United States Patent 4,275,063: Claim Scope, Razoxane Coverage, Expiration and Patent Landscape

U.S. Patent No. 4,275,063 covers pharmaceutical compositions and treatment methods using 1,2-bis(3,5-dioxopiperazin-1-yl)propane, commonly associated with razoxane and its d-enantiomer, dexrazoxane. The patent claims racemic, d- and l-forms; acid-addition salts; sterile injectable preparations; oral solid formulations; unit doses; and treatment of sarcoma, lymphosarcoma, leukemia and colorectal carcinoma.

The patent issued June 23, 1981. Because it predates the Uruguay Round Agreements Act patent-term transition, its ordinary U.S. term was 17 years from issuance. On that basis, the patent expired in 1998. Its claims no longer create an enforceable U.S. exclusivity barrier. The patent remains relevant as prior art and as the foundational U.S. patent for the claimed pharmaceutical use and dosage concepts.

What compound does U.S. Patent 4,275,063 protect?

The central compound is:

Characteristic	Scope
Chemical name	1,2-bis(3,5-dioxopiperazin-1-yl)propane
Historical development designation	ICRF-159 for razoxane; ICRF-187 for dexrazoxane
Stereochemistry	dl, d or l form
d-enantiomer	Dexrazoxane
Drug class	Bis-dioxopiperazine compound
Claimed salts	Hydrochloride, isethionate, tartrate and methanesulfonate, plus broader physiologically acceptable acid-addition salts
Claimed dosage forms	Injectable solutions, suspensions, emulsions, oral solid formulations and unit-dose preparations
Claimed diseases	Sarcoma, lymphosarcoma, leukemia, colorectal carcinoma and broader cancer language in selected claims

The claims are directed to pharmaceutical use rather than to a broad chemical genus. They do not claim every bis-dioxopiperazine compound. They identify a specific propane-linked molecule and its stereoisomers and salts.

The chemical identity is important because dexrazoxane is now primarily associated with cardioprotection during anthracycline therapy and treatment of anthracycline extravasation, while the patent claims oncology treatment of malignant disease itself. The difference limits the practical relevance of the old method claims to current dexrazoxane products.

How many independent claims are in U.S. Patent 4,275,063?

The supplied claim set contains seven independent claims: claims 1, 10, 11, 12, 21, 22, 30 and 32. On a strict count, that is eight independent claims because claim 21 and claim 32 are also independent. The independent claim categories are:

Claim	Category	Principal subject
1	Composition	Sterile, pyrogen-free diluent plus razoxane or acid-addition salt for sarcoma, lymphosarcoma or leukemia
10	Composition	Sterile injectable aqueous or oily solution, suspension or emulsion
11	Composition	Oily solution, suspension or emulsion for cancer
12	Composition	Solid carrier formulation
21	Composition	Sterile, pyrogen-free diluent plus compound for colorectal carcinoma, lymphosarcoma or leukemia
22	Method	Administration for sarcoma, lymphosarcoma or leukemia
30	Method	Administration for sarcoma, including soft-tissue sarcoma
32	Method	Administration for colorectal carcinoma

Claims 2-9 depend from claim 1. Claims 13-20 depend from claim 12. Claims 23-29 depend from claim 22. Claims 31 depends from claim 30.

What do claims 1 through 9 cover?

Claims 1-9 establish the broadest formulation framework in the patent.

Claim 1 requires all of the following:

A pharmaceutical composition.
A therapeutically effective amount of dl, d or l 1,2-bis(3,5-dioxopiperazin-1-yl)propane, or an acid-addition salt.
A physiologically acceptable diluent.
A sterile and pyrogen-free preparation.
Intended use in aiding regression or palliation of sarcoma, lymphosarcoma or leukemia in humans.

This is not a claim to the compound standing alone. It is a combination claim requiring a drug product containing the compound and a specified diluent, together with a therapeutic purpose.

The dependent claims narrow the scope as follows:

Claim	Limitation
2	dl form
3	d form
4	l form
5	Hydrochloride, isethionate, tartrate or methanesulfonate salt
6	Solution
7	Suspension
8	Unit dosage form
9	Unit dose of approximately 500 mg to 3 g

The broad salt language in claim 1 potentially reaches acid-addition salts beyond the four expressly named in claim 5. Claim 5 is narrower and expressly enumerates four salt types.

The dosage range in claim 9 is approximately 500 milligrams to 3 grams per unit. It does not necessarily require that every dose administered during a treatment course fall within that range. The claim is directed to the unit dosage form.

What do claims 10 and 11 cover?

Claim 10 focuses on parenteral pharmaceutical preparations. It requires:

Razoxane or an acid-addition salt;
A therapeutically effective amount;
A physiologically acceptable sterile injectable preparation; and
An aqueous or oily solution, suspension or emulsion.

The claim is broader than a simple aqueous injection because it includes oily vehicles, suspensions and emulsions. It does not limit the product to a particular concentration, container, route beyond the injectable form, excipient, pH, particle size or manufacturing process.

Claim 11 covers an oily solution, suspension or emulsion for aiding regression and palliation of “cancer.” Its disease language is broader than claims directed specifically to sarcoma, lymphosarcoma, leukemia or colorectal carcinoma. The claim still requires the identified compound, a physiologically acceptable oily formulation and a therapeutically effective amount.

A product could fall within claim 10 without falling within claim 11 if it is an aqueous injectable preparation. Conversely, an oily preparation for the claimed cancer treatment could implicate claim 11 even if it is not presented as a sterile injectable product, subject to the precise construction of the claim language.

What do claims 12 through 20 cover?

Claims 12-20 address solid-carrier formulations, including tablets and unit-dose products.

Claim 12 requires:

Razoxane or an acid-addition salt;
A therapeutically effective amount;
A physiologically acceptable solid carrier; and
Use for sarcoma, lymphosarcoma or leukemia.

The dependent claims add stereochemical, salt, dosage-form and dose limitations:

Claim	Limitation
13	dl form
14	d form
15	l form
16	Specified acid-addition salts
17	Tablet form
18	Unit dosage form
19	Approximately 250 mg to 3 g
20	Approximately 250 mg to 1 g

Claims 19 and 20 are composition claims with quantitative limitations. They do not expressly define a daily regimen. That distinction matters because claims 28 and 29 separately address the amount administered on each treatment day.

The solid-carrier claims could historically have reached tablets, capsules or other oral solid products if the product satisfied the “solid carrier” and therapeutic-use limitations. Claim 17 is narrower because it requires a tablet.

What do claims 21 through 32 cover?

Claims 21-32 extend the patent into colorectal carcinoma and treatment-method coverage.

Claim 21

Claim 21 is a composition claim requiring a sterile, pyrogen-free diluent and the active compound for colorectal carcinoma, lymphosarcoma or leukemia. It overlaps materially with claim 1 but substitutes a different disease set by expressly adding colorectal carcinoma.

Claim 22

Claim 22 is a method claim requiring administration to a human with sarcoma, lymphosarcoma or leukemia. It covers administration with either:

A sterile, pyrogen-free physiologically acceptable diluent; or
A physiologically acceptable solid carrier.

The claim requires continued treatment until the stated regression or palliation is obtained. That treatment-duration language may affect infringement analysis because a single isolated administration may not satisfy the full method limitation if the claim is construed to require treatment continuing to the specified outcome.

Claims 23-25 narrow claim 22 to the dl, d or l form. Claims 26 and 27 distinguish oral administration from injection. Claims 28 and 29 specify daily treatment amounts:

Approximately 250 mg to 3 g per day; or
Approximately 250 mg to 1 g per day.

Claims 30 and 31

Claim 30 targets sarcoma treatment. Claim 31 narrows the disease to soft-tissue sarcoma. These claims require a composition containing a physiologically acceptable diluent and the active compound.

Claim 32

Claim 32 targets colorectal carcinoma. It is a method claim, not merely a product claim. A product manufacturer would not necessarily infringe claim 32 merely by selling the product unless the required knowledge, intent or induced-use facts were present under the applicable infringement theory.

What are the strongest and weakest elements of the patent claims?

Strongest claim features

The patent’s strongest historical coverage was the combination of:

The specifically identified razoxane molecule;
Both racemic and enantiomeric forms;
Pharmaceutical formulations rather than unsupported chemical use;
Injectable and solid dosage forms;
Specified dose ranges;
Human therapeutic use;
Multiple cancer indications.

The claims also provide alternative routes to infringement. A product could potentially be analyzed under an injectable formulation claim, a solid-carrier claim, a unit-dose claim or a treatment-method claim.

Limiting claim features

The claims contain several narrowing elements:

Many claims require a disease-specific therapeutic purpose.
Claims 1, 21 and 22 require a sterile, pyrogen-free diluent or a solid carrier.
Claim 10 requires an injectable preparation.
Claim 11 requires an oily preparation.
Claims 9, 19, 20, 28 and 29 contain dose limitations.
Method claims require administration to a human and a specified disease.
The therapeutic objective is “aiding regression and palliation,” which may create construction issues if applied to modern indications such as anthracycline extravasation or cardioprotection.
The claims do not expressly cover every modern formulation architecture, such as lyophilized vials, reconstitution systems, premixed bags, specific stabilizer systems or device-assisted delivery.

The patent therefore had meaningful product and method coverage in its original therapeutic context, but it was not a modern formulation patent with detailed control over excipients, reconstitution, container closure, particle engineering or manufacturing parameters.

When did U.S. Patent 4,275,063 lose exclusivity?

U.S. Patent 4,275,063 issued on June 23, 1981. For a patent governed by the pre-June 8, 1995 term rule, the standard term was 17 years from issue. The resulting ordinary expiration date was June 23, 1998, absent a terminal disclaimer or an unusual adjustment.

Event	Date
Patent issue	June 23, 1981
Ordinary 17-year expiration	June 23, 1998
Current enforceability	Expired
Current blocking effect on U.S. launch	None from this patent

The patent cannot presently support an infringement action for post-expiration conduct. Patent expiration does not erase the patent’s prior-art status or its relevance to validity analysis of later patents.

The patent’s term should not be confused with FDA regulatory exclusivity. Patent expiration and FDA exclusivity are separate legal mechanisms. Any FDA approval exclusivity associated with later dexrazoxane products would arise from the later approval, not from U.S. Patent 4,275,063.

What is the Orange Book status of this patent?

U.S. Patent 4,275,063 is an expired 1981 patent and is not a current Orange Book exclusivity asset.

The Orange Book lists patents submitted by sponsors for approved drug products, subject to FDA listing rules. A patent that expired decades ago does not provide current Orange Book protection. The patent also predates the modern Hatch-Waxman patent-listing system and is not the type of patent that ordinarily controls current abbreviated new drug application timing.

For current dexrazoxane products, Orange Book analysis must be performed against the approved product and its sponsor-submitted patents. The old patent should be treated as historical prior art, not as an active listed patent that delays generic approval.

Are Paragraph IV challenges relevant to this patent?

A Paragraph IV certification against U.S. Patent 4,275,063 would have no practical present-day value because the patent expired in 1998.

Paragraph IV litigation is relevant when an ANDA applicant asserts that a listed patent is invalid, unenforceable or not infringed before expiration. An expired patent cannot ordinarily delay approval through the modern 30-month stay mechanism. Any historical Paragraph IV challenge would have been overtaken by expiration unless resolved earlier.

For current dexrazoxane products, the relevant challenges would concern later patents listed for the specific reference product, not U.S. Patent 4,275,063.

What later patent landscape affects dexrazoxane?

The modern dexrazoxane landscape is centered on different technical and clinical questions:

Patent area	Relevance to current products
Anthracycline cardioprotection	Dexrazoxane use with doxorubicin or related anthracyclines
Anthracycline extravasation	Use of dexrazoxane for tissue injury after extravasation
Pediatric oncology	Age, dosing and treatment protocols
Reconstitution	Vial, diluent and administration systems
Stability	Shelf life, storage and degradation control
Formulation	Concentration, pH, excipients and injectable presentation
Manufacturing	Enantiomer control, impurity limits and scale-up
Labeling	Approved indications and induced-use exposure
Device and packaging	Vials, transfer systems and infusion administration

These later rights must be evaluated patent-by-patent. U.S. Patent 4,275,063 does not itself claim anthracycline cardioprotection, extravasation rescue, a particular vial system or a modern reconstitution protocol.

Dexrazoxane’s commercial products have included Zinecard and Totect. Zinecard was associated with reduction of doxorubicin-related cardiomyopathy risk in specified clinical settings. Totect was approved for anthracycline extravasation. FDA labeling, rather than the 1981 patent, defines the current approved uses and dosing instructions for those products.[2][3]

Is biosimilar risk relevant to razoxane or dexrazoxane?

Biosimilar risk is generally not the primary issue for dexrazoxane.

Dexrazoxane is a chemically synthesized small molecule, not a biologic. Competitors would typically use an ANDA or another small-molecule pathway rather than the biosimilar pathway under the Public Health Service Act. The relevant risks are:

ANDA approval;
Paragraph I, II, III or IV certifications;
Formulation equivalence;
Injectable product quality;
Sterility and container-closure compliance;
Labeling and induced-use exposure;
Manufacturing reproducibility.

The compound’s stereochemical identity remains important. A product containing dexrazoxane, the d-enantiomer, may raise different analytical and regulatory questions from a racemic razoxane product. The old patent claims all three stereochemical forms, but it does not create current regulatory exclusivity over the d-enantiomer.

What manufacturing and intellectual-property barriers remain?

The expired patent does not eliminate technical barriers to commercial entry. A current manufacturer may still face:

Control of stereochemical purity.
Control of residual solvents and degradation products.
Sterile manufacturing for injectable products.
Reconstitution and dilution performance.
Stability after reconstitution.
Container-closure integrity.
Scale-up of the bis-dioxopiperazine synthesis.
Analytical methods for related substances.
Compliance with current good manufacturing practice.
Potential later patents directed to formulation, use or manufacturing.

These are regulatory and commercial barriers, not continuing rights under U.S. Patent 4,275,063.

The compound itself is not protected by this patent today. A manufacturer may still need to design around later patents, satisfy FDA chemistry, manufacturing and controls requirements, and demonstrate bioequivalence or other applicable product comparability.

How does the patent compare with modern dexrazoxane protection?

Issue	U.S. Patent 4,275,063	Modern dexrazoxane patent strategy
Active ingredient	Razoxane, including d-form	Usually dexrazoxane-specific product or use
Main claim type	Composition and treatment method	Formulation, use, manufacturing or delivery
Disease focus	Sarcoma, leukemia, lymphosarcoma, colorectal carcinoma	Cardioprotection and anthracycline extravasation
Dosage detail	Broad milligram ranges	Often protocol-specific
Injectable coverage	Broad aqueous or oily preparations	May target reconstitution, stability or presentation
Stereochemistry	dl, d and l forms	Often focused on dexrazoxane
Current enforceability	None after expiration	Depends on individual later patent terms
Orange Book significance	Historical only	Product-specific and sponsor-specific
Biosimilar pathway	Not relevant	Not generally relevant because dexrazoxane is a small molecule

What generic launch scenarios exist for dexrazoxane?

A generic entrant would generally assess four launch scenarios:

1. Paragraph III launch

If a listed patent remains unexpired, the applicant may accept a launch date after expiration. This is the lowest litigation-risk pathway but delays market entry.

2. Paragraph IV launch

If later listed patents remain, the applicant may challenge them as invalid, unenforceable or not infringed. This can trigger patent litigation and, for an eligible listed patent, a statutory approval stay.

3. Immediate launch after patent clearance

If no unexpired blocking patent remains and regulatory requirements are satisfied, the applicant may launch without relying on U.S. Patent 4,275,063.

4. Carve-out or label strategy

For method-of-use patents, an applicant may seek approval with a restricted label if the patented use can be omitted and the remaining approved uses are legally and commercially viable. The feasibility depends on the FDA-approved indications, labeling language and later patent listings.

The expired 1981 patent does not prevent any of these pathways.

What litigation and settlement issues arise?

No current enforcement action can be based on U.S. Patent 4,275,063 because the patent expired. Historical litigation involving this patent would have concluded, become moot or lost prospective significance by 1998 unless it involved pre-expiration conduct.

Current litigation risk would instead arise from:

Later formulation patents;
Anthracycline cardioprotection patents;
Extravasation-treatment patents;
ANDA Paragraph IV certifications;
Induced infringement based on product labeling;
Trade-secret or manufacturing disputes;
Regulatory exclusivity disputes.

A settlement involving a later dexrazoxane patent would not revive or extend the term of U.S. Patent 4,275,063.

What geographic coverage did the patent provide?

U.S. Patent 4,275,063 provided protection only in the United States. Corresponding foreign applications or patents would require separate analysis by country and family member. Expiration in the United States does not establish the status of foreign rights.

For international launch planning, the relevant variables include:

National filing and grant dates;
Local patent-term rules;
Supplementary protection certificates;
National regulatory exclusivity;
Local patent listings;
Litigation and settlement history;
Product-specific use and formulation patents.

The U.S. patent cannot be used to infer current protection in Europe, Japan, Canada, China or other jurisdictions.

Key Takeaways

U.S. Patent 4,275,063 covers pharmaceutical compositions and treatment methods using 1,2-bis(3,5-dioxopiperazin-1-yl)propane, including razoxane and dexrazoxane.
The claims cover dl, d and l forms, acid-addition salts, injectable preparations, solid formulations, tablets, unit doses and specified dosage ranges.
The patent claims historical treatment of sarcoma, lymphosarcoma, leukemia and colorectal carcinoma.
The patent issued June 23, 1981 and ordinarily expired June 23, 1998.
It is no longer an enforceable U.S. patent and does not create a current generic-launch barrier.
Paragraph IV analysis against this patent is no longer commercially material.
Biosimilar analysis is generally inapplicable because dexrazoxane is a synthetic small molecule.
Current intellectual-property risk must be assessed against later dexrazoxane patents covering cardioprotection, anthracycline extravasation, formulations, manufacturing, stability and delivery systems.
The patent’s current value is historical and analytical: it remains relevant as prior art and as evidence of the early claimed therapeutic and formulation concepts.

Frequently Asked Questions

Does U.S. Patent 4,275,063 cover dexrazoxane?

Yes. The claims expressly cover the d-form of 1,2-bis(3,5-dioxopiperazin-1-yl)propane, the stereochemical form associated with dexrazoxane. The patent is expired.

Can a generic dexrazoxane manufacturer still infringe this patent?

No, not through conduct occurring after the patent’s expiration. The patent expired in 1998 and cannot support a current infringement claim.

Did the patent claim treatment of anthracycline extravasation?

No. The supplied claims address sarcoma, lymphosarcoma, leukemia, colorectal carcinoma and broader cancer language. They do not expressly claim anthracycline extravasation treatment.

Does the patent cover oral dexrazoxane tablets?

Historically, yes. Claims 12-20 cover solid-carrier formulations, including tablets and unit doses, subject to the compound, disease and dosage limitations. Those claims are no longer enforceable.

Is dexrazoxane subject to biosimilar competition?

No. Dexrazoxane is a chemically synthesized small molecule. Competition generally proceeds through abbreviated new drug application pathways rather than biosimilar applications.

What patent should be checked before launching a dexrazoxane injection?

The relevant analysis should focus on unexpired patents listed for the applicable reference product and on later patents covering injectable formulation, reconstitution, stability, manufacturing, cardioprotection or anthracycline extravasation treatment. U.S. Patent 4,275,063 is not a current blocking patent.

References

United States Patent and Trademark Office. (1981). U.S. Patent No. 4,275,063: Pharmaceutical compositions.
U.S. Food and Drug Administration. (n.d.). Zinecard (dexrazoxane hydrochloride) prescribing information.
U.S. Food and Drug Administration. (n.d.). Totect (dexrazoxane for injection) prescribing information.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, commonly known as the Orange Book.
United States Code, 35 U.S.C. § 154. Patent term and adjustment.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	30617/67	Jul 03, 1967

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	3683771	⤷ Start Trial
Australia	470566	⤷ Start Trial
Belgium	729217	⤷ Start Trial
Belgium	776958	⤷ Start Trial
Canada	1002049	⤷ Start Trial
Canada	922720	⤷ Start Trial
Canada	941378	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 4,275,063