Details for Patent: 4,898,724

Summary for Patent: 4,898,724

Title:	Organis amine phosphonic acid complexes for the treatment of calcific tumors
Abstract:	Particle-emitting radionuclides, e.g. Samarium-153, have been complexed with organic aminoalkylenephosphonic acids wherein the nitrogen and phosphorus are interconnected by an alkylene group or substituted alkylene group. These complexes have been found useful in compositions for the therapeutic treatment of calcific tumors in animals.
Inventor(s):	Jaime Simon, David A. Wilson, Wynn A. Volkert, David E. Troutner, William F. Goeckeler
Assignee:	Dow Chemical Co
Application Number:	US07/050,263
Patent Claim Types: see list of patent claims	Use; Composition; Formulation; Dosage form;

US Patent 4,898,724: Samarium-153 Aminophosphonate Compositions, Claim Scope, Expiration, and Competitive Patent Landscape

US Patent 4,898,724 protects therapeutic compositions and treatment methods using radioactive samarium-153 complexed with specified aminophosphonic acids, particularly ethylenediaminetetramethylenephosphonic acid, commonly known as EDTMP. The claims require excess uncomplexed aminophosphonate and cover sterile injectable compositions, treatment of calcific tumors, and treatment of bone pain.

The patent issued in 1990 and its original 17-year patent term expired in 2007. It therefore does not provide current US patent exclusivity for samarium-153 lexidronam or related Sm-153-EDTMP products. FDA approval of the commercial product Quadramet occurred in 1997. [1-3]

What does US Patent 4,898,724 protect?

The patent has 26 claims organized around four independent claim groups:

Claim group	Independent claims	Protected subject matter
General therapeutic composition	1	Sm-153 complexed with one of six aminophosphonic acids plus excess aminophosphonic acid
EDTMP composition	4	Sm-153-EDTMP plus excess EDTMP
Calcific tumor treatment	7	Administration to an animal with one or more calcific tumors
EDTMP tumor treatment	11	Administration of Sm-153-EDTMP plus excess EDTMP
Sterile composition with dose threshold	15	Sterile composition containing at least 0.02 mCi/kg Sm-153
EDTMP sterile composition	18	Sterile Sm-153-EDTMP composition with at least 0.02 mCi/kg
Bone-pain treatment	21	Administration for bone pain
EDTMP bone-pain treatment	24	Administration of Sm-153-EDTMP for bone pain

The claims use “comprising” language. That generally permits the presence of additional components, provided the accused product still contains each required claimed element.

What chemical agents are covered by the patent?

Claim 1 identifies six aminophosphonic acids:

1. Ethylenediaminetetramethylenephosphonic acid, or EDTMP.
2. Diethylenetriaminepentamethylenephosphonic acid.
3. Hydroxyethylethylenediaminetrimethylenephosphonic acid.
4. Tris(2-aminoethyl)aminehexamethylenephosphonic acid.
5. Bis(aminoethyl)piperazinetetramethylenephosphonic acid.
6. (1-Carboxy)ethylenediaminetetramethylenephosphonic acid.

The claim also covers physiologically acceptable salts of those acids. The patent is therefore broader than a claim limited to Sm-153-EDTMP. However, claims 4, 11, 18, and 24 narrow the chemistry to EDTMP or an acceptable EDTMP salt.

The commercial product associated with this technology, Quadramet, used samarium Sm-153 lexidronam, the radiopharmaceutical designation for a Sm-153 complex with EDTMP. [2]

What is the central claim limitation?

The central limitation is the combination of:

1. A complex containing Sm-153 and a specified aminophosphonic acid; and
2. Excess aminophosphonic acid beyond the quantity required to form the complex.

This excess-ligand requirement is material. A composition containing only fully complexed Sm-153, with no excess claimed aminophosphonate, would present a noninfringement argument against the literal composition claims. The argument would depend on the actual formulation, equilibrium chemistry, analytical measurements, and claim construction.

The claims do not state a numerical excess-ligand ratio. They require only that the ligand be present “in excess of that required to make the complex.” That language creates a formulation-specific infringement issue. The relevant comparison is not merely the total EDTMP concentration, but whether the amount exceeds the stoichiometric quantity needed to complex the Sm-153 under the product’s formulation conditions.

How do the composition claims differ from the method claims?

Composition claims

Claims 1 and 4 cover the composition itself. Claims 15 and 18 add sterility and a minimum radioactive dose concentration of 0.02 mCi/kg.

A composition claim may be implicated by manufacture, sale, offer for sale, importation, or use of a product containing the claimed components. The composition claims do not require that the product actually be administered to a patient.

Method claims

Claims 7, 11, 21, and 24 require administration to an animal. Claims 8 and 12 limit the animal to a human. The therapeutic targets are:

• Calcific tumors under claims 7 and 11.
• Bone pain under claims 21 and 24.

The method claims require a therapeutically effective amount. That limitation ties infringement to the administered product, amount, patient, and treatment context.

The bone-pain claims are commercially more relevant to Quadramet’s approved indication than the calcific-tumor claims. FDA approved Quadramet for relief of pain in patients with osteoblastic metastatic bone lesions that demonstrated increased osteogenic activity on a radionuclide bone scan. [2]

What formulations are protected by US 4,898,724?

The patent expressly covers liquid injectable formulations through dependent claims requiring a physiologically acceptable liquid carrier. Claims 3, 6, 10, 14, 17, 20, 23, and 26 specify:

• Water as the carrier; and
• A solution pH of approximately 7 to 8.

The patent therefore reaches a sterile, aqueous, near-neutral formulation containing:

• Sm-153;
• One of the claimed aminophosphonic acids;
• Excess aminophosphonic acid; and
• A therapeutic amount of radioactivity.

The claims do not require a particular vial, container, preservative, stabilizer, excipient, manufacturing process, or trade name. They also do not require a particular Sm-153 specific activity, radionuclidic purity, administration route, infusion time, or dosing schedule beyond the 0.02 mCi/kg threshold in claims 15 and 18.

What does the 0.02 mCi/kg limitation cover?

Claims 15 and 18 require the Sm-153 in dosage form to be present in an amount containing at least 0.02 mCi per kilogram of mammal body weight.

This is a minimum threshold, not a fixed dose. The claim does not establish an upper limit. A product may satisfy the limitation if the dosage contains at least the stated activity per kilogram, subject to the remaining claim elements.

The threshold applies to the sterile composition claims, not to claims 1, 4, 7, 11, 21, or 24. A product could therefore fall within a non-dose-limited composition or method claim even if the 0.02 mCi/kg threshold is not met.

How broad is the patent’s protection?

The patent has meaningful chemical breadth but limited commercial breadth after expiration.

Scope element	Breadth
Radionuclide	Narrowly limited to Sm-153
Chelating agent	Six listed aminophosphonic acids, including EDTMP
Salt forms	Physiologically acceptable salts included
Excess ligand	Required
Carrier	Optional in independent claims; aqueous carrier and pH 7-8 in dependent claims
Sterility	Required only in claims 15-20
Dose threshold	At least 0.02 mCi/kg in claims 15 and 18
Disease use	Calcific tumors and bone pain
Patient	Animal claims, with dependent human claims
Product type	Therapeutic composition, including injectable solution
Patent status	Expired in the United States

The claims are narrower than a generic claim to any Sm-153 chelate. They do not cover Sm-153 complexed with every possible ligand. A competing Sm-153 product using a non-listed chelator could avoid literal infringement, although other patents or regulatory exclusivities could apply.

When did US Patent 4,898,724 lose exclusivity?

US Patent 4,898,724 issued on February 6, 1990. For a US patent governed by the pre-1995 patent-term regime, the ordinary term was 17 years from issuance. On that basis, the patent expired on February 6, 2007. [1]

Event	Date
Patent issue	February 6, 1990
Approximate original patent term	17 years from issue
Expiration	February 6, 2007
Quadramet FDA approval	March 28, 1997
Current patent status	Expired

The patent’s expiration preceded the modern Hatch-Waxman patent-certification framework for many products now entering the market. A patent that has already expired cannot support a current Paragraph IV challenge or block a lawful generic launch.

What is the Orange Book status of Quadramet?

FDA approved Quadramet under NDA 20-732 on March 28, 1997. The product is samarium Sm-153 lexidronam injection. [2]

The Orange Book is relevant to FDA-listed patents and exclusivity for approved drug products. A listed patent may support a Paragraph IV certification while it remains unexpired. US Patent 4,898,724, however, expired in 2007 and cannot currently create an Orange Book-based patent barrier.

Regulatory issue	Assessment
FDA product	Quadramet
Active ingredient	Samarium Sm-153 lexidronam
Dosage form	Injection
Approval pathway	NDA
FDA approval date	March 28, 1997
Reference product category	Radiopharmaceutical
Patent 4,898,724	Expired
Current Paragraph IV relevance	None from this patent

FDA approval and patent protection are separate. The patent’s expiration did not itself withdraw FDA approval. Conversely, FDA approval did not extend the patent’s term.

Are there Paragraph IV challenges to this patent?

No current Paragraph IV challenge can be directed to US Patent 4,898,724 as an enforceable barrier because the patent expired in 2007.

A Paragraph IV certification is relevant when an abbreviated new drug application applicant asserts that a listed patent is invalid, unenforceable, or will not be infringed. Once the patent has expired, an applicant does not need to defeat it to launch. The applicant may still need to address other listed patents, regulatory exclusivities, product-specific requirements, and manufacturing controls.

For samarium Sm-153 lexidronam, practical entry issues are more likely to involve:

• Radioactive-material licensing;
• Short product shelf life;
• Access to Sm-153 production;
• Radiochemical quality;
• Sterile manufacturing;
• FDA approval requirements; and
• Commercial distribution to nuclear medicine sites.

What patent litigation affects Sm-153-EDTMP?

US Patent 4,898,724 is not a current litigation barrier based on its expired status. The patent claims provided do not identify any continuing patent litigation, settlement, or license restriction.

A historical license or settlement relating to the technology would not revive the expired patent or extend its exclusionary term. Contractual obligations could have commercial relevance between the original parties, but those obligations would be distinct from patent enforceability against unrelated manufacturers.

No reliable conclusion about a specific licensing deal should be drawn solely from the patent claims. Quadramet’s commercial history involved Cytogen and CIS Bio International, but product commercialization and patent ownership are separate questions. [2]

How does Quadramet compare with competing bone-pain radiopharmaceuticals?

The main competitive products have used different radionuclides or different chemical platforms.

Product or technology	Radionuclide	Principal use	Relationship to US 4,898,724
Quadramet	Sm-153	Pain relief from osteoblastic bone metastases	Directly associated with Sm-153-EDTMP technology
Metastron	Sr-89	Relief of pain from metastatic bone disease	Different radionuclide and chemistry
Re-186 HEDP products	Re-186	Bone-pain palliation	Different radionuclide and ligand
Radium-223 dichloride	Ra-223	Bone-metastasis treatment in specified cancer settings	Different alpha-emitting radionuclide and chemical form
Sm-153 products using another ligand	Sm-153	Potential radiotherapeutic use	May avoid the listed aminophosphonate limitation

The patent does not cover Sr-89, Re-186, Ra-223, or a non-listed Sm-153 chelator. Those products may have separate patent and regulatory estates.

What generic-entry risks remain after patent expiration?

Patent risk from US 4,898,724 is low because the patent expired. Commercial and regulatory risk remains material.

Manufacturing and supply barriers

Sm-153 has a radioactive half-life of approximately 46.3 hours. [2] The short half-life limits inventory duration and increases dependence on:

• Reactor or accelerator production;
• Radiochemical processing;
• Same-day or near-term distribution;
• Validated sterile filling;
• Dose calibration;
• Radioactive shipping infrastructure.

These factors can delay or prevent entry even when patent protection is absent.

Product-specific regulatory barriers

A follow-on product may need to demonstrate equivalence or obtain approval through an FDA pathway appropriate to the product and reference drug. The radioactive ingredient, chelation chemistry, radiochemical purity, sterility, endotoxin control, activity calibration, and stability profile are central technical issues.

Formulation and process patents

Later patents could potentially cover:

• Improved Sm-153 production;
• Alternative chelators;
• Lyophilized formulations;
• Stabilized radiopharmaceutical solutions;
• Automated compounding systems;
• Specific manufacturing or purification methods;
• New indications or combination regimens.

Those rights must be analyzed separately from US 4,898,724. The expired patent itself does not block such products.

How strong is the patent estate for Sm-153 lexidronam?

The patent was strong for its original target: a therapeutic aqueous Sm-153 aminophosphonate composition containing excess ligand. Its strongest practical coverage focused on Sm-153-EDTMP, sterile injectable formulations, and bone-pain treatment.

Its present exclusionary strength is zero because the patent has expired.

Factor	Assessment
Chemical specificity	Moderate to strong
EDTMP coverage	Strong within the claimed formulation
Alternative chelator coverage	Limited to six named aminophosphonates
Formulation coverage	Strong for aqueous pH 7-8 compositions
Dose coverage	Limited to claims 15 and 18
Method-of-use coverage	Calcific tumors and bone pain
Design-around potential	Available through different ligands or formulations
Current enforceability	None
Biosimilar relevance	None; this is a small-molecule radiopharmaceutical, not a biologic
Current generic-entry barrier	Regulatory and manufacturing, not this patent

Geographic coverage and international patent risk

US Patent 4,898,724 provided rights only in the United States. Foreign counterparts, if filed, would have had separate prosecution histories, claim scopes, and expiration dates. Foreign patent rights do not automatically expire on the same date in every jurisdiction.

The commercial value of the technology depended on country-specific:

• National-phase filings;
• Patent term rules;
• Supplementary protection certificates;
• Regulatory exclusivity;
• Radioactive-material licensing;
• Local product approvals.

The US patent cannot establish freedom to operate in Europe, Canada, Japan, or other markets. A geographic patent landscape requires a separate family-level review of published applications, granted counterparts, legal-status records, and national regulatory listings.

Key Takeaways

• US Patent 4,898,724 claims Sm-153 complexes with six specified aminophosphonic acids, especially EDTMP.
• Excess uncomplexed aminophosphonate is a central limitation.
• The patent covers compositions, sterile injectable formulations, calcific-tumor treatment, and bone-pain treatment.
• Claims 15 and 18 require at least 0.02 mCi/kg of Sm-153.
• The patent issued February 6, 1990 and expired approximately February 6, 2007.
• Quadramet was FDA-approved in 1997 as samarium Sm-153 lexidronam injection.
• The expired patent cannot support a current Paragraph IV barrier.
• No biosimilar framework applies because Quadramet is a radiopharmaceutical small-molecule product, not a biologic.
• Current entry barriers are more likely to involve radioactive supply, sterile manufacturing, FDA approval, radiochemical quality, and distribution logistics.
• Any later patent covering manufacturing, alternative chelators, stabilized formulations, or new uses must be analyzed separately.

Frequently Asked Questions

Does US 4,898,724 cover all samarium-153 radiopharmaceuticals?

No. It covers Sm-153 complexes using six specified aminophosphonic acids and requires excess aminophosphonate. Sm-153 products using different ligands fall outside the literal chemical listing.

Does the patent cover Quadramet specifically?

The claims are consistent with Sm-153-EDTMP products such as Quadramet. The patent expired, so it no longer blocks manufacture, sale, or use based on patent rights.

Is EDTMP the same as lexidronam?

EDTMP is the aminophosphonate chelator. Samarium Sm-153 lexidronam is the radiopharmaceutical complex formed with Sm-153 and EDTMP.

Could a new Sm-153-EDTMP product require a Paragraph IV certification?

Not to US Patent 4,898,724, because that patent expired. A certification could still be relevant to another unexpired patent listed for the reference product.

Is a later patent on Sm-153 production relevant to Quadramet freedom to operate?

Yes. A later patent on radionuclide production, purification, formulation, manufacturing equipment, or a new therapeutic use could create a separate infringement issue even though US 4,898,724 has expired.

References

1. U.S. Patent No. 4,898,724. (1990). Radiopharmaceutical compositions and methods of use. United States Patent and Trademark Office.

2. U.S. Food and Drug Administration. (1997). Quadramet (samarium Sm-153 lexidronam injection) prescribing information. FDA.

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

Drugs Protected by US Patent 4,898,724

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

International Family Members for US Patent 4,898,724

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0164843		SPC/GB98/028	United Kingdom
European Patent Office	0164843		98C0023	Belgium
European Patent Office	0164843		C980021	Netherlands
African Regional IP Organization (ARIPO)	163
African Regional IP Organization (ARIPO)	9000202
Argentina	248140
Austria	112689