United States Patent 6,458,811: Raloxifene Particle-Size, Crystal-Form, Formulation and Method-of-Use Analysis

U.S. Patent 6,458,811 covers particulate raloxifene hydrochloride, particularly non-solvated crystalline raloxifene hydrochloride with defined particle-size distributions and a specified copper-radiation X-ray diffraction pattern. The patent also claims pharmaceutical formulations and methods for osteoporosis, serum-lipid reduction and breast-cancer prevention.

The patent is associated with raloxifene hydrochloride, marketed by Eli Lilly and Company as Evista. Its commercial exclusivity has ended. Generic raloxifene products entered the U.S. market years before the present date, and U.S. Patent 6,458,811 should be treated as expired or no longer capable of blocking ordinary U.S. generic entry, subject to confirmation from the USPTO term-adjustment record and any terminal disclaimer.

What drug and molecular form does U.S. Patent 6,458,811 protect?

The claimed active pharmaceutical ingredient is raloxifene hydrochloride, chemically identified in the claims as:

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

Raloxifene is a selective estrogen receptor modulator, or SERM. Evista was approved for osteoporosis-related indications and later received approval for reducing the risk of invasive breast cancer in certain postmenopausal women. The drug also has lipid-related pharmacological effects, although serum-lipid reduction is not the principal current commercial indication.

The patent does not claim every form of raloxifene hydrochloride in an unrestricted manner. Its central limitation is physical form:

Claim element	Scope
Chemical identity	Raloxifene, including pharmaceutically acceptable salts and solvates
Particle form	Particulate material
Mean particle size	Less than about 25 microns in claim 1
Preferred mean size	About 5 to about 20 microns in claims 2 and 7
Particle-size distribution	At least about 90% below 50 microns in claim 1
Narrower distribution	At least about 90% below 35 microns in claims 3 and 7
Crystal form	Non-solvated crystalline raloxifene hydrochloride
Structural fingerprint	Specified X-ray diffraction pattern using copper radiation
Product use	Pharmaceutical formulations and specified treatment methods

How many patents cover raloxifene and what role does Patent 6,458,811 play?

Raloxifene was protected by a layered patent estate rather than by a single patent. The principal layers were:

Early composition-of-matter patents covering benzothiophene SERMs and raloxifene-related compounds.
Drug-specific patents covering raloxifene hydrochloride.
Formulation and physical-property patents, including particle-size and crystalline-form claims.
Method-of-use patents for osteoporosis, lipid effects and breast-cancer risk reduction.
Regulatory exclusivity associated with the Evista NDA.

Patent 6,458,811 belongs primarily to the third and fourth categories. It is not the foundational composition-of-matter patent for the raloxifene molecule. Its commercial value came from limiting the physical form of raloxifene used in an oral pharmaceutical product and from coupling that form with treatment methods.

The patent therefore had greater relevance to generic product development than to research involving raloxifene as a chemical entity. A generic manufacturer could not avoid the patent merely by using the same active ingredient if its manufacturing process produced the claimed particle-size distribution or crystalline form.

What are the independent claims of U.S. Patent 6,458,811?

The patent contains three principal independent claim groups.

Claim 1: particulate raloxifene

Claim 1 covers:

a compound of formula I;
pharmaceutically acceptable salts and solvates;
the compound in particulate form;
mean particle size below about 25 microns; and
at least 90% of particles below about 50 microns.

This claim is broad relative to claims 2 through 11 because it does not require the narrower 5-to-20-micron range or the specified crystalline hydrochloride form. It potentially reaches multiple salt or solvate states, provided the relevant material satisfies the particle-size limitations.

The claim has two independent quantitative limitations. A product must satisfy both the mean-size requirement and the cumulative particle-size requirement. A mean particle size below 25 microns alone would not establish infringement if 90% or more of the particles were not below 50 microns.

Claim 7: narrower crystalline hydrochloride particle claim

Claim 7 narrows the subject matter to:

non-solvated crystalline hydrochloride salt;
mean particle size of about 5 to about 20 microns; and
at least 90% of particles below about 35 microns.

This is the commercially more important physical-form claim because it is directed to the specific crystalline hydrochloride used in the marketed product and imposes a tighter size distribution.

Claims 4 and 8: X-ray-defined crystal form

Claims 4 and 8 require the non-solvated crystalline hydrochloride to have substantially the listed X-ray diffraction pattern obtained with copper radiation.

The strongest identifying peaks include the following d-line spacings:

d-spacing, angstroms	Relative intensity
13.3864	71.31
9.3598	33.16
6.6346	51.04
5.6467	38.47
4.6614	57.50
4.2516	69.99
4.2059	57.64
4.1740	65.07
3.9673	22.53
3.9318	100.00
3.7096	33.38
3.6561	21.65

The highest-intensity peak is at approximately 3.9318 angstroms. The use of “substantially” gives the claims some tolerance for ordinary analytical variation, but it does not convert the claims into coverage of every polymorph or amorphous form of raloxifene hydrochloride.

What formulations are protected by Patent 6,458,811?

Claims 5, 6, 9 and 10 cover pharmaceutical formulations and compositions containing the claimed raloxifene material with conventional pharmaceutical excipients.

The claims do not require a specific tablet, capsule, excipient, dissolution profile or manufacturing process. They require use of the claimed raloxifene physical form in a pharmaceutical composition.

Potentially relevant formulation components include:

fillers and diluents;
binders;
disintegrants;
lubricants;
coating materials;
stabilizers;
preservatives; and
other pharmaceutically acceptable excipients.

The formulation claims are subordinate to the active-material limitations. A tablet containing raloxifene hydrochloride would not infringe merely because it is an oral tablet. The material incorporated into the tablet must satisfy the applicable particle-size and, for claims 5 and 9, crystalline-form limitations.

This creates an important design-around distinction. A generic developer might avoid a particle-size claim by controlling milling, crystallization or agglomeration so that the final active ingredient falls outside the claimed distribution. That strategy would require validated particle-size testing because infringement may depend on the material as used in the finished formulation, not only on the material at an earlier manufacturing stage.

How important are the X-ray diffraction limitations?

The X-ray limitations create a technical boundary around a particular crystalline form. They are useful for distinguishing:

non-solvated crystalline raloxifene hydrochloride from solvated forms;
one polymorph from another;
crystalline material from amorphous material; and
the claimed form from mixtures with materially different diffraction patterns.

The phrase “having substantially the following X-ray diffraction pattern” raises ordinary claim-construction issues:

Which peaks are legally essential?
How much positional shift is permitted?
How much relative-intensity variation is acceptable?
Can a mixture containing the claimed form infringe?
What analytical protocol, sample preparation and instrument resolution apply?

A patent-holder infringement case would likely require comparative powder X-ray diffraction testing, together with evidence addressing sample preparation, instrument calibration, radiation source, peak assignment and statistical variation.

The claims are more vulnerable if the listed pattern is treated as requiring an exact peak-for-peak match. They are stronger if the court treats “substantially” as allowing normal experimental deviation while preserving the identifying peak set.

What method-of-use patents does Patent 6,458,811 cover?

Claims 12 through 17 cover three treatment categories.

Claims	Method
12 and 15	Inhibiting osteoporosis
13 and 16	Lowering serum lipid levels
14 and 17	Preventing breast cancer

Claims 12 through 14 depend on claim 1. Claims 15 through 17 depend on claim 7. The use claims therefore inherit the relevant physical-form limitations.

A method claim would generally require proof that:

the accused product contains the claimed raloxifene form;
the product is administered to the specified patient or person in need;
the administration is for the claimed therapeutic purpose; and
the required particle-size limitations are satisfied.

For generic manufacturers, induced-infringement exposure would depend heavily on the product label, promotional materials and the indication for which FDA approval was obtained. A label that includes only a non-patented indication can reduce method-of-use risk, but it does not eliminate direct or induced-infringement issues where the product is used for the patented indication.

When did U.S. Patent 6,458,811 expire?

Patent 6,458,811 issued on October 1, 2002. Its term was governed by the modern 20-year patent-term framework, calculated from the relevant earliest nonprovisional or international filing date, subject to patent-term adjustment and any terminal disclaimer.

Public patent records place the ordinary expiration of this patent in approximately the 2019-2020 period. The operative date is the expiration date shown in the USPTO Patent Center and applicable patent-term calculation record. The patent is not a current barrier to a conventional U.S. generic raloxifene launch.

The patent’s expiration must be distinguished from FDA regulatory exclusivity:

Protection	Commercial effect
Original composition patents	Protected the molecule and early raloxifene products
Patent 6,458,811	Protected selected physical forms, formulations and uses
NDA exclusivity	Restricted certain FDA approvals for a limited period
Current status	Generic raloxifene is commercially available

What is the FDA and Orange Book status of raloxifene?

Evista was approved under NDA 020815. The reference product is raloxifene hydrochloride tablets, including 60-mg oral tablets. FDA approval established the regulatory pathway for ANDA products referencing Evista.

Raloxifene is a small-molecule drug. It is not a biologic, so biosimilar regulation under the Public Health Service Act does not apply. Competing products proceed through the ANDA pathway, subject to bioequivalence and applicable labeling requirements.

The Orange Book historically listed patents associated with Evista and its approved uses. Orange Book listing is not permanent proof of enforceability. A listed patent can expire, be delisted, be subject to a statutory expiration date, or remain relevant only to a particular indication.

For a current commercial assessment, the relevant questions are:

whether Patent 6,458,811 remains listed;
whether its listed expiration date has passed;
whether any pediatric exclusivity attached;
whether other active patents remain listed for the reference product; and
whether a generic label includes or carves out protected uses.

The existence of an Orange Book listing would not revive an expired patent.

Which companies challenged the Evista patent estate?

Generic competition to raloxifene included major ANDA applicants and generic manufacturers such as Teva and other suppliers. Patent challenges generally could take the form of:

Paragraph IV certifications asserting invalidity, unenforceability or noninfringement;
Paragraph III certifications accepting a later patent date;
section viii statements carving out patented indications; or
post-expiration commercial launches.

The principal legal theories available against Patent 6,458,811 included:

Anticipation based on prior disclosure of the claimed particle-size distribution or crystalline form.
Obviousness based on routine micronization, crystallization and particle-size optimization.
Indefiniteness involving “about,” “substantially” and measurement methodology.
Written-description or enablement challenges to the full scope of formula I, salts and solvates.
Noninfringement based on particle-size results or a different crystal form.
Lack of induced infringement based on a carved-out generic label.

No current generic-launch restriction should be inferred from historical Paragraph IV litigation. Once the patent term ended, the practical value of those defenses became secondary to ordinary post-expiration entry.

How strong was the patent estate?

Strengths

The patent had several characteristics favorable to enforcement during its term:

It targeted a commercially important active pharmaceutical ingredient.
It included quantitative particle-size limitations.
Claims 4 and 8 supplied a physical fingerprint for the crystalline form.
The formulation claims reached finished pharmaceutical products.
The method claims covered multiple clinical uses.
Particle size and polymorph identity can be tested analytically.

Weaknesses

The principal weaknesses were:

Particle-size limitations can often be designed around.
“About” creates boundary disputes.
“Substantially” in an X-ray pattern claim can create evidentiary uncertainty.
Routine micronization and crystallization could support obviousness arguments.
The claims depend on analytical methods that may produce different results across laboratories.
Method claims can be narrowed by a generic label.
The patent did not broadly control all raloxifene molecules, all salts or all formulations.

Overall, Patent 6,458,811 was a targeted secondary patent. It could materially delay or complicate generic development while enforceable, but it was not a durable substitute for composition-of-matter protection.

What generic entry risks existed?

Before expiration, generic entry risk fell into four scenarios.

Scenario 1: same crystalline form and same particle distribution

This was the highest-risk scenario. A generic product matching the non-solvated crystalline hydrochloride form and the 5-to-20-micron, below-35-micron distribution could implicate claims 7, 8, 9 and 10.

Scenario 2: same active ingredient but different particle size

A product outside the claimed mean and cumulative distribution could avoid the principal composition and formulation claims, assuming the alternate product also avoided the XRPD limitations.

Scenario 3: alternate polymorph or amorphous material

A different crystal form could avoid claims 4, 8 and 11, but claims 1 and 7 would still require analysis of whether the material met the relevant particle-size limitations and whether the claim language reached the alternate form.

Scenario 4: indication carve-out

A generic label excluding breast-cancer-risk reduction or another patented use could reduce method-of-use exposure. It would not necessarily avoid product or formulation claims.

How does Patent 6,458,811 compare with a composition patent?

Characteristic	Composition patent	Patent 6,458,811
Subject matter	Chemical molecule or broad chemical class	Particle size, crystal form, formulations and uses
Design-around potential	Usually low	Moderate to high
Testing	Chemical identity	Particle-size and XRPD testing
Product coverage	Broad	Limited to specified physical characteristics
Litigation focus	Chemical identity and validity	Measurement, polymorphism, obviousness and label
Post-expiration value	None as an enforceable patent	None as an enforceable patent
Commercial role	Core exclusivity	Secondary or lifecycle exclusivity

What manufacturing and intellectual-property barriers did the patent create?

The patent could affect:

wet or dry milling;
spray drying;
precipitation and recrystallization;
particle-size classification;
crystal seeding;
drying conditions;
salt formation;
polymorph control;
blending and granulation; and
release testing.

A generic developer needed a documented control strategy showing that the active ingredient consistently fell outside any relevant claim or, alternatively, a Paragraph IV position supported by technical testing.

The most important manufacturing evidence would include:

laser-diffraction particle-size data;
D10, D50 and D90 values;
microscopy;
XRPD patterns;
solid-state characterization;
batch-to-batch variability;
milling and crystallization parameters; and
testing of the active ingredient in the final dosage form.

What licensing and settlement issues affected commercial entry?

Patent settlements involving Evista-related patents could include:

an agreed generic entry date;
a license tied to patent expiration;
supply or authorized-generic arrangements;
restrictions limited to certain indications;
covenants not to sue; or
settlement terms linked to other raloxifene patents.

A settlement involving another raloxifene patent would not necessarily resolve exposure under Patent 6,458,811 unless the agreement expressly covered it. The relevant documents would be the patent-litigation docket, settlement agreement, FTC review materials and any license terms incorporated into the judgment.

Key Takeaways

U.S. Patent 6,458,811 covers selected particulate and crystalline forms of raloxifene hydrochloride, not raloxifene in every form.
Claims 1 and 7 are centered on particle-size distributions.
Claims 4 and 8 use a copper-radiation XRPD pattern to define a non-solvated crystalline form.
Claims 5, 6, 9 and 10 extend coverage to pharmaceutical compositions.
Claims 12 through 17 cover osteoporosis, lipid-lowering and breast-cancer-prevention methods.
The patent was a secondary, lifecycle patent associated with Evista.
Its enforceable term falls in the 2019-2020 period under the applicable patent-term record.
Generic raloxifene competition is established, and the patent should not presently block ordinary U.S. generic entry.
The primary historical design-around strategies were alternate particle-size distributions, alternate polymorphs, amorphous material and indication carve-outs.
Raloxifene is a small molecule, so biosimilar analysis does not apply.

FAQs About U.S. Patent 6,458,811

Does Patent 6,458,811 cover all raloxifene hydrochloride tablets?

No. Coverage depends on the claimed particle-size distribution and, for narrower claims, the specified non-solvated crystalline form and XRPD pattern.

Is raloxifene a biologic subject to biosimilar competition?

No. Raloxifene is a small-molecule drug. Competing products use the ANDA generic-drug pathway rather than the biosimilar pathway.

Can a generic manufacturer avoid the patent by changing excipients?

Changing excipients alone may not avoid infringement if the active raloxifene material still satisfies the claimed particle-size or crystalline-form limitations.

What laboratory test is most important for claims 4 and 8?

Powder X-ray diffraction using copper radiation is the central test, supported by controlled sample preparation and comparison of peak positions and relative intensities.

Did the patent protect the Evista brand name?

No. Patent 6,458,811 protected specified pharmaceutical subject matter. The Evista name is a trademark and is governed separately from patent rights.

References

Eli Lilly and Company. (2002). U.S. Patent No. 6,458,811: Pharmaceutical compositions containing raloxifene hydrochloride. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (1997). Evista (raloxifene hydrochloride) prescribing information. FDA.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.
United States Patent and Trademark Office. (n.d.). Patent term adjustment and patent term calculation records for U.S. Patent No. 6,458,811. USPTO.
U.S. Food and Drug Administration. (n.d.). Drugs@FDA: Evista, NDA 020815. FDA.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	006387	⤷ Start Trial
Austria	464897	⤷ Start Trial
Australia	2215497	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,458,811

Summary for Patent: 6,458,811