Details for Patent: 5,055,288

Summary for Patent: 5,055,288

Title:	Vascular magnetic imaging method and agent comprising biodegradeable superparamagnetic metal oxides
Abstract:	The preparation and isolation of biodegradable superparamagnetic MR imaging contrast agents for the vascular compartment is described. These aggregates are comprised of individual biodegradable superparamagnetic metal oxide crystals which aggregates have an overall mean diameter less than about 4000 angstroms. The preferred vascular imaging contrast agent is comprised of aggregates of iron oxide crystals having an overall mean diameter less than about 500 angstroms. These contrast agents may be associated with a macromolecular species, which assist, among other things, in the preparation of these extremely small materials, and may be dispersed or dissolved in a physiologically acceptable medium. Preferred media also stabilize the materials against further aggregation even under harsh sterilization conditions. The autoclaved biodegradable superparamagnetic iron oxides of the invention are ideally suited for a pharmaceutical preparation and enjoy several advantages over prior intravascular imaging contrast media including low osmolality, low effective dose requirements, high relaxivities, long blood lifetimes, rapid biodegradability, and versatility with respect to a wide range of applicable MR data acquisition parameters.
Inventor(s):	Jerome M. Lewis, Edward T. Menz, Francis E. Kenny, Ernest V. Groman, Lee Josephson
Assignee:	Amag Pharmaceuticals Inc
Application Number:	US07/233,177
Patent Claim Types: see list of patent claims	Composition; Formulation;

US Patent 5,055,288: Claim Scope, Expiration, FDA Status, and Superparamagnetic MRI Contrast-Agent Patent Landscape

US Patent 5,055,288 covers biodegradable superparamagnetic metal-oxide particles, particularly dextran-associated iron-oxide aggregates formulated as injectable MRI contrast fluids. Its core limitations combine particle size, magnetic behavior, proton relaxivity, biodegradation, circulation time, macromolecular coating, buffer composition, and sterilization properties.

The patent issued on October 8, 1991. Because it was subject to the pre-URAA patent-term rule, its ordinary statutory term ran 17 years from issuance and ended on October 8, 2008, absent an earlier terminal disclaimer. The patent is therefore expired and cannot presently block manufacture, sale, or use of a product that falls within its claims.

What invention does US Patent 5,055,288 protect?

The patent protects a class of biodegradable superparamagnetic hydrated metal oxides used as MRI contrast agents. The commercial target was primarily superparamagnetic iron oxide, or SPIO, associated with dextran or another polysaccharide.

The claimed invention is defined through cumulative technical limitations:

Technical characteristic	Claimed requirement
Individual crystal diameter	About 500 Å or less
Preferred crystal diameter in dependent claims	About 100 Å or less
Aggregate diameter	About 4,000 Å or less
Preferred aggregate sizes	Less than 3,000, 2,000, 1,000, or 500 Å
Magnetic saturation	About 5 to 90 EMU/g at approximately 300 K
Magnetic squareness	Less than 0.1
Proton relaxivity	R1 at least about 10^4 M^-1 sec^-1; R2 at least about 10^5 M^-1 sec^-1
Biodegradation	Return of affected-tissue proton relaxation rates within about two weeks or less
Broader clearance limitation	Metabolized or excreted within 30 days or less
Blood half-life in rat	At least about 17 minutes at 2 mg/kg for claim 21
Long-circulating embodiment	At least about 50 minutes under dependent claims
Macromolecular species	1 to 250 kilodaltons; carbohydrate; dextran; polysaccharide
Formulation	Physiologically acceptable medium, including citrate buffer
Sterilization	Sterilizable or autoclavable fluid

The claims are product and composition claims. They do not require a particular manufacturing process, imaging sequence, disease indication, or anatomical target.

What are the independent claims in US 5,055,288?

Claims 1, 2, 11, 12, 18, and 21 are the principal independent claims.

Claims 1 and 2: biodegradable superparamagnetic metal oxide

Claim 1 covers the metal-oxide material itself. It requires aggregates of individual biodegradable, hydrated, superparamagnetic metal-oxide crystals.

Claim 2 adds association with a macromolecular species. This distinction is commercially important because the dextran-associated embodiment is more closely aligned with injectable SPIO products than the uncoated material in claim 1.

Both claims require all of the following:

1. Crystal and aggregate size limits.
2. Superparamagnetic behavior, including low magnetic squareness.
3. Ability to retain anions in solution, reflecting paramagnetic metal oxyhydroxide chemistry.
4. High R1 and R2 proton relaxivity.
5. Biodegradation in the subject within approximately two weeks, demonstrated by tissue proton-relaxation recovery.

The claims use "comprising," which generally makes them open-ended. A competing product could contain additional excipients, coatings, salts, stabilizers, or other components and still fall within the claim if every stated limitation is satisfied.

Claims 11 and 12: sterilizable superparamagnetic fluids

Claims 11 and 12 cover fluids containing the claimed metal oxide and a physiologically acceptable medium. Claim 12 includes the macromolecularly associated version.

These claims extend protection from the particle to the injectable formulation. A product could therefore face literal coverage even if the particle is made by a different process, provided the finished fluid satisfies the claimed structural and functional characteristics.

Claim 18: autoclavable dextran-coated iron oxide fluid

Claim 18 is the most commercially specific formulation claim. It requires:

• biodegradable superparamagnetic iron oxide;
• individual hydrated iron-oxide crystals;
• association with dextran;
• the specified particle size, magnetic, relaxivity, and biodegradation properties;
• an aqueous citrate buffer; and
• autoclavability.

This claim is directed to a narrow but commercially relevant product architecture. It is materially narrower than claim 21 because it requires dextran, iron, citrate buffer, and autoclavability.

Claim 21: MRI contrast agent with pharmacokinetic limitations

Claim 21 is broader in composition but narrower in pharmacokinetic requirements. It covers an MRI contrast agent containing biodegradable superparamagnetic metal oxide that:

• is metabolized or excreted within 30 days or less; and
• has a rat blood half-life of at least about 17 minutes at a 2 mg/kg dose.

The claim does not expressly require dextran, iron, citrate, the 4,000 Å aggregate limit, or the stated relaxivity thresholds. Those limitations appear in dependent claims or in the separate composition and fluid claims.

Claims 22 and 23 narrow the clearance period to approximately two weeks and one week, respectively. Claims 32, 42, and 43 raise the rat blood half-life threshold to at least about 50 minutes.

How do the dependent claims narrow the patent scope?

The dependent claims create several commercially relevant subgroups.

Claims	Added limitation	Commercial significance
3	Metal selected from iron, cobalt, chromium, copper, manganese, molybdenum, nickel, or tungsten	Broadens the chemical genus beyond iron
4, 17, 26, 33, 41	Iron	Captures the principal SPIO embodiment
5, 35-38	Aggregate size below 3,000, 2,000, 1,000, or 500 Å	Targets smaller particle populations
6	Macromolecule of about 1-250 kDa	Defines coating or association range
7, 25, 27	Carbohydrate or polysaccharide	Covers common biological coatings
8	Dextran	Directly targets dextran-coated SPIO
9, 10	Macromolecule-to-metal weight ratio	Limits coating density
13-16	Polyfunctional organic molecules, buffers, and salts	Covers injectable formulation environments
18	Autoclavable iron oxide/dextran/citrate formulation	Narrow formulation claim
19, 20	Hypotonic or isotonic formulation	Covers injectable tonicity
28	Crystals about 100 Å or less; aggregates about 500 Å or less	Narrow nanoparticle-size embodiment
29-31	Brightening, darkening, or mixed MRI effect	Covers T1, T2, and combined contrast behavior
34, 39, 40	Crystal and largest-aggregate limits	Narrows particle-size distribution
42, 43	Rat half-life at least about 50 minutes	Targets longer-circulating products

The claims contain overlapping dependencies and several apparent drafting errors, including inconsistent references to "meal" rather than "metal," typographical corruption in units, and inconsistent use of "rate" and "rat." Those errors do not automatically invalidate the claims. Their practical effect would depend on whether a court could correct the language or determine that the claim is indefinite.

What products and technologies are most closely associated with the patent?

The patent is most closely associated with dextran-coated SPIO MRI contrast agents, including the technology underlying ferumoxides-type products.

Product or technology	Active material	Relationship to US 5,055,288
Feridex IV / Endorem	Ferumoxides, dextran-coated iron oxide	Closest commercial product class to claims 8, 17, 18, and 41
Combidex / Sinerem	Ferumoxtran-10, ultrasmall iron oxide with dextran-related coating	Relevant to claims requiring prolonged circulation and polysaccharide association
Resovist	Ferucarbotran, carboxydextran-coated iron oxide	Relevant technical competitor; product-specific claim coverage would require limitation-by-limitation analysis
GastroMARK	Oral SPIO formulation	Related SPIO technology but not necessarily within injectable-fluid claims
Ferumoxytol / Feraheme	Carboxymethyl dextran-coated iron-carbohydrate complex	Later iron-replacement product; MRI use is not the same as the approved indication and requires separate claim analysis

Feridex IV was approved by the FDA in 1996 for liver imaging. The FDA label identifies ferumoxides as an iron-oxide nanoparticle preparation associated with dextran and administered intravenously (U.S. Food and Drug Administration, 1996). Feridex was later discontinued in the United States for commercial reasons. Discontinuation did not revive or extend US Patent 5,055,288.

What is the FDA and Orange Book status of US Patent 5,055,288?

US Patent 5,055,288 is expired and has no current exclusionary effect on FDA approval or commercial launch.

FDA status

The patent covered technology used in the development of SPIO MRI contrast agents, but FDA approval attaches to a specific drug product, manufacturing process, quality system, clinical dossier, and labeling. Patent coverage does not establish FDA approval.

Relevant regulatory status includes:

• Feridex IV received FDA approval as an MRI contrast agent for hepatic imaging.
• Ferumoxtran-10 products such as Combidex/Sinerem did not become broadly approved FDA products in the United States.
• Ferumoxytol was approved as an intravenous iron-replacement product, not as an FDA-approved MRI contrast agent.
• No current FDA exclusivity period can be based on US 5,055,288 because the patent expired in 2008.

Orange Book status

The Orange Book lists patents submitted by sponsors for approved drug products. An expired patent cannot provide a current Orange Book barrier to an ANDA applicant.

For practical diligence, the relevant conclusions are:

1. US 5,055,288 should not be treated as a live Orange Book blocking patent.
2. Any historical listing associated with a ferumoxides product would have no current patent-term effect.
3. Current products containing iron-carbohydrate nanoparticles must be evaluated against their own approved labeling, regulatory pathway, and later patents rather than against the expired patent.

The Orange Book is not a complete database of all pharmaceutical patent rights. It does not generally capture every manufacturing, formulation, method-of-use, or foreign patent relevant to a product (FDA, 2024).

When did US Patent 5,055,288 lose exclusivity?

The patent lost statutory patent exclusivity on October 8, 2008, based on its October 8, 1991 issue date and the 17-year term applicable to pre-June 8, 1995 applications.

Event	Date or period
Patent issued	October 8, 1991
Applicable term rule	17 years from issue
Ordinary expiration	October 8, 2008
Current status	Expired
Patent Term Extension relevance	No current extension changes the expired status
Current infringement risk	None based solely on this patent

The patent cannot be used today to prevent a generic, follow-on, or reformulated SPIO product from practicing the disclosed subject matter. A later patent could still create risk if it covers a distinct composition, coating, manufacturing process, dosage regimen, or imaging use.

What patent landscape surrounds the invention?

The relevant landscape has four layers: foundational SPIO patents, product-specific formulation patents, later iron-carbohydrate patents, and regulatory exclusivity.

Foundational SPIO patents

Advanced Magnetics and related entities developed a series of patents directed to biodegradable magnetic particles and MRI contrast agents. US 5,055,288 sits within that early SPIO patent cluster and is best viewed as a composition and formulation patent rather than a process patent.

Related early patent families addressed:

• magnetic resonance imaging contrast agents;
• dextran-associated iron oxide particles;
• biodegradable magnetic particles;
• particle size and magnetic response;
• injectable and sterilizable formulations; and
• tissue-specific imaging applications.

A freedom-to-operate review must identify continuation, divisional, and continuation-in-part patents rather than rely on the 5,055,288 patent number alone. The expiration of 5,055,288 does not establish that every related family member expired on the same date.

Later product and formulation patents

Later patents in this field generally focused on:

• alternative polysaccharide coatings;
• carboxydextran and modified dextran;
• ultra-small iron oxide particles;
• prolonged circulation;
• lymph-node imaging;
• macrophage-targeted imaging;
• tumor imaging;
• injectable stability;
• sterilization and autoclaving;
• iron-carbohydrate complexes; and
• therapeutic rather than diagnostic use.

These later rights may be more relevant to a current product than the expired foundational patent.

Ferumoxytol-related landscape

Ferumoxytol is a distinct later-generation iron-carbohydrate nanoparticle. Its principal commercial protection centered on anemia treatment, manufacturing, particle structure, and formulation rather than the historical MRI claims in US 5,055,288.

The patent landscape for ferumoxytol includes later patents and regulatory exclusivity associated with Feraheme. A company developing ferumoxytol-based MRI applications would need to separate:

• the expired 5,055,288 patent;
• active composition or manufacturing patents;
• method-of-use patents;
• approved labeling restrictions; and
• any contractual or regulatory controls held by the product sponsor.

Are there Paragraph IV challenges to US Patent 5,055,288?

No current Paragraph IV challenge can have commercial effect against US Patent 5,055,288 because the patent expired in 2008.

Paragraph IV certifications apply when an ANDA applicant asserts that a listed patent is invalid, unenforceable, or will not be infringed. A certification against an expired patent does not create a 30-month stay based on a live Orange Book patent. Any historical ANDA activity involving ferumoxides would need to be assessed against the product’s complete historical listing record, not solely against this patent.

For a current SPIO or iron-carbohydrate product, the relevant challenge mechanisms may instead involve:

• ANDA patent certifications against later listed patents;
• 505(b)(2) patent certifications;
• citizen petitions or FDA product-quality disputes;
• Hatch-Waxman litigation involving later patents; and
• state or federal patent litigation over manufacturing or use claims.

What generic entry risks exist for products practicing this patent?

The patent-specific generic entry risk is zero because the patent is expired. Commercial entry risk remains substantial for other reasons.

Regulatory and technical barriers

A follow-on SPIO product would still need to address:

• nanoparticle size distribution;
• aggregation control;
• magnetic saturation and squareness;
• relaxivity comparability;
• dextran or polysaccharide characterization;
• endotoxin and sterility limits;
• autoclave stability;
• iron-release and biodegradation profiles;
• pharmacokinetics;
• immunogenicity and hypersensitivity;
• MRI performance across field strengths; and
• clinical or bridging requirements under the selected FDA pathway.

SPIO products are complex drug products. An ANDA may be difficult if the reference product is discontinued, unavailable, or lacks a currently marketed reference product. A 505(b)(2) application may be more practical where the sponsor relies partly on published literature or prior FDA findings but introduces a new formulation, route, indication, or imaging use.

How strong are the claims from a patent-law perspective?

The claims were commercially meaningful when unexpired but have no present enforcement strength. Their historical scope was strongest against products that combined the following elements:

• iron oxide;
• dextran or polysaccharide association;
• submicron aggregates;
• high T1/T2 relaxivity;
• injectable citrate-buffer formulation;
• sterilization or autoclaving;
• rapid biodegradation; and
• measurable circulation in animal models.

The broadest claims, especially claims 1, 2, and 21, contain substantial functional language. Potential historical validity and enforcement issues would have included:

1. Indefiniteness: terms such as "capable of retaining anions," "capable of producing" specified relaxivity, and "capable of being biodegraded."
2. Measurement reproducibility: particle sizes depend on preparation, sonication, medium, concentration, and light-scattering methodology.
3. Biodegradation proof: the claim uses return of proton relaxation rates as the evidentiary endpoint.
4. Enablement: claim 3 spans eight metals, although the specification and commercial development may have centered on iron.
5. Overlap with prior art: earlier iron-oxide and magnetic-particle disclosures could have affected novelty or obviousness.
6. Claim dependency errors: typographical errors and inconsistent units could have affected construction.

The narrow claims are technically easier to evaluate because they identify iron, dextran, citrate, particle-size thresholds, and formulation properties. Their narrowness would have reduced the number of potentially infringing products but improved claim-comparison precision.

Which companies challenged or commercialized competing SPIO technology?

The historical competitive field included:

Company	Relevant activity
Advanced Magnetics	Originator and developer of ferumoxides and related iron-oxide technology
Berlex Laboratories	US commercial partner for Feridex
Bayer HealthCare	Later commercial owner associated with Berlex operations
Schering AG / Schering-Plough	Development and commercialization activities involving ferumoxtran and related SPIO products
Guerbet	Commercial development of ferucarbotran and other contrast technologies
AMAG Pharmaceuticals	Later owner of Advanced Magnetics and ferumoxytol assets

The principal commercial competition came from gadolinium-based extracellular agents, liver-specific agents, and other SPIO products. SPIO products competed on liver uptake, macrophage targeting, T2/T2* signal reduction, circulation time, and iron metabolism rather than solely on particle composition.

What licensing deals affected the patent landscape?

Advanced Magnetics licensed or partnered its ferumoxides technology for commercial development and distribution, including arrangements involving Berlex Laboratories. The commercial relationship later connected to Bayer HealthCare through Bayer’s ownership of Berlex operations.

These arrangements matter for historical commercialization and know-how access, but they do not extend the patent term. A license to an expired patent may remain relevant to confidential manufacturing know-how, trademarks, technical data, or contractual obligations, but it does not restore patent exclusivity.

What geographic coverage did US Patent 5,055,288 provide?

The patent provided protection only in the United States. Foreign protection required separate national or regional patent rights.

A global freedom-to-operate review would require examination of:

• European Patent Office family members;
• Japanese and Canadian counterparts;
• national-phase applications;
• continuation and divisional applications;
• foreign patent-term adjustments or supplementary protection certificates; and
• country-specific validity and lapse records.

US expiration in 2008 did not necessarily mean that every foreign counterpart expired on the same day. Most corresponding rights from this period have also expired, but the status must be verified jurisdiction by jurisdiction.

What is the revenue exposure from this patent?

There is no current revenue exposure from US 5,055,288 itself because it is expired. Historical revenue exposure was concentrated in:

• Feridex IV sales;
• licensing royalties;
• hospital MRI contrast use;
• development-stage ferumoxtran programs; and
• follow-on formulations using dextran-coated iron oxide.

Current revenue exposure shifts to later patents, proprietary manufacturing, regulatory approvals, supply contracts, and clinical differentiation. The patent does not provide a current basis for forecasting exclusivity-adjusted revenue.

Key Takeaways

• US 5,055,288 is a foundational US patent for biodegradable SPIO MRI contrast agents.
• Its strongest commercial embodiment is dextran-associated iron oxide in an aqueous citrate-buffer formulation.
• The patent claims particles, injectable fluids, autoclavable formulations, and MRI contrast agents defined by size, magnetic behavior, relaxivity, biodegradation, and blood half-life.
• The patent issued October 8, 1991 and ordinarily expired October 8, 2008.
• It presents no current US patent barrier to generic or follow-on SPIO development.
• Feridex IV is the product class most closely associated with the patent.
• Ferumoxtran, ferucarbotran, and ferumoxytol require separate product-specific patent and regulatory analysis.
• Current risk is more likely to arise from later formulation, manufacturing, method-of-use, or iron-carbohydrate patents.
• SPIO products remain technically and regulatorily complex despite the expiration of the foundational patent.
• No current Paragraph IV challenge can create a statutory stay or enforceable exclusivity period against this expired patent.

FAQs About US Patent 5,055,288 and SPIO MRI Contrast Agents

Can a company launch a dextran-coated iron-oxide MRI contrast agent after US 5,055,288 expired?

Yes, the expired patent no longer blocks launch. The company must still clear later patents and obtain FDA authorization for the specific product and indication.

Does US 5,055,288 cover ferumoxytol?

It may overlap technically with some particle characteristics, but it does not by itself determine ferumoxytol freedom to operate. Ferumoxytol is governed primarily by later patents, approved labeling, manufacturing rights, and product-specific regulatory requirements.

Did US 5,055,288 protect the MRI use of iron oxide for liver imaging?

The patent includes MRI contrast-agent claims and claims directed to brightening, darkening, and combined contrast effects. It is not limited to one organ or one imaging protocol.

Can an expired SPIO patent still create FDA approval problems?

The patent cannot create patent exclusivity problems, but the historical product may lack a suitable reference product, current manufacturing data, or an available FDA pathway. Those are regulatory issues rather than patent barriers.

Are biosimilar rules relevant to products covered by US 5,055,288?

No. The claimed products are nanoparticulate iron-oxide drug products, not biologics subject to the 351(k) biosimilar pathway. A follow-on sponsor would generally evaluate an ANDA, 505(b)(2), or another applicable pathway based on the product and reference-product circumstances.

References

1. Advanced Magnetics, Inc. (1991). Biodegradable magnetic resonance imaging contrast agents (U.S. Patent No. 5,055,288). United States Patent and Trademark Office.

2. U.S. Food and Drug Administration. (1996). Feridex I.V. (ferumoxides injectable solution) prescribing information. FDA.

3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.

4. U.S. Food and Drug Administration. (2009). Feraheme (ferumoxytol injection) prescribing information. FDA.

5. United States Patent and Trademark Office. (n.d.). Patent term calculator and patent term guidance. USPTO.

Drugs Protected by US Patent 5,055,288

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 5,055,288

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