinarily expired April 25, 2006.
• The patent is no longer an enforceable barrier to generic immediate-release ropinirole.
• It does not cover restless legs syndrome treatment, extended-release formulations or every ropinirole dosage form.
• Requip XL requires separate analysis of formulation, release-control and dosing patents.
• Ropinirole is a small molecule, so biosimilar analysis is inapplicable.
• Generic entry risks now center on formulation patents, indication-specific patents, manufacturing rights and FDA requirements.

FAQs

Does Patent 4,824,860 claim ropinirole as a chemical compound?

No. The quoted claims are method claims. They cover administering ropinirole and related indolone compounds for Parkinson’s disease rather than claiming possession or manufacture of ropinirole in the broadest product-claim format.

Is ropinirole hydrochloride still patent protected?

Patent 4,824,860 no longer protects ropinirole hydrochloride because it expired in 2006. Separate patents may have covered extended-release formulations or other product features, but they are distinct from this patent.

Could a generic company sell ropinirole for restless legs syndrome under a skinny label?

Potentially, subject to the Orange Book status and expiration of any separate restless-legs-syndrome method patents. Patent 4,824,860 itself is limited to Parkinson’s disease and does not claim RLS treatment.

Does the patent cover ropinirole extended-release tablets?

Not based on the quoted claims. The claims require administration of the compound for Parkinson’s disease but do not recite extended-release technology, dissolution profiles, tablet matrices or once-daily delivery.

Is Patent 4,824,860 relevant to a current Paragraph IV filing?

Not as an enforceable barrier. Because the patent expired in 2006, a current ANDA applicant would ordinarily address it as an expired patent rather than mount a commercially meaningful Paragraph IV challenge.

References

1. United States Patent and Trademark Office. (1989). U.S. Patent No. 4,824,860: Indolone derivatives.
2. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
3. U.S. Food and Drug Administration. (n.d.). Abbreviated new drug application approvals and patent certifications.
4. U.S. Food and Drug Administration. (2007). Requip XL prescribing information. GlaxoSmithKline.
5. U.S. Food and Drug Administration. (n.d.). Requip prescribing information. GlaxoSmithKline.
6. U.S. Food and Drug Administration. (n.d.). Biological product and biosimilar development pathways.

Drugs Protected by US Patent 4,824,860

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: 4,824,860

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	8712073	May 21, 1987

International Family Members for US Patent 4,824,860

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0299602		SPC/GB96/040	United Kingdom
European Patent Office	0299602		97C0036	Belgium
European Patent Office	0299602		C970006	Netherlands
Austria	83659
Australia	1644588
Australia	599792
Canada	1305421