Details for Patent: 5,069,216

Summary for Patent: 5,069,216

Title:	Silanized biodegradable super paramagnetic metal oxides as contrast agents for imaging the gastrointestinal tract
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:	US07/409,384
Patent Claim Types: see list of patent claims	Use; Composition;

US Patent 5,069,216: Claim Scope, Expiration, Patent Strength, and MRI Contrast-Agent Landscape

US Patent 5,069,216 protects a method of obtaining an in vivo magnetic-resonance image of the gastrointestinal tract after enteral administration of a contrast agent containing silanized aggregates of biodegradable superparamagnetic metal-oxide crystals. The central technical limitation is the particle-size threshold: an overall mean aggregate diameter of about 4,000 angstroms or less, measured by light scattering. The patent is directed to imaging methods, not to a stand-alone composition or manufacturing process.

The patent issued in 1991 and, under the pre-1995 United States patent-term rule, its ordinary term ended in 2008. It therefore does not create a current U.S. blocking right, although its claims remain relevant to historical freedom-to-operate analysis, validity research, patent-family mapping, and interpretation of the ferumoxsil gastrointestinal MRI technology.

What does US Patent 5,069,216 protect?

The patent protects use of a particular class of orally, rectally, or otherwise enterally administered superparamagnetic contrast agents to image the gastrointestinal tract by MRI.

The independent claims require the following elements:

Claim element	Claim 1	Claim 2
In vivo MR imaging	Yes	Yes
Gastrointestinal tract target	Yes	Yes
Animal or human subject	Yes	Yes
Enteral administration	Yes	Yes
Effective amount of contrast agent	Yes	Yes
Physiologically acceptable carrier	Yes	Yes
Buffered aqueous carrier	No	Yes
Biodegradable superparamagnetic contrast agent	Yes	Yes
Silanized aggregates of metal-oxide crystals	Yes	Yes
Overall mean diameter of about 4,000 Å or less	Yes	Yes
Image acquisition after administration	Yes	Yes

A product or procedure must satisfy the limitations of at least one claim. For literal infringement, the accused agent would need to contain silanized aggregates meeting the claimed material characteristics and would need to be administered enterally for gastrointestinal MRI.

The patent does not broadly cover every MRI contrast agent, every iron-oxide nanoparticle, or every gastrointestinal imaging method. Its scope is tied to the combination of:

1. Superparamagnetic metal-oxide crystals.
2. Biodegradability.
3. Aggregation into particles or structures having the specified mean diameter.
4. Silanization.
5. Enteral delivery.
6. MRI of at least part of the gastrointestinal tract.

How do claims 1 and 2 differ?

Claim 1 requires a contrast agent in a physiologically acceptable carrier. Claim 2 requires a superparamagnetic fluid containing the contrast agent in a physiologically acceptable buffered aqueous carrier.

Claim 2 is narrower because it adds both a fluid formulation requirement and a buffered aqueous-carrier limitation. Claim 1 is the broader independent claim for products administered in a physiologically acceptable carrier, including water under dependent claim 12.

The two claims also create separate infringement paths. A formulation that does not satisfy the buffered aqueous-carrier limitation could still fall within claim 1 if all other limitations are met. A formulation that satisfies the buffered aqueous-fluid limitation could fall within both claims.

What particle sizes are protected by claims 3 through 5?

Claims 3 through 5 add progressively narrower size limitations:

Claim	Maximum overall mean diameter
Claims 1 and 2	About 4,000 Å or less
Claim 3	About 3,000 Å or less
Claim 4	About 2,000 Å or less
Claim 5	About 1,000 Å or less

One angstrom equals 0.1 nanometer. The thresholds therefore correspond approximately to:

• 4,000 Å: 400 nanometers.
• 3,000 Å: 300 nanometers.
• 2,000 Å: 200 nanometers.
• 1,000 Å: 100 nanometers.

The measurement method matters. The claims specify overall mean diameter as measured by light scattering. That language focuses on the hydrodynamic or effective aggregate size measured in the relevant dispersion, rather than necessarily the crystallite size observed by electron microscopy.

A formulation could contain iron-oxide crystallites smaller than 100 nanometers but still fall outside claims 4 or 5 if the silanized aggregates have a larger light-scattering diameter.

What chemical compositions are covered?

Claims 6 through 8 identify the metal-oxide system.

Claim 6 covers metal oxide derived from a trivalent metal salt and a divalent metal salt. Claim 7 narrows the trivalent component to a trivalent iron salt and retains a divalent metal salt. Claim 8 covers iron oxide.

The claims therefore encompass mixed-metal oxide systems, including compositions derived from ferric and divalent-metal salts, as well as iron-oxide embodiments. The claim language does not limit the divalent metal to a particular species in the text provided.

The phrase "biodegradable superparamagnetic metal oxide crystals" imposes two functional and structural requirements:

• The particles must exhibit superparamagnetic behavior under the relevant imaging conditions.
• The metal-oxide crystal or aggregate system must be biodegradable in the intended biological context.

A conventional nondegradable magnetic particle, a permanently ferromagnetic material, or a nonmagnetic gastrointestinal marker would not satisfy the central limitation without an equivalent theory.

What administration routes are protected?

Claims 9 through 11 expressly cover three administration routes:

Claim	Route
Claim 9	Oral administration
Claim 10	Intubation
Claim 11	Enema

The independent claims use the broader term "enterally." The dependent claims clarify that enteral administration includes oral delivery, administration through an intubation device, and rectal delivery by enema.

The target anatomy is also broad. Claims 14 through 18 cover:

• Esophagus.
• Stomach.
• Small intestine.
• Large intestine.
• Colon.

A method directed to only one of these gastrointestinal regions may satisfy the claims. The patent does not require imaging of the entire gastrointestinal tract.

What formulations are protected by US 5,069,216?

Claim 12 covers a claim 1 embodiment in which the physiologically acceptable carrier includes water. Claim 13 covers a claim 2 embodiment in which the buffered aqueous carrier includes a polycarboxylic acid.

These claims reach formulation details beyond the magnetic particle itself. Relevant formulation issues include:

• Aqueous dispersion stability.
• Buffer identity and concentration.
• Polycarboxylic-acid content.
• Physiological tolerability.
• Aggregate size after formulation and administration.
• Stability during storage and passage through the gastrointestinal tract.

A formulation analysis should measure aggregate size in the actual finished dosage form. Dry-powder particle size, primary-crystal size, and aggregate size in the administered suspension may differ substantially.

What silanization and biological-targeting limitations are claimed?

Claim 19 requires a polymerizable organosilane as the silanizing agent. Claim 20 identifies N-2-aminoethyl-3-aminopropyltrimethoxysilane, commonly abbreviated APTS or related terminology depending on the analytical record.

The silane limitation is material to the claim. A coating based solely on a non-silane polymer, lipid, sugar, or inorganic layer would not literally meet claims 19 or 20, although it might still be evaluated against claims 1 or 2 if the underlying agent is otherwise within those claims.

Claims 21 through 23 add covalently coupled biological molecules recognized by receptors in the gastrointestinal tract. Claim 22 identifies antibodies. Claim 23 narrows the antibody to one directed against neoplastic tissue.

These claims extend the patent toward targeted gastrointestinal imaging. They require more than merely mixing an antibody with the contrast agent. The biological molecule must be covalently coupled to the silanized aggregate system and recognized by a receptor in the gastrointestinal tract. An antibody attached through a noncovalent interaction may not satisfy the express limitation.

How strong is the patent estate for the claimed technology?

The claim estate has meaningful technical specificity but limited present commercial force because the patent term has expired.

Strengths

The claims combine several limitations that can make anticipation more difficult:

• Enteral gastrointestinal MRI.
• Biodegradable superparamagnetic particles.
• Silanized aggregates.
• A quantified aggregate-size ceiling.
• Light-scattering measurement.
• Optional aqueous buffering.
• Optional antibody or neoplastic-tissue targeting.

The size limitation also provides a measurable technical parameter. If reproducible testing establishes that an accused product has aggregates above the claimed threshold, that evidence could be important in a historical infringement analysis.

Weaknesses

The claims have several potential vulnerability points:

• The patent claims a method rather than a broad composition.
• The claims require use for gastrointestinal MRI.
• The material must be both biodegradable and superparamagnetic.
• The aggregate-size measurement is dependent on analytical conditions.
• "About" introduces a scope question around the numerical thresholds.
• Silanization may be absent from later-generation formulations.
• The patent does not expressly claim every coating chemistry or every magnetic nanoparticle architecture.

The dependent claims are narrower and generally more vulnerable to design-around strategies. For example, a competitor could investigate a non-silanized coating, a different particle-size distribution, a nonenteral imaging route, or a nonmagnetic contrast mechanism.

When did US Patent 5,069,216 lose exclusivity?

US Patent 5,069,216 issued in 1991. Because the application predates the change to the United States patent-term regime, the ordinary term was generally 17 years from issue rather than 20 years from the earliest effective filing date. On that basis, the patent expired in December 2008, subject to any adjustment or extension recorded in the official patent file.[1]

There is no current patent exclusivity under the claims quoted. A party commercializing a modern gastrointestinal MRI contrast agent would not face an enforceable infringement claim under an expired U.S. patent.

The expiration does not eliminate the patent’s historical significance. It may still be relevant to:

• Prior-art analysis.
• Patentability of later formulations.
• Inventorship and ownership investigations.
• Licensing diligence.
• Product-development chronology.
• Interpretation of ferumoxsil and related iron-oxide agents.

What was the FDA status of the associated gastrointestinal MRI technology?

The claimed technology is associated with oral superparamagnetic iron-oxide gastrointestinal MRI contrast agents, including ferumoxsil-based products historically marketed under names such as GastroMARK and Lumirem. Ferumoxsil products were developed to reduce signal from gastrointestinal contents and improve visualization of abdominal structures.

The regulatory status of a particular product must be separated from the patent status:

Issue	Assessment
Patent protection under US 5,069,216	Expired
Product approval	Historical approval associated with ferumoxsil gastrointestinal MRI use
Current commercial availability	Limited or discontinued in major markets
Current patent barrier	None from the expired patent
Biosimilar pathway	Not applicable to a small-molecule or particulate contrast agent
Generic pathway	Potentially relevant only if an approved reference product and commercial market remain available

FDA approval does not extend an expired patent. Conversely, patent expiration does not automatically establish that an equivalent product can be marketed without satisfying current FDA requirements for chemistry, manufacturing, controls, safety, imaging performance, and labeling.

Are Paragraph IV challenges or settlements associated with this patent?

A Paragraph IV certification applies to patents listed in the FDA Orange Book for an approved drug product. The quoted patent is a method-of-use patent for gastrointestinal MRI and is not, based on the claim text, a composition patent.

No current Paragraph IV barrier arises from an expired patent. Any historical Paragraph IV dispute would have depended on whether the patent was listed for the relevant reference product and whether the challenger filed an ANDA directed to that product. A patent can be legally important without being Orange Book-listed, particularly where the claims cover a research method, an off-label use, or a product no longer marketed.

There is no basis in the supplied claim set to identify a patent settlement, launch date, or litigation outcome. The patent’s expiration independently removes the practical need for a current Paragraph IV challenge to these claims.

What generic-entry risks exist for gastrointestinal MRI contrast agents?

The main current risk is regulatory and technical rather than patent-based.

A prospective entrant would need to address:

1. Demonstration of a pharmaceutically acceptable and reproducible particle system.
2. Control of crystallite size and aggregate size.
3. Superparamagnetic performance.
4. Biodegradation and tissue-clearance characteristics.
5. Gastrointestinal tolerability.
6. MRI contrast performance across relevant sequences.
7. Product stability and aggregate growth during shelf life.
8. Manufacturing controls for silane chemistry and surface functionalization.
9. FDA pathway selection.
10. Commercial demand for an oral or rectal MRI contrast agent.

The expired patent may simplify freedom to operate, but it does not remove manufacturing barriers. Aggregate-size control can be difficult because ionic strength, pH, buffer composition, concentration, temperature, and storage can alter dispersion behavior.

How does this patent compare with modern MRI contrast-agent patents?

US Patent 5,069,216 is narrower than many modern nanoparticle patent estates in some respects and broader in others.

Technology category	Typical protection focus	Relationship to US 5,069,216
Gadolinium extracellular agents	Chelate structure, formulation, dosing, use	Usually outside the claimed magnetic-oxide system
Ultrasmall superparamagnetic iron oxides	Composition, coating, pharmacokinetics, liver or lymph-node imaging	May overlap technically but not necessarily enteral GI use
Oral gastrointestinal agents	Formulation, suspension, dosing, imaging method	Closest commercial and technical category
Targeted nanoparticles	Ligand, antibody, receptor, tumor targeting	Potentially overlaps claims 21-23 if GI administration and all other limits are met
Manufacturing patents	Particle synthesis, coating, purification, scale-up	Not directly claimed by US 5,069,216
Diagnostic software	Image processing and lesion detection	Outside the quoted claims

The patent’s strongest historical contribution is the combination of enteral gastrointestinal MRI with biodegradable, silanized superparamagnetic aggregates and controlled light-scattering size.

What geographic coverage does the patent have?

US Patent 5,069,216 provided rights only in the United States. International protection would have required separate national patents or regional rights in jurisdictions such as Europe, Canada, Japan, or Australia.

Expiration in the United States does not establish expiration dates elsewhere. Foreign counterparts could have:

• Different filing dates.
• Different claim scope.
• Different term adjustments.
• Patent-term extensions.
• Abandonment or lapse for nonpayment.
• National-phase differences.
• Separate litigation or settlement histories.

A global freedom-to-operate review therefore cannot rely on the U.S. expiration date alone.

What manufacturing and intellectual-property barriers remain?

The patent does not claim a detailed manufacturing process. It does not expressly require a particular crystallization protocol, milling process, purification sequence, or filling operation.

The practical barriers are more likely to arise from later patents and know-how covering:

• Formation of uniform iron-oxide crystallites.
• Silane coupling and surface activation.
• Prevention of aggregation.
• Sterile or low-bioburden manufacture.
• Control of residual silane and metal ions.
• Buffered aqueous suspension stability.
• Scale-up without loss of magnetic performance.
• Analytical validation of light-scattering measurements.

Because US 5,069,216 has expired, proprietary manufacturing know-how or later unexpired process patents would be more commercially relevant than the claims quoted here.

Key Takeaways

• US Patent 5,069,216 is a method patent for gastrointestinal MRI using enterally administered silanized aggregates of biodegradable superparamagnetic metal-oxide crystals.
• Claims 1 and 2 are the principal independent claims.
• The central particle-size limitation is an overall mean aggregate diameter of about 4,000 angstroms or less by light scattering.
• Claims 3 through 5 narrow the threshold to approximately 300, 200, and 100 nanometers.
• The patent covers oral administration, intubation, and enema delivery.
• It reaches imaging of the esophagus, stomach, small intestine, large intestine, and colon.
• Claims 19 and 20 focus on polymerizable organosilanes, including N-2-aminoethyl-3-aminopropyltrimethoxysilane.
• Claims 21 through 23 cover covalently coupled biological molecules, including antibodies against neoplastic tissue.
• The patent’s ordinary U.S. term ended in December 2008.
• No current U.S. blocking right exists under the quoted claims.
• Biosimilar analysis is not applicable; any generic pathway would depend on the regulatory status of the relevant reference product.
• Current commercial barriers are more likely to involve FDA requirements, formulation stability, manufacturing know-how, and later patent families.

FAQs About US Patent 5,069,216

Does US Patent 5,069,216 claim ferumoxsil itself?

No. The quoted claims are method claims. They cover specified use of silanized biodegradable superparamagnetic metal-oxide aggregates for gastrointestinal MRI rather than claiming ferumoxsil as a composition in the abstract.

Does the patent cover intravenous superparamagnetic iron-oxide imaging?

No. The claims require enteral administration and imaging of at least part of the gastrointestinal tract. Intravenous imaging of the liver, spleen, lymph nodes, or other tissues falls outside the literal scope of the quoted claims.

Does a particle below 100 nanometers automatically infringe claim 5?

No. Claim 5 requires the overall mean diameter of the silanized aggregates to be about 1,000 angstroms or less as measured by light scattering, plus all limitations inherited from claim 1 or claim 2. Primary crystal size alone is not determinative.

Are antibody-targeted gastrointestinal MRI agents covered?

They may fall within claims 21 through 23 only if the biological molecule is covalently coupled to the silanized aggregates, is recognized by a gastrointestinal receptor, and the base limitations for enteral gastrointestinal MRI and particle composition are satisfied.

Can a company launch a competing gastrointestinal MRI contrast agent today without licensing this patent?

The expired U.S. patent does not require a current license. A launch would still require evaluation of later U.S. and foreign patents, FDA requirements, manufacturing controls, product-specific exclusivities, and any rights held by the relevant product developer.

References

1. United States Patent and Trademark Office. (1991). United States Patent No. 5,069,216: Magnetic resonance imaging contrast agents.
2. United States Patent and Trademark Office. (2024). Patent term adjustment and patent term calculation resources.
3. U.S. Food and Drug Administration. (n.d.). Drugs@FDA: FDA-approved drugs database.
4. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations.
5. U.S. Food and Drug Administration. (n.d.). Orange Book: Approved drug products with therapeutic equivalence evaluations.

Drugs Protected by US Patent 5,069,216

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 5,069,216

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