United States Patent 6,472,563: Formoterol L-Tartrate Polymorph Claims and Patent Landscape

U.S. Patent No. 6,472,563 protects selected crystalline forms of (R,R)-formoterol L-tartrate and manufacturing processes that convert polymorph B into polymorph C and, ultimately, thermodynamically stable polymorph A. The strongest protection is directed to the specifically characterized crystal forms and their preparation, not to formoterol generally. The patent issued on October 29, 2002, and its ordinary 20-year term has expired. The patent therefore presents historical prior-art and claim-construction significance but does not presently block U.S. commercial activity.

What does U.S. Patent 6,472,563 cover?

The patent covers four related subject-matter categories:

Claim group	Protected subject matter	Practical scope
Claims 1-5	Processes for preparing polymorph C	Solvent composition, temperature, seeding, crystallization, and conversion from polymorph B
Claim 6	Process for preparing polymorph A	Sequential conversion B to C, followed by crystallization of A
Claim 7	Solid (R,R)-formoterol L-tartrate containing at least 95% polymorph C	Product-by-composition claim defined by XRPD
Claim 8	Highly pure formoterol L-tartrate containing at least 95% polymorph A	Product claim requiring more than 99.5% formoterol L-tartrate and the specified A polymorph
Claims 9-14	Therapeutic and pharmaceutical compositions containing polymorph A	Bronchodilation, aerosol, oral, tablet, capsule, syrup, and dry-powder inhalation uses

The patent does not claim all formoterol salts, all formoterol polymorphs, or every method of producing formoterol. Its central subject is the solid-state form of the L-tartrate salt of the R,R enantiomer.

The claims use X-ray powder diffraction, or XRPD, peak positions and relative intensities to identify polymorphs. That makes infringement dependent on analytical characterization, not merely on the chemical name appearing on a batch record.

What are the key polymorphs in U.S. Patent 6,472,563?

The patent distinguishes three crystalline forms:

Polymorph	Role in the patent	Principal XRPD marker
B	Starting material	Strong peaks at 8.5°, 17.3°, and 20.6° 2-theta
C	Intermediate and separately claimed product	Strong peaks at 6.4°, 17.5°, and 24.1° 2-theta
A	Thermodynamically stable final form	Strong peaks at 15.2°, 15.5°, and 23.7° 2-theta

Polymorph C is identified by a dominant 6.4° peak and substantial peaks at 17.5° and 24.1°. Polymorph A is identified by a dominant 23.7° peak, with major peaks at 15.2°, 15.5°, 16.8°, and 25.6°.

A batch does not fall within claims 7 or 8 merely because it contains R,R-formoterol L-tartrate. The relevant polymorphic content must meet the claim threshold and the XRPD definition.

How do claims 1 through 6 protect the manufacturing process?

Claims 1 through 3: crystallization of polymorph C

Claim 1 requires crystallizing polymorph C from aqueous isopropyl alcohol. It also requires the specific XRPD profile for C. The process therefore has both:

A solvent and crystallization limitation; and
A structural result limitation based on XRPD.

Claim 2 narrows claim 1 to a two-stage process:

Dissolution in 50% by volume isopropyl alcohol and water at 50-55°C;
Immediate seeding;
Addition of sufficient isopropyl alcohol to reach 25% by volume isopropyl alcohol and water.

Claim 3 provides an alternative operating window based on weight:

One part polymorph C;
About two parts isopropyl alcohol;
About 2.5 parts water;
Addition of 1.5 to 4 additional parts isopropyl alcohol;
Cooling and separation.

Claims 2 and 3 are narrower than claim 1. A process that produces polymorph C through a different solvent system could avoid these dependent claims, but it could still implicate claim 1 if the process uses aqueous isopropyl alcohol and produces the required form.

Claims 4 and 5: conversion of polymorph B to polymorph C

Claim 4 requires stirring polymorph B in water, isopropyl alcohol, and 13%-75% by weight toluene at 40-55°C. The process must produce polymorph C with the specified XRPD pattern.

Claim 5 narrows the process to a defined solvent and loading range:

One part by weight of polymorph B;
2.7-3.1 parts by volume of solvent mixture;
About 3.6 parts isopropyl alcohol;
About 1 part toluene;
About 0.5 parts water;
45-50°C;
Conversion to more than 98% polymorph C.

The claims are process claims, so they focus on the steps used rather than only the identity of the final solid. A manufacturer could avoid claims 4 and 5 by using a different starting polymorph, different solvent system, different temperature range, or a non-slurry route, subject to the scope of claim 1 and any applicable doctrine of equivalents.

Claim 6: sequential preparation of polymorph A

Claim 6 requires:

Conversion of polymorph B to C in water, isopropyl alcohol, and toluene at 40-55°C;
Crystallization of C from aqueous isopropyl alcohol to produce A; and
Separation of A from the aqueous isopropyl alcohol system.

This is a particularly process-specific claim. It does not reach every process capable of making polymorph A. A process that directly produces A from another precursor, or that converts B to A without isolating or forming C under the claimed sequence, would require separate analysis.

What do claims 7 and 8 protect?

Claim 7: polymorph C product claim

Claim 7 covers crystalline R,R-formoterol L-tartrate comprising at least 95% polymorph C. The claim is not limited to a particular manufacturing route. A product meeting the composition and XRPD limitations could fall within the claim regardless of whether it was produced using the solvent conditions in claims 1-5.

This distinction matters in freedom-to-operate analysis. A manufacturer may avoid the process claims but still produce a solid covered by claim 7.

Claim 8: highly pure polymorph A

Claim 8 covers a crystalline solid that:

Contains more than 99.5% by weight formoterol L-tartrate;
Contains at least 95% polymorph A;
Has the claimed A-form XRPD profile; and
Is described as the thermodynamically stable third polymorph.

Claim 8 is the principal product claim for the final solid. It is broader than claim 6 in one respect because it does not require a particular manufacturing sequence. It is narrower in another respect because it imposes a high chemical-purity threshold and at least 95% A-form content.

What do claims 9 through 14 protect?

Claims 9-14 extend claim 8 into therapeutic and formulation contexts.

Claim	Subject
9	Preventing bronchoconstriction or inducing bronchodilation in a mammal
10	Pharmaceutical composition with a pharmaceutically acceptable carrier
11	Aerosol pharmaceutical composition
12	Oral pharmaceutical composition
13	Tablet, capsule, or syrup
14	Dry-powder inhalation composition

These claims are dependent on the solid defined in claim 8. They do not independently claim every formoterol inhaler or every bronchodilator composition. The composition must contain the specific claimed A-form solid.

The patent therefore differs from a conventional active-ingredient patent. Its commercial significance depends on whether a product uses R,R-formoterol L-tartrate polymorph A, rather than formoterol fumarate, another salt, another enantiomeric composition, or a different crystalline form.

When did U.S. Patent 6,472,563 expire?

U.S. Patent No. 6,472,563 was issued on October 29, 2002. Based on the patent’s 20-year term measured from its effective nonprovisional filing date, the patent expired in 2017, subject to any patent-term adjustment or other term calculation recorded in the USPTO patent file.[1]

The patent is therefore no longer an enforceable U.S. exclusion right. Expiration eliminates ordinary infringement liability for activities occurring after expiration, but the patent remains relevant to:

Prior-art analysis;
Validity and obviousness assessments for later patents;
Claim construction;
Historical licensing and settlement analysis;
Development of polymorph-screening strategies; and
Determining whether later patent claims are genuinely distinct from the disclosed A, B, and C forms.

Patent expiration does not create FDA approval, does not establish pharmaceutical equivalence, and does not remove independent regulatory requirements for a generic or follow-on product.

What is the Orange Book status of U.S. Patent 6,472,563?

The patent should not be treated as an automatically Orange Book-listed patent merely because it claims a pharmaceutical solid and pharmaceutical compositions. Orange Book listing depends on submission by the relevant NDA holder and the FDA’s treatment of the patent under the listing rules.[2]

The patent’s composition and method claims could have been candidates for listing if they claimed an approved drug product, formulation, or method of use associated with an NDA. Its process claims would not ordinarily function as product or method-of-use listings for every product containing formoterol.

The key commercial distinction is between:

Patent validity and enforceability under Title 35; and
FDA patent-listing and certification consequences under the Hatch-Waxman framework.

A patent can be enforceable without being listed in the Orange Book. Conversely, an Orange Book listing does not establish that every listed claim is valid or infringed.

Were Paragraph IV challenges likely under this patent?

A Paragraph IV certification would have been relevant only if the patent was listed against an NDA and a generic applicant sought approval for a product covered by a listed claim.[3]

For a generic formoterol product, the principal design-around positions would have included:

Use of formoterol fumarate rather than L-tartrate;
Use of a racemic or different stereochemical composition;
Use of a different salt;
Use of a different polymorph;
Use of a solid containing less than 95% polymorph A or C, where scientifically and regulatorily acceptable;
Use of a different manufacturing sequence;
Use of a different inhalation formulation; or
Certification that the patent had expired.

A Paragraph IV challenge directed only to claims 7 or 8 would require analytical evidence concerning XRPD patterns, polymorphic percentage, and chemical purity. A challenge directed to claims 1-6 would focus on the actual manufacturing process, not simply on the identity of the final drug substance.

Because the patent expired in 2017, any current Abbreviated New Drug Application strategy would ordinarily rely on patent expiration rather than a live Paragraph IV dispute involving this patent.

How does this patent relate to marketed formoterol products?

The principal marketed formoterol products have historically used formoterol fumarate, often as formoterol fumarate dihydrate, including products such as Foradil, Perforomist, and combination inhalers containing formoterol.[4][5]

That distinction is central:

Attribute	U.S. Patent 6,472,563	Common marketed formoterol products
Active stereochemical entity	(R,R)-formoterol	Product-specific; commonly formoterol fumarate
Salt	L-tartrate	Commonly fumarate
Claimed solid	Polymorphs A and C	Product-specific fumarate solid or formulation
Main protection	Crystal form and process	Drug product, formulation, delivery device, or method patents
Biosimilar pathway	Not applicable	Not applicable; formoterol is a small molecule
Generic pathway	ANDA, if product criteria are met	ANDA, subject to product-specific patents and exclusivities

A formulation using formoterol fumarate is not automatically covered by claims directed to R,R-formoterol L-tartrate. Salt identity, stereochemistry, crystal form, and formulation composition must be analyzed separately.

What formulation patents and method-of-use patents remain relevant?

For a formoterol product, the relevant patent estate may include rights covering:

The active salt;
Particle-size distribution;
Polymorph or hydrate;
Dry-powder carrier systems;
Metered-dose aerosol formulations;
Nebulizer solutions;
Device geometry and dose metering;
Combination therapy with inhaled corticosteroids;
Long-acting bronchodilator dosing;
Treatment of asthma or chronic obstructive pulmonary disease;
Manufacturing and micronization processes; and
Packaging and stability systems.

U.S. Patent 6,472,563 has formulation claims, but those claims are subordinate to claim 8 and therefore require the specified polymorph A solid. It is not a general inhaler-formulation patent.

The patent also does not create biosimilar risk. Formoterol is a chemically synthesized small molecule. FDA approval generally proceeds through the ANDA pathway, not the 351(k) biosimilar pathway.[6]

How strong was the patent estate?

The patent was technically focused and commercially strongest against a manufacturer using the same R,R-formoterol L-tartrate polymorphs.

Strengths

Claims 7 and 8 are product claims and do not require proof of the patented manufacturing process.
XRPD provides a reproducible analytical fingerprint.
Claim 8 combines polymorphic identity with high chemical purity.
Claim 6 captures a defined industrial sequence for producing thermodynamically stable polymorph A.
Claims 9-14 connect the solid to therapeutic and inhalation uses.

Limitations

The patent did not cover formoterol generally.
It did not cover every formoterol salt.
The process claims contain detailed solvent, temperature, and sequencing limitations.
Product claims depend on reliable XRPD comparison and polymorph quantification.
The patent expired in 2017.
The patent’s commercial reach depended on use of the L-tartrate salt rather than a different formoterol salt.

The patent was therefore a narrow-to-moderate solid-state patent rather than a foundational composition-of-matter patent for formoterol.

What generic launch scenarios applied?

Before expiration, the principal launch scenarios were:

Scenario	Risk under Patent 6,472,563
Generic uses formoterol fumarate	Generally low risk from this patent, subject to separate patents
Generic uses R,R-formoterol L-tartrate polymorph A	High risk before expiration if claim 8 limitations are met
Generic uses polymorph C at 95% or higher	High risk before expiration under claim 7
Generic uses another salt	Low risk from the asserted claims
Generic uses a non-A, non-C polymorph	Potentially lower risk, subject to analytical proof
Generic uses the same final form but a different process	Product-claim risk remains
Product launches after patent expiration	No ordinary infringement risk from this patent

A post-expiration launch still requires FDA approval, pharmaceutical-equivalence or other applicable regulatory showing, manufacturing validation, and compliance with current good manufacturing practice requirements.

What litigation and settlement issues should be checked?

The patent number alone does not establish that a particular litigation or settlement occurred. A complete diligence review would distinguish among:

District-court infringement actions;
ANDA litigation under 21 U.S.C. § 355(j);
Federal Circuit appeals;
Inter partes or post-grant proceedings;
License agreements;
Supply agreements;
Royalty arrangements; and
Confidential settlement terms.

The relevant legal issues would have included claim construction of “at least 95%,” interpretation of XRPD peak tolerances, polymorph quantification, inherent infringement, anticipation by earlier crystalline forms, obviousness, enablement, and written description.

After expiration, any historical settlement remains relevant to market-entry history but does not preserve the patent’s exclusionary effect.

What geographic coverage did the patent have?

U.S. Patent 6,472,563 provided rights only in the United States. Corresponding applications or patents in Europe, Canada, Japan, Australia, and other jurisdictions would require separate review. Patent term, prosecution history, claim scope, opposition proceedings, and expiration dates could differ by country.

A U.S. expiration did not terminate foreign rights. Conversely, a foreign patent could expire earlier or later depending on filing dates, patent-term adjustments, supplementary protection certificates, and national prosecution history.

Key Takeaways

U.S. Patent 6,472,563 is a polymorph and process patent for (R,R)-formoterol L-tartrate.
Claims 1-6 protect specified processes involving polymorphs B, C, and A.
Claim 7 covers crystalline polymorph C at a minimum 95% level.
Claim 8 covers highly pure polymorph A at a minimum 95% level.
Claims 9-14 cover therapeutic, aerosol, oral, tablet, capsule, syrup, and dry-powder compositions containing the claimed A form.
The patent does not broadly cover formoterol, formoterol fumarate, or all inhaled formoterol products.
The patent expired in 2017 under the ordinary U.S. patent-term calculation.
It is not a biosimilar patent because formoterol is a small molecule.
Any current generic assessment should focus on separate, unexpired patents covering formoterol fumarate, inhaler devices, formulations, combinations, methods of use, and manufacturing.

FAQs

Does U.S. Patent 6,472,563 cover formoterol fumarate?

No. The claims are directed to (R,R)-formoterol L-tartrate and specified polymorphs of that salt. Formoterol fumarate is a different salt and requires separate claim analysis.

Is polymorph A the most important claimed form?

Yes. Polymorph A is the final thermodynamically stable form in claim 8 and is incorporated into claims 9-14 for therapeutic and pharmaceutical compositions.

Can a product infringe claim 7 without using the patented process?

Yes. Claim 7 is a product claim. A crystalline product meeting the polymorph C and XRPD limitations could raise infringement issues regardless of the manufacturing route, although the patent is expired.

Does expiration of this patent permit immediate sale of any formoterol inhaler?

No. Expiration removes this patent as a barrier but does not satisfy FDA approval, ANDA, labeling, bioequivalence, device, manufacturing, or other regulatory requirements.

Does the patent create biosimilar competition risk?

No. Formoterol is a chemically synthesized small molecule. Competition generally proceeds through the generic-drug framework rather than the FDA biosimilar pathway.

References

United States Patent and Trademark Office. (2002). U.S. Patent No. 6,472,563, Polymorphs of formoterol L-tartrate.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, commonly known as the Orange Book.
Drug Price Competition and Patent Term Restoration Act, 21 U.S.C. § 355(j).
U.S. Food and Drug Administration. (2024). Drugs@FDA: FDA-approved drugs database.
U.S. Food and Drug Administration. (2024). Approved drug labeling for formoterol fumarate inhalation products.
U.S. Food and Drug Administration. (2024). Biosimilars and interchangeable biosimilars.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	450497	⤷ Start Trial
Australia	2002349914	⤷ Start Trial
Australia	2008253696	⤷ Start Trial
Canada	2477642	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,472,563

Summary for Patent: 6,472,563