Details for Patent: 5,219,554

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Summary for Patent: 5,219,554

Title:	Hydrated biodegradable superparamagnetic metal oxides
Abstract:	This invention relates to materials exhibiting certain magnetic and biological properties which make them uniquely suitable for use as magnetic resonance imaging (MRI) agents to enhance MR images of animal organs and tissues. More particularly, the invention relates to the in vivo use of biologically degradable and metabolizable superparamagnetic metal oxides as MR contrast agents. Depending on their preparation, these metal oxides are in the form of superparamagnetic particle dispersoids or superparamagnetic fluids where the suspending medium is a physiologically-acceptable carrier, and may be uncoated or surrounded by a polymeric coating to which biological molecules can be attached. These materials are administered to animals, including humans, by a variety of routes and the metal oxides therein collect in specific target organs to be imaged; in the case of coated particles, the biological molecules can be chosen to target specific organs or tissues. The biodistribution of the metal oxides in target organs or tissues results in a more detailed image of such organs or tissues because the metal oxides, due to their superparamagnetic properties, exert profound effects on the hydrogen nuclei responsible for the MR image. In addition, the dispersoids and fluids are quite stable and, in the case of the fluids, can even be subjected to autoclaving without impairing their utility. Furthermore, the materials are biodegradable and, in the case of iron oxide compounds, can eventually be incorporated into the subject's hemoglobin, making them useful in treating anemia. Thus, the materials are well-suited for in vivo use.
Inventor(s):	Ernest V. Groman, Lee Josephson, Jerome M. Lewis
Assignee:	Amag Pharmaceuticals Inc
Application Number:	US07/863,360
Patent Claim Types: see list of patent claims	Formulation; Compound;

US Drug Patent 5,219,554: Claim Scope, Expiration, MRI Contrast Landscape, and Generic Risk

U.S. Patent No. 5,219,554 covers a broad class of hydrated, biodegradable, superparamagnetic metal oxides, with a narrower independent claim directed to ferric oxyhydroxide. The claims combine composition, particle-size, magnetic, magnetic-resonance, anion-retention, and aqueous-concentration limitations. The patent issued June 15, 1993, and its ordinary 17-year patent term expired June 15, 2010, assuming no applicable term extension or later adjustment. It therefore presents no current U.S. blocking right. [1][2]

The patent is historically relevant to iron-oxide magnetic-resonance-imaging contrast agents, including products and development programs associated with ferumoxides, ferumoxtran, ferucarbotran, and related superparamagnetic iron oxide nanoparticles.

What does U.S. Patent 5,219,554 protect?

The patent protects a functional class of hydrated biodegradable superparamagnetic metal oxides rather than a single commercial formulation. Claim 1 is the broader genus claim. Claim 2 limits the genus to hydrated biodegradable superparamagnetic ferric oxide.

Both claims require every listed limitation. A material that satisfies only the particle-size and magnetic-saturation limitations would not fall within the claim unless it also satisfies the relaxivity, anion-retention, hydration, biodegradability, and aqueous-solution requirements.

Claim element	Practical meaning
Hydrated	The claimed material contains water or exists in a hydrated form. The term is broader than a specific coating or excipient.
Biodegradable	The material must be capable of biological degradation or processing. The claim does not specify one exclusive metabolic pathway.
Superparamagnetic	The crystals must exhibit superparamagnetic behavior, including low magnetic remanence or squareness.
Metal oxide or ferric oxide	Claim 1 covers a broader metal-oxide genus. Claim 2 focuses on ferric oxide and ferric oxyhydroxide crystals.
Crystal diameter of about 500 angstroms or less	The individual crystals must be approximately 50 nanometers or smaller.
Magnetic saturation of about 5 to 90 EMU/g	The material must fall within the stated saturation range at approximately 300 K.
Magnetic squareness below 0.1	The hysteresis-loop remanence characteristic must remain below the claimed threshold.
R1 of at least about 10^4 M^-1 sec^-1	The material must have high longitudinal proton relaxivity.
R2 of at least about 10^5 M^-1 sec^-1	The material must have high transverse proton relaxivity.
Anion retention	The material must retain anions in solution, a property associated with paramagnetic oxyhydroxides.
Aqueous concentration up to about 5 molar	The claimed material must be capable of forming aqueous solutions at concentrations up to approximately 5 M.

The superscript notation in the claims should be read as approximately 10^4 and 10^5, not as “10 plus 4” and “10 plus 5.”

How do Claims 1 and 2 differ?

Claim 1 is the broader independent claim because it covers hydrated biodegradable superparamagnetic metal oxides generally. Claim 2 is a narrower independent claim directed to ferric oxide.

Claim 1: broad metal-oxide genus

Claim 1 can potentially reach materials based on ferric oxide, ferric oxyhydroxide, and other metal-oxide systems if they satisfy the full set of functional and physical limitations. The claim does not appear limited to a particular:

• Polymer coating;
• Carbohydrate coating;
• Particle-production process;
• Route of administration;
• MRI indication;
• Dosage;
• Pharmaceutical container;
• Commercial brand; or
• Named formulation.

The genus is narrowed substantially by the requirement that the material be biodegradable, highly relaxive, capable of retaining anions, and capable of forming concentrated aqueous solutions.

Claim 2: ferric oxide species

Claim 2 requires ferric oxide comprising one or more biodegradable superparamagnetic ferric oxyhydroxide crystals. A competing product based on iron oxide would face the closest literal comparison under Claim 2 if its solid phase includes ferric oxyhydroxide crystals and the remaining properties are demonstrated.

Claim 2 does not, on its face, require dextran, carboxydextran, starch, polyethylene glycol, citrate, or another named stabilizing or coating material. A product could therefore fall within the claim even if its surface chemistry differed from a disclosed example, provided the claimed composition and measurable characteristics were present.

What technical features determine infringement?

The claim is difficult to assess from a product label alone because several limitations require laboratory characterization.

Crystal size

The 500-angstrom threshold corresponds to approximately 50 nanometers. The claim refers to the diameter of each crystal, not necessarily the hydrodynamic diameter of an agglomerate or coated nanoparticle.

This distinction matters. A formulation can contain:

• Individual iron-oxide crystals below 50 nm;
• Agglomerates with much larger hydrodynamic diameters; and
• A polymer or carbohydrate coating that substantially increases the measured particle size.

Transmission electron microscopy, X-ray diffraction, or another validated crystallite-size method could produce different results. The relevant measurement method would become important in a claim-construction or infringement dispute.

Magnetic saturation and squareness

Magnetic saturation must be between approximately 5 and 90 EMU/g of metal oxide at about 300 K. The claim appears to normalize saturation to the metal-oxide mass, not the total formulation mass. A coated nanoparticle may show a lower value if the coating is incorrectly included in the denominator.

Magnetic squareness below 0.1 is a ratio-based hysteresis characteristic. The claim uses this limitation to distinguish superparamagnetic materials from particles with significant remanent magnetization.

Proton relaxivity

The R1 and R2 thresholds are unusually important because they provide performance-based limitations:

• R1 must be at least approximately 10^4 M^-1 sec^-1.
• R2 must be at least approximately 10^5 M^-1 sec^-1.

Relaxivity depends on magnetic field strength, temperature, pulse sequence, solvent, concentration, aggregation state, and measurement method. A claim analysis must therefore compare test conditions, not only numerical results from different studies.

Anion retention

Anion retention is a functional property associated in the claim with paramagnetic ferric oxyhydroxides. This limitation may require experimental evidence involving anion adsorption or retention in solution.

The wording does not identify a single required anion, retention percentage, equilibrium condition, or assay protocol. That creates potential disputes over:

• Which anions must be retained;
• Whether reversible adsorption qualifies;
• Whether retention must occur at physiological pH;
• Whether the property must be present in the final drug product; and
• How much retention is sufficient.

Aqueous concentration

The product must be capable of forming an aqueous solution up to approximately 5 M. The use of “about” gives some numerical flexibility, but the limitation is not unlimited. A suspension, colloidal dispersion, or formulation that cannot reasonably be characterized as an aqueous solution could present a claim-construction issue.

When did U.S. Patent 5,219,554 expire?

The patent issued on June 15, 1993. For a U.S. patent filed before June 8, 1995, the ordinary term was generally 17 years from the grant date. On that basis, the patent expired June 15, 2010. [1][3]

Event	Date or status
U.S. patent issued	June 15, 1993
Ordinary term basis	17 years from grant
Expected ordinary expiration	June 15, 2010
Current enforceability	Expired
Current U.S. blocking effect	None, absent an unusual surviving right unrelated to the expired claims

The patent does not present a current Paragraph IV barrier. A generic or follow-on developer does not need to wait for this patent to expire because it already expired more than a decade ago.

Was Patent 5,219,554 an Orange Book patent?

Patent 5,219,554 should not be treated as an automatically applicable Orange Book patent. The Orange Book lists patents submitted by sponsors for approved drug products under the relevant FDA listing framework. A patent number by itself does not establish Orange Book coverage. [4]

The patent is also not a substitute for product-specific analysis of:

• Listed formulation patents;
• Method-of-use patents;
• FDA exclusivity;
• Pediatric exclusivity;
• New chemical entity exclusivity;
• Patent term extensions; or
• Later patents directed to manufacturing or delivery systems.

Feridex, an iron-oxide MRI contrast product, was approved by FDA in 1996. FDA’s product information describes ferumoxides as an iron-oxide injectable suspension used as an imaging adjunct for liver lesions. [5] The patent at issue predates that approval but had no unexpired term by 2010.

Which products and programs are technically relevant?

The closest commercial and development comparators are superparamagnetic iron-oxide products, not conventional gadolinium agents.

Product or program	Active material	Relevance to Patent 5,219,554	U.S. status
Feridex	Ferumoxides, superparamagnetic iron oxide	Closest historical technical category	FDA-approved; product later discontinued in the U.S.
Endorem	Ferumoxides	European counterpart associated with iron-oxide MRI imaging	Market history varies by jurisdiction
Resovist	Ferucarbotran	Superparamagnetic iron-oxide MRI agent with distinct formulation and coating characteristics	Not broadly marketed in the U.S.
Combidex or Sinerem	Ferumoxtran-10	Investigational ultrasmall superparamagnetic iron-oxide agent	No general U.S. commercial approval
Feraheme	Ferumoxytol	Iron-carbohydrate nanoparticle with superparamagnetic properties	FDA-approved for iron-deficiency anemia, not approved as an MRI contrast agent
Gad-based agents	Gadolinium chelates	Competing MRI contrast technology, not generally within the claimed iron-oxide composition	Multiple FDA-approved products

Ferumoxytol is commercially important because it is an injectable iron-carbohydrate nanoparticle with magnetic properties. Its approved indication is treatment of iron-deficiency anemia in specified patients, not MRI contrast enhancement. FDA approval for one indication does not establish freedom from later patents covering a different use, formulation, manufacturing process, or diagnostic method. [6]

What patents protect formulations and manufacturing methods?

Patent 5,219,554 is composition-centered and does not appear, from the quoted claims, to require a particular pharmaceutical formulation. Later or related patent families can create separate risks around:

• Carbohydrate-coated iron-oxide nanoparticles;
• Dextran or carboxydextran stabilization;
• Particle-size control;
• Oxidation and precipitation conditions;
• Removal of unbound iron;
• Sterile injectable formulations;
• MRI diagnostic use;
• Anemia treatment;
• Pharmaceutical concentration and viscosity;
• Long-term storage; and
• Administration regimens.

A freedom-to-operate review must separate three patent categories:

1. Composition claims covering the nanoparticle itself.
2. Formulation claims covering the injectable product.
3. Method claims covering MRI imaging, iron replacement, or another clinical use.

An expired composition patent does not invalidate later formulation or method-of-use patents.

What is the patent landscape for superparamagnetic iron-oxide MRI agents?

The landscape developed in several stages.

Early iron-oxide composition patents

Early families established biodegradable magnetic particles, coatings, and injectable suspensions. These patents generally focused on making iron oxide biologically tolerable and dispersible in water.

Relaxivity and MRI-use patents

Later filings emphasized MRI contrast performance, including high R2 relaxivity, liver or lymph-node imaging, and detection of tumors or other lesions. Method claims could remain commercially relevant even after a base composition patent expired.

Ultrasmall superparamagnetic iron oxides

Ferumoxtran-related programs focused on smaller particles and lymphatic or macrophage-mediated distribution. Such products could have distinct particle-size, coating, and pharmacokinetic claims even when they shared the same general iron-oxide technology.

Iron-carbohydrate nanoparticles

Ferumoxytol and comparable products use iron-carbohydrate complexes designed primarily for iron replacement. Their patent estates generally emphasize complex structure, carbohydrate chemistry, manufacturing controls, dosing, and therapeutic use rather than MRI contrast claims.

Gadolinium competition

Gadolinium-based extracellular, blood-pool, hepatobiliary, and macrocyclic agents compete with iron-oxide products in many MRI applications. Their patent and regulatory issues are different, particularly because the active chelate, ligand, formulation, and safety profile drive the relevant claims.

Which companies challenged or litigated Patent 5,219,554?

No current Paragraph IV challenge is relevant because Patent 5,219,554 expired in 2010. The patent number should not be used as evidence of active litigation or a current generic-entry barrier.

The commercial parties historically relevant to this technology include Advanced Magnetics and companies involved in ferumoxides, ferucarbotran, ferumoxtran, and iron-carbohydrate products. A complete litigation conclusion would require a docket-specific review of district-court, Federal Circuit, and Patent Trial and Appeal Board records. The expired status, however, eliminates present-day injunctive or damages exposure based solely on the asserted claims of Patent 5,219,554.

Are there licensing deals associated with the patent?

The patent was part of the broader intellectual-property environment surrounding superparamagnetic iron-oxide MRI agents. Commercial development in this area involved licensing, collaboration, acquisition, and product-rights transactions among biotechnology companies, imaging companies, and larger pharmaceutical manufacturers.

The patent number alone does not establish the existence, scope, royalty rate, field restrictions, or continuing effect of a license. Any historical license tied to this patent would not revive the expired statutory claims. Its current value would be limited to historical know-how, family rights in other jurisdictions if still alive, or related patents that were not coextensive with the U.S. claims.

How strong was the patent estate?

The patent had meaningful historical breadth because it combined a broad material category with measurable performance criteria. Its strength can be assessed as follows:

Factor	Assessment
Claim breadth	Broad at the genus level, narrower in practical application because all functional limitations must be met
Technical relevance	High for early superparamagnetic iron-oxide MRI agents
Enablement risk	Potentially significant because the claims span multiple metals and broad functional properties
Definiteness risk	Potential issues around “biodegradable,” “about,” anion retention, aqueous solution, and test conditions
Design-around potential	Moderate to high through altered crystal composition, magnetic properties, coating, relaxivity, or formulation
Current enforceability	None because the patent expired
Historical blocking value	High during the period before expiration for products meeting the full limitations
Current commercial value	Primarily historical and evidentiary

What generic launch scenarios exist today?

A generic or follow-on developer faces no launch delay from Patent 5,219,554 itself. Current launch risk would instead depend on:

• FDA approval pathway;
• Reference-listed drug status;
• Remaining product patents;
• Formulation patents;
• Method-of-use patents;
• Manufacturing patents;
• Injectable-product requirements;
• Drug-master-file access;
• Particle-size and impurity specifications; and
• Clinical or bioequivalence requirements.

For an iron-oxide MRI agent, FDA approval may require more than a conventional small-molecule generic approach because nanoparticle composition, size distribution, coating, biodistribution, and imaging performance can materially affect clinical behavior.

Key Takeaways

• Patent 5,219,554 covers hydrated biodegradable superparamagnetic metal oxides.
• Claim 2 is narrower and focuses on ferric oxide containing ferric oxyhydroxide crystals.
• The claims require simultaneous satisfaction of particle-size, magnetic, relaxivity, anion-retention, biodegradability, hydration, and concentration limitations.
• Individual crystals must be approximately 50 nm or smaller.
• The quoted relaxivity thresholds are approximately 10^4 M^-1 sec^-1 for R1 and 10^5 M^-1 sec^-1 for R2.
• The patent issued June 15, 1993, and its ordinary term expired June 15, 2010.
• The patent presents no current U.S. exclusivity or Paragraph IV barrier.
• Feridex and related superparamagnetic iron-oxide products are the closest historical commercial comparators.
• Ferumoxytol is technically related but is FDA-approved for iron-deficiency anemia, not MRI contrast.
• Current diligence must focus on later formulation, manufacturing, diagnostic-use, and therapeutic-use patents.

FAQs

Does Patent 5,219,554 cover all iron-oxide nanoparticles?

No. A product must satisfy every claim limitation, including the specified crystal size, magnetic saturation, magnetic squareness, R1 and R2 relaxivity, anion-retention behavior, biodegradability, hydration, and aqueous-concentration capability.

Does a dextran-coated iron-oxide nanoparticle automatically infringe?

No. Dextran coating is not expressly required by the quoted claims. The product would need to satisfy the complete set of structural and functional limitations.

Can an expired patent still affect FDA approval?

It can remain relevant as prior art or historical technical disclosure, but it does not create a current patent bar. FDA approval and patent enforceability are separate issues.

Is ferumoxytol covered by Patent 5,219,554?

The patent may be technically relevant to ferumoxytol because ferumoxytol is an iron-carbohydrate nanoparticle with superparamagnetic characteristics. The expired patent does not create current infringement exposure. Ferumoxytol’s operative patent estate must be analyzed separately.

What testing is needed to evaluate a competing product?

The key tests include crystallite-size analysis, magnetic hysteresis and saturation measurements at approximately 300 K, R1 and R2 relaxivity testing under matched conditions, anion-retention testing, biodegradation assessment, and concentration or solubility characterization.

References

1. U.S. Patent and Trademark Office. (1993). U.S. Patent No. 5,219,554.
2. Google Patents. (n.d.). US5219554A: Hydrated biodegradable superparamagnetic metal oxides.
3. United States Code, 35 U.S.C. § 154.
4. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, Orange Book.
5. U.S. Food and Drug Administration. (1996). Feridex I.V. prescribing information.
6. U.S. Food and Drug Administration. (2009). Feraheme prescribing information.

Drugs Protected by US Patent 5,219,554

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 5,219,554

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	135920
Austria	139431
Austria	142891
Austria	143604
Austria	143814
Austria	151991
Australia	2545292