Details for Patent: 4,659,516

Summary for Patent: 4,659,516

Title:	Steroid derivatives
Abstract:	A steroid derivative of the formula: ST-A-X-R1 wherein ST is a 7 alpha -linked steroid nucleus of the general formula: wherein the double bond(s) between carbon atoms 6 and 7 and/or carbon atoms 8 and 9 are optional; wherein the aromatic ring A may optionally bear one or two halogen or alkyl substituents; wherein R3 is hydrogen, alkyl, or acyl; wherein R16 is hydrogen, alkyl or hydroxy; wherein either R17 is hydroxy or acyloxy and R27 is hydrogen, alkyl, alkenyl or alkynyl, or R17 and R27 together form oxo (=O); wherein R18 is alkyl; wherein A is alkylene, alkenylene or alkynylene optionally fluorinated and optionally interrupted by -O-, -S-, -SO-, -SO2-, -CO-, -NR-, -NRCO-, -CONR-, -COO-, -OCO- or phenylene, wherein R is hydrogen or alkyl; wherein R1 is hydrogen, alkyl, alkenyl, cycloalkyl, halogenoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryl, arylalkyl, or dialkylaminoalkyl, or R1 is joined to R2 as defined below; and wherein X is -CONR2-, -CSNR2-, -NR12CO-, -NR12CS-, -NR12 CONR2-, -SO2NR2- or -CO-; or, when R1 is not hydrogen, is -O-, -NR2-, -(NO)R2-, -(PO)R2-, -NR12COO-; -NR12SO2-, -S-, -SO- or -SO2-; wherein R2 is hydrogen or alkyl or R1 and R2 together form alkylene or halogenoalkylene; wherein R12 is hydrogen or alkyl and wherein R22 is hydrogen, cyano or nitro; or a salt thereof when appropriate.
Inventor(s):	Jean Bowler, Brian S. Tait
Assignee:	AstraZeneca UK Ltd , Syngenta Ltd
Application Number:	US06/656,466
Patent Claim Types: see list of patent claims	Use; Composition; Process; Dosage form;

# United States Drug Patent 4,659,516: Claim Scope, Fulvestrant Coverage, Expiration, and Patent Landscape

US Patent 4,659,516 covered a broad class of 7α-substituted estrogenic steroid derivatives with antiestrogenic activity. Its most commercially important compound was fulvestrant, marketed as Faslodex. The patent was assigned to Imperial Chemical Industries PLC and issued on April 21, 1987. Because it was governed by the pre-URAA patent-term regime, its 17-year term expired on April 21, 2004. It no longer creates an enforceable barrier to generic fulvestrant manufacture, marketing, or sale.

The patent had broad historical importance but has no current blocking strength. Later formulation patents, FDA regulatory exclusivities, and product-specific litigation were more commercially relevant to Faslodex after US 4,659,516 expired.

What drug does US Patent 4,659,516 protect?

The patent protects 7α-substituted steroid derivatives designed to function as antiestrogens. Fulvestrant is the principal commercial embodiment.

Fulvestrant is chemically:

7α-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5(10)-triene-3,17β-diol

It is a steroidal estrogen-receptor antagonist and degrader. The compound was developed by Imperial Chemical Industries and later commercialized by AstraZeneca as Faslodex.

Item	Details
US patent	US 4,659,516
Patent title	7α-substituted steroids
Applicant/assignee	Imperial Chemical Industries PLC
Issue date	April 21, 1987
Principal commercial compound	Fulvestrant
Brand	Faslodex
Drug class	Estrogen-receptor antagonist/degrader
Original US regulatory approval	April 25, 2002
US patent expiration	April 21, 2004
Current enforceability	Expired

The patent claims compounds, pharmaceutical compositions, therapeutic use, and manufacturing processes. The claims are not limited to fulvestrant.

What is the scope of claim 1 in US 4,659,516?

Claim 1 is a large Markush claim covering a genus of steroid derivatives with multiple independently variable structural elements.

The core architecture is:

ST-A-X-R1

where:

• ST is a 7α-linked steroid nucleus;
• A is a hydrocarbon or heteroatom-containing linker;
• X is a broad functional connector;
• R1 is a variable terminal substituent;
• salts are included where appropriate.

Steroid nucleus

The steroid nucleus is an estrogenic steroid framework bearing a substituent at the 7α position. The claim permits substantial variation at several steroid positions:

• Optional double bonds between C6-C7 and C8-C9.
• Optional halogen or alkyl substitution on the aromatic A ring.
• R3 substitution, including hydrogen, alkyl, alkanoyl, alkoxycarbonyl, carboxyalkanoyl, or aroyl groups.
• R16 as hydrogen, alkyl, or hydroxy.
• R17 as hydroxy or an esterified hydroxy group.
• R27 as hydrogen, alkyl, alkenyl, or alkynyl.
• A 17-keto configuration where R17 and R27 together form oxo.
• R18 as alkyl.

This structure captures estrane-like and related steroid systems while preserving the 7α side-chain position associated with fulvestrant activity.

Linker A

The A group is one of the broadest claim elements. It can be:

• Straight-chain or branched alkylene;
• Alkenylene;
• Alkynylene;
• Fluorinated versions of those groups;
• A heteroatom-containing chain;
• A chain incorporating oxygen, sulfur, sulfoxide, sulfone, carbonyl, nitrogen, amide, ester, sulfonamide, or phenylene functionality.

The carbon-length limits generally range from one or two carbons up to 14 carbons, depending on the specific linker format.

Fulvestrant uses a long hydrocarbon linker connecting the steroid nucleus to a terminal fluorinated alkyl sulfoxide group. That structure falls within the claim's broad linker and terminal-group definitions.

Connector X

Claim 1 permits numerous connection types, including:

• Amides;
• Thioamides;
• Ureas;
• Guanidine-related structures;
• Sulfonamides;
• Carbonyl groups;
• Amines;
• Oximes or related nitrogen-oxygen structures;
• Phosphorus-containing groups;
• Carbamates;
• Sulfonyl groups;
• Sulfoxides;
• Sulfides;
• Ethers.

This breadth means claim 1 reaches far beyond fulvestrant. A compound could potentially infringe claim 1 without having fulvestrant's sulfoxide, fluorinated tail, or exact steroid substitution pattern.

Terminal group R1

R1 may be:

• Hydrogen;
• Alkyl;
• Alkenyl;
• Cycloalkyl;
• Halogenoalkyl;
• Carboxyalkyl;
• Alkoxycarbonylalkyl;
• Aryl;
• Arylalkyl;
• Dialkylaminoalkyl.

R1 and the adjacent nitrogen may also form a five- to seven-membered heterocyclic ring.

The claim therefore covers a large chemical space that includes hydrophobic alkyl tails, fluorinated alkyl groups, aromatic groups, benzyl groups, and cyclic amine substituents.

How does claim 2 narrow the genus?

Claim 2 narrows the claim 1 genus to compounds with a more defined estrogenic steroid nucleus and a restricted set of side-chain structures.

The claim limits:

• R17 to hydroxy;
• R27 to hydrogen or ethynyl, unless the two groups form a 17-keto group;
• A primarily to -(CH2)n-, where n is 3 to 14;
• Certain sulfur-containing and amide connectors;
• R1 to alkyl, fluoroalkyl, cycloalkyl, phenyl, chlorophenyl, or benzyl groups;
• Nitrogen substituents to smaller alkyl groups.

Fulvestrant falls within the practical scope of claim 2 because it contains:

• A 3,17β-dihydroxy estratriene nucleus;
• A nine-carbon nonyl linker;
• A sulfoxide connector;
• A fluorinated pentyl terminal group.

Claim 2 is materially narrower than claim 1 but still covers a substantial number of possible compounds.

What does claim 3 add?

Claim 3 requires the total carbon count in groups A and R1 to be between 12 and 16 inclusive.

This limitation is commercially important because it narrows the compounds toward a defined hydrophobic side-chain size. Fulvestrant satisfies the limitation based on its nine-carbon steroid-to-sulfoxide linker and five-carbon fluorinated terminal group, subject to the patent's method of counting the relevant groups.

Claim 3 offers a narrower fallback position than claims 1 and 2. It would have been useful in prosecution or litigation if broader claims were challenged for lack of enablement, written description, or prior art.

What compounds are specifically listed in claim 8?

Claim 8 is a species claim directed to named compounds. It includes:

• N-n-butyl-N-methyl steroid undecamides;
• N-heptylfluorobutyl analogues;
• A cyclic tertiary amide;
• Phenylpropionamide derivatives;
• Chlorophenylthio and chlorophenylsulfinyl derivatives;
• Fluorinated alkylsulfinyl derivatives;
• A chlorobenzylsulfinyl derivative;
• A heptylsulfinyl derivative.

The fulvestrant structure is represented by the listed compound:

7α-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(10)-triene-3,17β-diol

Claim 8 is narrower than the Markush claims and identifies specific compounds that were likely supported by examples and biological testing. From a historical enforcement standpoint, the species claim would generally have been easier to defend than the full scope of claim 1.

What does claim 4 protect?

Claim 4 is a process claim. It covers multiple synthetic routes corresponding to the different X groups.

The process alternatives include:

1. Coupling activated carboxylic, thiocarboxylic, or sulfonic acid derivatives with amines.
2. Reacting steroid-linked carboxylic acids with organometallic compounds.
3. Displacing a leaving group with thiols, alcohols, amines, or phosphorous reagents.
4. Acylating or sulfonylating steroid-linked amines.
5. Constructing alkenylene linkers through a Wittig-type reaction.
6. Removing protecting groups.
7. Oxidizing sulfides to sulfoxides or sulfones.
8. Reducing amides to amines.
9. Hydrogenating alkenylene linkers.
10. Converting alcohol or ketone functionality into alternative 17-substituted steroid structures.

Claim 4 does not simply cover the finished drug. It covers specified manufacturing pathways. A generic manufacturer using a materially different process might avoid literal infringement, although the doctrine of equivalents and process-specific claim construction could have been relevant while the patent was in force.

Because the patent expired in 2004, the process claims no longer create current manufacturing risk.

What do claims 5 and 6 protect?

Claims 5 and 6 cover pharmaceutical compositions.

Claim 5 covers a composition containing a claimed steroid derivative with a pharmaceutically acceptable diluent or carrier. Claim 6 narrows the composition to oral administration with 5 to 500 mg of active compound.

These claims do not specifically protect the modern Faslodex injectable formulation. Claim 6 is directed to oral administration, while Faslodex is administered by intramuscular injection.

The composition claims could have covered oral formulations of the claimed compounds, but they expired with the patent in 2004.

What does claim 7 protect?

Claim 7 is a method-of-use claim covering the administration of a claimed steroid derivative to produce an antiestrogenic effect in a warm-blooded animal.

The claim is broad in several respects:

• It is not limited to breast cancer.
• It is not limited to postmenopausal women.
• It does not specify a particular dose.
• It does not require a particular route of administration.
• It is not limited to fulvestrant.

The claim could historically have been asserted against a use involving a compound within claim 1 and an antiestrogenic therapeutic purpose. It would have faced potential issues involving claim construction, prior art, enablement, and the specificity of the claimed therapeutic effect.

The method claim expired on April 21, 2004.

When did US 4,659,516 lose exclusivity?

US 4,659,516 lost patent exclusivity on April 21, 2004.

Milestone	Date
Priority filing in the United Kingdom	June 1983
US application filing	1984
US patent issue	April 21, 1987
Pre-URAA 17-year term	April 21, 2004
Current patent status	Expired

The patent was filed before the June 8, 1995 effective date of the Uruguay Round Agreements Act patent-term change. The applicable US term was generally 17 years from grant, rather than 20 years from the earliest effective filing date.

No patent-term extension under the Hatch-Waxman framework could restore enforceability to the patent after that expiration date.

What is the Orange Book status of US 4,659,516?

US 4,659,516 is historically associated with Faslodex but is not a current enforceable Orange Book barrier. Any historical listing did not extend the patent term.

The relevant regulatory product is:

Regulatory item	Details
Brand	Faslodex
Active ingredient	Fulvestrant
NDA	021344
Sponsor	AstraZeneca
Dosage form	Intramuscular injection
Original approval	April 25, 2002
Current product protection issue	Later formulation and regulatory patents, not US 4,659,516

Orange Book listings must be assessed by patent number, expiration date, use code, and the specific NDA. An expired compound patent cannot block an abbreviated new drug application after expiration, although it may remain visible in historical patent records.

What later patents protected Faslodex?

The main post-expiration patent issue was the injectable formulation rather than the original steroid compound genus.

US Patent 6,774,122

US 6,774,122 covered fulvestrant formulations, including pharmaceutical compositions designed to deliver the poorly water-soluble active ingredient by intramuscular injection. The formulation used a vehicle system involving components such as:

• Fulvestrant;
• An alcohol cosolvent;
• Benzyl benzoate;
• Castor oil or another pharmaceutically suitable vehicle.

The patent had a later expiration date than US 4,659,516 and was the principal formulation patent relevant to generic injectable fulvestrant competition. Its term expired in 2021, subject to any applicable patent-term adjustment or regulatory calculations shown in the official patent and Orange Book records.

Regulatory exclusivity

Faslodex received FDA approval in 2002. FDA regulatory exclusivity was separate from patent protection and did not extend the expired term of US 4,659,516. Later indications, including combination-use indications with CDK4/6 inhibitors, could generate separate regulatory and method-of-use issues, but they did not revive the original compound patent.

Were there Paragraph IV challenges to fulvestrant patents?

Generic fulvestrant applicants targeted the later formulation patent rather than US 4,659,516 because the compound patent had expired.

The commercial litigation pattern was therefore:

1. ANDA filing for generic fulvestrant injection.
2. Paragraph IV certification against one or more listed formulation patents.
3. Patent-holder litigation under Hatch-Waxman.
4. A 30-month stay or other statutory litigation consequence where applicable.
5. Generic launch following patent expiration, settlement, judgment, or regulatory clearance.

Known generic competitors have included Sandoz, Teva, Mylan/Viatris, Amneal, and other injectable-drug manufacturers. The competitive dispute centered on formulation design, patent listing scope, and the timing of generic approval.

A Paragraph IV certification against a later formulation patent did not establish any continuing right under US 4,659,516. The expired patent was relevant as prior patent history and as evidence of the original compound disclosure, not as a live litigation asset.

Which companies challenged the Faslodex patent estate?

The main competitive group consisted of:

Company	Role in the landscape
AstraZeneca	Faslodex sponsor and holder of later product-related rights
Sandoz	Generic fulvestrant applicant and commercial competitor
Teva	Generic injectable-drug competitor
Mylan/Viatris	Generic fulvestrant competitor
Amneal	Generic injectable-drug competitor
Other ANDA sponsors	Potential applicants after formulation-patent expiry

The relevant challenges were directed primarily to injectable formulation patents and related Orange Book listings. There was no meaningful current challenge to US 4,659,516 because its patent term had already expired.

How strong was the patent estate for fulvestrant?

The historical estate was strong at the compound level because US 4,659,516 claimed both a broad genus and specifically identified embodiments, including fulvestrant. Its commercial weakness was timing: the patent expired before Faslodex achieved its later-market revenue scale.

Estate component	Historical strength	Current strength
Broad steroid genus	High breadth, potential validity exposure	None
Fulvestrant species claim	Stronger than genus claims	None
Manufacturing process claims	Dependent on process used	None
Oral composition claims	Narrow commercial relevance	None
Antiestrogen method claim	Broad therapeutic scope	None
Injectable formulation patents	Commercially important after 2004	Expired by 2021 for principal formulation protection
Biosimilar protection	Not applicable to a small-molecule drug	Not applicable

The primary legal weakness of the original patent was overbreadth. Claim 1 covers many combinations of steroid nuclei, linkers, connectors, and terminal groups. Such claims can face written-description and enablement challenges if the specification does not adequately support the full genus. Claim 8 had a more defensible species-level profile because it identified specific compounds.

What generic launch risks existed?

For a generic manufacturer, the risk profile changed over time:

Before April 2004

A manufacturer faced direct infringement risk from:

• The fulvestrant species claim;
• The broader genus claims;
• The formulation claims;
• The method-of-use claim;
• Potentially the process claims.

Between 2004 and 2021

The original compound patent no longer blocked entry. The principal risks were:

• Injectable formulation patents;
• Orange Book use codes;
• Regulatory exclusivity;
• Manufacturing-process patents;
• Supply-chain access to fulvestrant and injectable excipients.

After 2021

The principal patent-based barriers were substantially reduced. Remaining risks could include:

• Unexpired formulation or device patents;
• New method-of-use patents;
• Trade secrets relating to manufacturing;
• Regulatory deficiencies;
• Product-quality and injectable-manufacturing requirements.

Because fulvestrant is a small-molecule drug, biosimilar litigation is irrelevant. The relevant pathway is an ANDA for a generic drug, not a 351(k) biosimilar application.

What manufacturing and IP barriers remain?

The expired compound patent does not eliminate technical barriers. Fulvestrant is difficult to formulate because of its poor aqueous solubility and the need for a stable depot injection.

A generic manufacturer must address:

• Sterile manufacturing;
• Consistent particle or solution characteristics;
• Intramuscular depot performance;
• Excipient compatibility;
• Container-closure integrity;
• Extractables and leachables;
• Assay and impurity control;
• Batch-to-batch reproducibility;
• Bioequivalence for a complex injectable formulation.

These technical issues can create practical entry barriers even when compound and formulation patents have expired. They are regulatory and manufacturing barriers, not continuing rights under US 4,659,516.

How does US 4,659,516 compare with later Faslodex patents?

Issue	US 4,659,516	Later formulation patents
Primary subject	Steroid compounds and uses	Injectable fulvestrant formulations
Fulvestrant coverage	Direct, including named species	Product-specific formulation coverage
Claim breadth	Very broad Markush genus	Narrower composition and formulation claims
Commercial relevance	Foundational compound protection	Main post-2004 entry barrier
Expiration	April 21, 2004	Principal formulation protection expired in 2021
ANDA relevance today	None	Historical and potentially limited residual relevance
Biosimilar relevance	None	None
Litigation focus	Historical compound protection	Paragraph IV formulation disputes

Key Takeaways

• US 4,659,516 is the foundational fulvestrant compound patent.
• Claim 1 covers a broad genus of 7α-substituted steroid derivatives.
• Claims 2 and 3 narrow the genus through linker, substituent, and carbon-count limitations.
• Claim 8 specifically names fulvestrant and related steroid derivatives.
• Claim 4 covers multiple manufacturing routes.
• Claims 5 and 6 cover pharmaceutical compositions, including oral compositions.
• Claim 7 covers antiestrogenic therapeutic use.
• The patent expired on April 21, 2004.
• It has no current blocking effect on generic fulvestrant entry.
• Later injectable formulation patents, particularly US 6,774,122, were more important to post-2004 market protection.
• Fulvestrant is a small molecule, so biosimilar risk analysis does not apply.
• Current competition is governed primarily by generic injectable-drug regulation, manufacturing capability, formulation know-how, and any remaining product-specific rights.

FAQs

What is the expiration date of fulvestrant patent US 4,659,516?

The patent expired on April 21, 2004, based on the pre-URAA 17-year term measured from its issue date.

Does US 4,659,516 cover Faslodex injections?

It covers the fulvestrant active ingredient and broad steroid derivatives, but it is not limited to the Faslodex injectable formulation. Later formulation patents addressed the injection vehicle and delivery composition.

Can a generic company still infringe US 4,659,516?

No enforceable infringement claim can be brought under an expired patent. The patent may remain relevant as prior art, but it cannot block current commercial activity.

Is fulvestrant subject to biosimilar competition?

No. Fulvestrant is a chemically synthesized small-molecule drug. Competitors file ANDAs for generic fulvestrant rather than biosimilar applications.

What was the main patent obstacle to generic Faslodex?

The principal post-expiration obstacle was the injectable formulation patent estate, including US 6,774,122, rather than the expired compound patent US 4,659,516.

References

1. AstraZeneca Pharmaceuticals LP. (2002). Faslodex (fulvestrant) injection prescribing information. U.S. Food and Drug Administration.

2. Imperial Chemical Industries PLC. (1987). 7α-substituted steroids, U.S. Patent No. 4,659,516. U.S. Patent and Trademark Office.

3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA Center for Drug Evaluation and Research.

4. U.S. Patent and Trademark Office. (2024). Patent term calculator and patent term adjustment resources. U.S. Department of Commerce.

5. U.S. Patent and Trademark Office. (2002). Fulvestrant formulations, U.S. Patent No. 6,774,122. U.S. Patent and Trademark Office.

Drugs Protected by US Patent 4,659,516

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: 4,659,516

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	8327256	Oct 12, 1983

International Family Members for US Patent 4,659,516

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0138504		SPC/GB04/009	United Kingdom
European Patent Office	0138504		91068	Luxembourg
European Patent Office	0138504		300158	Netherlands
European Patent Office	0138504		2004C/004	Belgium
Austria	35814
Germany	122004000011