US Patent 4,418,068: Scope, Claims, Expiration, and Raloxifene Patent Landscape

US Patent 4,418,068 is an expired Eli Lilly patent covering substituted 2-phenyl-3-aroylbenzo[b]thiophenes, including raloxifene and several prodrug, ether, ester, and acid-addition-salt forms. The patent also covers antiestrogenic and antiandrogenic pharmaceutical compositions and treatment methods for estrogen- or androgen-dependent diseases.

The patent issued on November 29, 1983, and its ordinary 17-year patent term expired on November 29, 2000. It is no longer an enforceable barrier to manufacture, sale, or use in the United States. The patent’s historical importance is substantial because it disclosed and claimed the active pharmaceutical ingredient later developed as raloxifene hydrochloride, marketed as Evista. Its current commercial value is limited to prior-art, freedom-to-operate, and patent-history analysis.

What drug and chemical class does US 4,418,068 protect?

The patent protects a family of substituted benzothiophenes with the following core structure:

A benzo[b]thiophene nucleus.
A phenyl substituent at the 2-position.
A benzoyl substituent at the 3-position.
A piperidinoethoxy substituent on the benzoyl phenyl ring.
Variable substitution at the phenolic positions.

The principal compound identified in claim 3 is:

6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene

This compound is raloxifene in its free-base form. The hydrochloride salt is raloxifene hydrochloride, the active ingredient in Evista.

What is the relationship between US 4,418,068 and raloxifene?

US 4,418,068 is an early composition-of-matter and therapeutic-use patent for raloxifene-type benzothiophenes. Claim 3 specifically covers the raloxifene free base or a physiologically acceptable acid-addition salt. Claim 26 extends the same subject matter to pharmaceutical compositions, and claims 53 and 54 extend it to therapeutic use and the hydrochloride salt.

Raloxifene is a selective estrogen receptor modulator. It has estrogen-antagonist activity in breast tissue and estrogen-agonist or partial agonist activity in bone. The patent itself describes broader antiestrogenic and antiandrogenic activity, including treatment of breast and prostate disorders.

How many patents cover the core chemical subject matter?

US 4,418,068 contains 62 claims, but the claims form a nested hierarchy rather than 62 independent chemical inventions.

Claim group	Subject matter	Commercial relevance
Claims 1-23	Compounds and salts	Core chemical protection
Claims 3, 20-23	Named raloxifene and specific derivatives	Direct molecule and analog coverage
Claims 24-38	Pharmaceutical compositions	Formulation and composition coverage
Claims 39-62	Therapeutic methods	Estrogen- and androgen-dependent disease treatment
Claims 17-19	Free bases and acid-addition salts	Salt-form coverage, including hydrochloride

The strongest claims historically were claims 3, 19, 26, 27, 53, and 54 because they specifically identify raloxifene or raloxifene hydrochloride. The broadest generic coverage appears in claims 1, 2, 24, 25, and 39, subject to the structural definitions represented by the omitted chemical formulae.

What chemical structures are covered by the claims?

Claim 1: broad substituted benzothiophene genus

Claim 1 covers a compound represented by the patent’s first structural formula, together with:

Physiologically acceptable esters;
Physiologically acceptable ethers; and
Physiologically acceptable acid-addition salts.

The claim is a composition-of-matter claim. It does not require a pharmaceutical composition or a therapeutic use.

Because the structural formula is not reproduced in the supplied claim text, the full ring-substitution limits cannot be independently reconstructed from the text alone. The named compounds and dependent claims establish that the claimed scaffold includes the raloxifene arrangement.

Claim 2: substitution at the two hydroxy positions

Claim 2 defines R and R1 independently as:

Hydrogen;
-COR2; or
R3.

R2 may be:

Hydrogen;
C1-C14 alkyl;
C1-C3 chloroalkyl;
C1-C3 fluoroalkyl;
C5-C7 cycloalkyl;
C1-C4 alkoxy;
Phenyl; or
Mono- or disubstituted phenyl.

The permitted phenyl substituents include alkyl, alkoxy, hydroxy, nitro, chloro, fluoro, and trichloromethyl or trifluoromethyl groups.

R3 may be:

C1-C4 alkyl;
C5-C7 cycloalkyl; or
Benzyl.

This creates a broad set of protected derivatives, including phenolic esters, carbonates or carbamates depending on the precise structural formula, ethers, and alkyl or benzyl derivatives.

Claims 3 and 20-23: specifically named compounds

The patent expressly claims five important embodiments:

Claim	Named compound
3	Raloxifene free base or acceptable acid-addition salt
20	6-acetoxy-2-(4-acetoxyphenyl) derivative
21	6-benzoyloxy-2-(4-benzoyloxyphenyl) derivative
22	6-ethoxycarbonyloxy-2-(4-ethoxycarbonyloxyphenyl) derivative
23	6-methoxy-2-(4-methoxyphenyl) derivative

These claims are narrower than the genus claims but provide clearer protection for specific analogs. Claims 20-23 are important from a historical medicinal-chemistry perspective because they cover derivatives that could have been evaluated as prodrugs, analytical standards, intermediates, or alternative active forms.

Do the claims cover raloxifene hydrochloride?

Yes. The patent covers raloxifene hydrochloride through multiple claim paths.

Claim 3 covers raloxifene and physiologically acceptable acid-addition salts.
Claim 18 covers a physiologically acceptable acid-addition salt.
Claim 19 specifically identifies the hydrochloride.
Claim 26 covers a composition containing raloxifene or an acceptable salt.
Claim 27 specifies the hydrochloride composition.
Claim 53 covers raloxifene or an acceptable salt in the treatment method.
Claim 54 specifies the hydrochloride in that method.

The hydrochloride is therefore covered as both a chemical form and a pharmaceutical composition ingredient.

What formulations are protected by US 4,418,068?

The formulation claims are relatively broad. Claim 24 covers an antiestrogenic and antiandrogenic pharmaceutical composition containing:

A pharmaceutically acceptable diluent; and
An effective amount of a claimed compound, ester, ether, or acid-addition salt.

The patent does not appear, from the supplied claims, to require a particular tablet, capsule, coating, dissolution profile, excipient, particle size, polymorph, or release mechanism.

Formulation coverage by claim group

Claims	Formulation scope
24-25	Broad composition claims
26-27	Raloxifene, specifically the hydrochloride
28-35	Derivatives with identical substituents and acyl groups
36-37	Alkyl or related ether derivatives
38	Compounds with one unsubstituted phenolic position

The phrase “pharmaceutically acceptable diluent” is broad but does not automatically cover every later formulation innovation. A later patent directed to a specific polymorph, particle-size distribution, excipient system, dosage form, or manufacturing process would require separate analysis.

The supplied text contains apparent transcription errors. Claim 36 states “wherein R and R1 and R3,” which is grammatically incomplete. The likely intended language is that R and R1 are R3-type groups. This defect does not affect the principal claims covering raloxifene hydrochloride.

What diseases and methods are protected?

Claims 39-62 cover treatment methods for pathological conditions of endocrine target organs that are dependent, or partially dependent, on estrogen or androgen.

Estrogen-related indications

The patent identifies:

Mammary cancer;
Fibrocystic breast disease; and
Other estrogen-dependent pathological conditions.

The claimed dose ranges are:

Broad range: approximately 0.05 to 50 mg/kg/day.
Breast disease range: approximately 0.1 to 10 mg/kg/day.

Androgen-related indications

The patent identifies:

Prostatic cancer;
Benign prostatic hypertrophy; and
Other androgen-dependent pathological conditions.

The claimed dose ranges are:

Broad range: approximately 0.05 to 50 mg/kg/day.
Prostate disease range: approximately 0.1 to 10 mg/kg/day.

The method claims are not limited to raloxifene hydrochloride. They reach the broader compound genus, including esters, ethers, salts, and the specifically named derivatives.

When did US 4,418,068 lose exclusivity?

US 4,418,068 issued on November 29, 1983. Because it was filed before June 8, 1995, its ordinary United States term was generally 17 years from grant rather than 20 years from filing. On that basis, the patent expired on November 29, 2000. [1]

Event	Date
Earliest priority period	1979
United States filing period	1980
Patent issued	November 29, 1983
Ordinary 17-year expiration	November 29, 2000
Current status	Expired

No current patent-enforcement right arises from the expired patent. A patent expiration analysis should still distinguish this patent from later patents covering raloxifene formulations, polymorphs, medical uses, or manufacturing methods.

What was the FDA status of raloxifene?

The FDA approved raloxifene hydrochloride under the brand name Evista. The original indication was reduction in the risk of invasive breast cancer in postmenopausal women with osteoporosis or high risk of invasive breast cancer. The drug is also used for osteoporosis-related indications. [2]

FDA item	Status
Active ingredient	Raloxifene hydrochloride
Drug class	Selective estrogen receptor modulator
Original sponsor	Eli Lilly
Reference product	Evista
FDA pathway	NDA
Initial approval	1997
Dosage form	Oral tablet
Common strength	60 mg

The current regulatory status is separate from the patent status. FDA approval does not preserve an expired patent, and patent expiration does not eliminate regulatory requirements for an abbreviated new drug application.

What is the Orange Book status of raloxifene?

The Orange Book identifies FDA-approved drug products and relevant patent or exclusivity information. For an older product such as Evista, the original composition patent is no longer a live Orange Book barrier. Any later-listed patent must be evaluated separately by patent number, listed use, expiration date, and whether the patent is still active.

The key implications are:

US 4,418,068 is expired.
It should not create a current Paragraph IV litigation risk.
A generic applicant would not need to certify against this patent as an unexpired barrier.
Any remaining challenge would involve later-listed patents, if any, rather than US 4,418,068 itself.

Orange Book records can change by supplement and product listing. The legal status of a specific generic application depends on the patents listed against the relevant reference-listed drug and dosage form. [3]

Are there Paragraph IV challenges to US 4,418,068?

No current Paragraph IV challenge to US 4,418,068 has meaningful commercial significance because the patent expired in 2000.

A Paragraph IV certification is relevant only to an unexpired patent listed for an approved drug. A generic applicant may certify that a listed patent is invalid, unenforceable, or will not be infringed. That mechanism has no practical role for an expired patent.

Historically, generic raloxifene litigation focused on later-listed patents or product-specific regulatory issues rather than continued enforcement of US 4,418,068. The expired patent may still be cited in invalidity arguments against later patents, particularly for claims directed to known raloxifene compositions, salts, or uses.

Which companies challenged the raloxifene patent estate?

The principal commercial originator was Eli Lilly. Generic competition has involved companies seeking approval for raloxifene hydrochloride tablets after expiration of the core patent and any applicable later protections.

The original patent does not create a current competitor-specific barrier. Any company with an approved or pending generic product would assess:

Active Orange Book patents;
Paragraph IV certifications;
30-month stays;
Pediatric exclusivity;
Formulation or polymorph patents;
Manufacturing-process patents; and
State and federal regulatory requirements.

Because the core composition patent expired more than two decades ago, the competitive landscape is primarily a generic oral solid-dose market rather than a patent-protected innovator market.

What licensing deals are associated with US 4,418,068?

The patent was associated with Eli Lilly’s development and commercialization of raloxifene. Publicly relevant commercialization rights centered on Lilly’s Evista program. The supplied record does not establish a current license, assignment, or royalty obligation attached to the expired patent.

Any historical assignment or license would not restore patent exclusivity after expiration. Contractual obligations can survive patent expiration in limited circumstances, but they cannot be inferred from the claims or patent record alone. The patent’s present value is therefore not based on an enforceable royalty right.

How strong was the patent estate?

Historical strength

The estate was strong during its enforceable term because it combined:

Composition-of-matter claims;
Specific claims to raloxifene;
Hydrochloride-salt claims;
Pharmaceutical-composition claims;
Anti-estrogen treatment claims;
Anti-androgen treatment claims; and
Claims to multiple prodrug and derivative structures.

Composition claims generally provide the strongest protection because they can block manufacture, sale, or use of the compound regardless of a particular indication.

Current strength

The current enforceability rating is zero for US 4,418,068 because the patent expired.

Category	Historical assessment	Current assessment
Core molecule	Strong	Expired
Hydrochloride salt	Strong	Expired
General composition	Moderate to strong	Expired
Method of treatment	Moderate	Expired
Specific ester and ether derivatives	Moderate	Expired
Formulation protection	Limited by broad claim language	Expired
Generic entry barrier	High before expiration	None from this patent

What generic launch risks exist for raloxifene?

US 4,418,068 does not create a present generic launch risk. The relevant risks are regulatory, commercial, and any rights under later patents.

Generic launch scenarios

Scenario	Effect of US 4,418,068
ANDA for raloxifene hydrochloride tablet	No barrier
Paragraph III certification	Not required for this expired patent
Paragraph IV certification	No current significance
Generic launch after later patent expiry	Depends on later patents
New raloxifene formulation	Requires separate patent review
New indication	Requires separate method-of-use review
Raloxifene manufacturing process	Requires separate process-patent review

The main technical barrier is not the expired chemical patent. It is the ability to demonstrate pharmaceutical equivalence, bioequivalence, product quality, and compliant manufacturing for the approved reference product.

What manufacturing and IP barriers remain?

The expired patent does not prevent manufacture of raloxifene hydrochloride. A current freedom-to-operate review would instead focus on:

Synthetic routes and process conditions;
Starting materials and intermediates;
Crystalline forms and polymorphs;
Salt selection and purification;
Impurity controls;
Particle engineering;
Tablet formulation;
Coating systems;
Stability processes;
Analytical methods; and
Manufacturing jurisdictions.

A process patent can create a separate risk even where the composition patent has expired. The same applies to a patent on a crystalline form or a specific formulation. A generic manufacturer can avoid some process risk by using a non-infringing route, but that requires claim-by-claim comparison against active patents.

How does US 4,418,068 compare with later raloxifene patents?

US 4,418,068 is the foundational compound patent. Later patents, where applicable, generally have narrower subject matter.

Patent category	Typical scope	Relative strength
Early compound patent	Broad chemical genus and named molecule	Highest historical value
Salt patent	Specific salt or preparation	Narrower
Polymorph patent	Crystal form or solid-state property	Product-specific
Formulation patent	Excipients, release, dosage form	Narrower but commercially targeted
Method patent	Specific indication or patient population	Depends on label and use
Process patent	Synthetic route or purification	Manufacturing-specific

A later patent cannot extend the term of US 4,418,068. It must stand on its own validity, enforceability, and infringement case.

Key Takeaways

US 4,418,068 covers raloxifene-type substituted benzothiophenes.
Claim 3 specifically covers raloxifene, including acceptable acid-addition salts.
Claim 19 specifically identifies the hydrochloride salt.
Claims 24-38 cover pharmaceutical compositions.
Claims 39-62 cover antiestrogenic and antiandrogenic treatment methods.
The patent issued on November 29, 1983.
Its ordinary United States term expired on November 29, 2000.
It is not a current Orange Book or Paragraph IV barrier.
Generic raloxifene entry is not blocked by this patent.
Current freedom-to-operate risk must be assessed against later patents covering formulations, polymorphs, processes, or specific uses.
The patent’s strongest historical protection was its composition-of-matter coverage for raloxifene and its hydrochloride.

FAQs

Does US 4,418,068 cover Evista?

Yes. The patent covers raloxifene and raloxifene hydrochloride, the active ingredient in Evista. The relevant claims include claims 3, 19, 26, 27, 53, and 54.

Can a company manufacture raloxifene after US 4,418,068 expired?

Yes, expiration removes the patent’s composition, salt, composition, and method claims as barriers. The manufacturer must still comply with FDA requirements and avoid infringement of later unexpired patents.

Is raloxifene hydrochloride a separate invention from raloxifene?

Raloxifene hydrochloride is an acid-addition salt of raloxifene. US 4,418,068 expressly covers physiologically acceptable acid-addition salts and specifically identifies the hydrochloride.

Does the patent cover raloxifene osteoporosis treatment?

The patent claims estrogen-dependent endocrine conditions and identifies breast disorders in the supplied claims. It does not expressly recite every later FDA-approved osteoporosis indication in the listed claims. Later-use analysis must therefore distinguish the patent’s claim language from the subsequent Evista label.

Does expiration of the core raloxifene patent eliminate all patent risk?

No. It eliminates the risk from US 4,418,068. Later patents may cover crystalline forms, formulations, manufacturing processes, analytical methods, or specific medical uses.

References

Eli Lilly and Company. (1983). 2-Phenyl-3-aroylbenzothiophenes, U.S. Patent No. 4,418,068. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (2020). Evista (raloxifene hydrochloride) prescribing information. FDA.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	14429	⤷ Start Trial
Austria	17243	⤷ Start Trial
Australia	555658	⤷ Start Trial
Australia	8226582	⤷ Start Trial
Bulgaria	37378	⤷ Start Trial
Canada	1167036	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,418,068

Summary for Patent: 4,418,068