Details for Patent: 4,827,945

Summary for Patent: 4,827,945

Title:	Biologically degradable superparamagnetic materials for use in clinical applications
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:	US07/067,586
Patent Claim Types: see list of patent claims	Use; Composition; Formulation; Dosage form;

US Patent 4,827,945: Scope, Claims, Expiration, and MRI Contrast-Agent Patent Landscape

US Patent 4,827,945 covers methods of using biodegradable superparamagnetic metal-oxide particles as magnetic-resonance-imaging contrast agents, with additional claims directed to polymer-coated particles, polycarboxylic-acid buffers, organ targeting, reticuloendothelial-system blocking, blood-flow detection, and anemia treatment. The patent issued May 9, 1989, and its ordinary 17-year term expired May 9, 2006. It therefore does not create a current exclusionary barrier in the United States, although its claims remain relevant as prior art and as an origin point for later MRI contrast-agent patent families. [1, 2]

What does US Patent 4,827,945 cover?

The patent is a method-of-use patent rather than a simple composition patent. Its central inventive concept is the administration of biodegradable superparamagnetic metal oxides, particularly iron oxides, to produce MRI contrast while allowing eventual biological degradation.

The claims define the agent through a combination of structural, magnetic, physicochemical, and functional limitations:

Limitation	Claimed requirement
Particle type	Biodegradable superparamagnetic metal oxide
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 and R2 at least about 10^5 M^-1 sec^-1
Crystal size	About 10 to 500 Å
Overall particle size	About 10 to 4,000 Å by light scattering
Solubility or dispersibility	Aqueous concentrations up to about 5 molar
Biological behavior	Retention long enough for imaging, followed by biodegradation
Optional coating	Polymer, including dextran, albumin, polysaccharides, proteins, carbohydrates, polypeptides, organosilanes, or composites
Optional formulation	Polycarboxylic-acid buffer at specified metal concentration and pH
Imaging targets	Liver, spleen, bone marrow, lymph nodes, brain, spinal cord, vasculature, lungs, and gastrointestinal organs
Administration	Intravascular, parenteral, oral, intubation, or enema
Special applications	Organ targeting, blood-flow imaging, and anemia reduction

The claims do not cover every iron-oxide nanoparticle. A potentially relevant product must satisfy the specific magnetic, size, relaxivity, biodegradation, and administration limitations recited in the asserted claim.

How broad are the independent claims?

Claims 1, 2, 3, 32, 35, 38, and 39 are the principal independent claims or independent claim groups.

Claims 1 and 2: core MRI imaging methods

Claim 1 covers administering a biodegradable superparamagnetic metal oxide in a physiologically acceptable carrier and obtaining an in vivo MR image.

Claim 2 covers the same general method where the metal oxide is associated with a polymeric substance.

The distinction is commercially important:

• Claim 1 reaches uncoated or non-polymer-associated biodegradable superparamagnetic metal oxides.
• Claim 2 requires association with a polymeric substance.
• Claim 2 does not require the specific polycarboxylic-acid buffer recited in claim 3.
• Claim 2 is narrowed by its polymer requirement but remains broad as to the type of polymer.

The polymer list in claim 6 is expansive. Claim 7 narrows the polymer to dextran with a molecular weight of 5,000 to 250,000 daltons. Claims 8 and 9 separately identify albumin and a polymer of N-2-aminoethyl-3-aminopropyltrimethoxysilane.

Claim 3: formulation-specific MRI method

Claim 3 adds a defined aqueous polycarboxylic-acid buffer. The formulation must have:

• Metal concentration of 0.05 to 5 molar;
• Polycarboxylate concentration of 0.001 to 0.1 moles per mole of metal; and
• pH of approximately 6 to 8.3.

Claim 4 limits the metal to iron and identifies citrate, tartrate, succinate, and maleate buffers. Claim 5 further narrows the formulation to approximately 1.3 molar iron, 0.04 molar citrate, and pH 7.

Claim 3 is narrower than claims 1 and 2 because infringement requires the claimed buffer characteristics. A modern iron-oxide MRI product could fall within the particle definition but avoid claim 3 if it uses a different buffer system or does not meet the stated concentration and pH ranges.

What do claims 4 through 31 protect?

Claims 4 through 31 are dependent method claims that add formulation, delivery, tissue, and targeting limitations.

Formulation and polymer claims

Claims 4 and 5 focus on iron-based citrate, tartrate, succinate, or maleate formulations. Claim 5 is highly specific and would be vulnerable to design-around through changes in:

• Iron concentration;
• Citrate concentration;
• Buffer identity;
• pH;
• Counterion ratio; or
• Use of a nonaqueous or differently buffered formulation.

Claims 6 through 9 cover particular polymer classes. Dextran-coated iron oxide is the most commercially relevant embodiment because dextran or modified dextran has historically been used to stabilize superparamagnetic iron-oxide particles.

Route-of-administration claims

Claim 10 covers intravascular administration. Claim 40 separately covers parenteral administration.

Claims 11 and 21 through 22 extend the claimed methods beyond intravenous imaging to oral administration, intubation, enema, and gastrointestinal imaging. These claims reflect the patent's attempt to cover both systemic and luminal or organ-specific delivery.

Anatomical targets

Claims 12 through 22 cover imaging of:

• The reticuloendothelial system;
• Liver, spleen, and bone marrow;
• Lymphatic tissue and lymph nodes;
• Brain and spinal cord;
• Blood capillaries and lymph vessels;
• Lungs; and
• Esophagus, stomach, small intestine, and large intestine.

These are use limitations. A product is not infringing solely because it is capable of accumulating in the liver or spleen. The asserted method must involve administration and acquisition of an MR image of the claimed organ or tissue.

Targeted contrast agents

Claim 23 covers a polymer-associated metal oxide carrying a covalently coupled biological molecule that directs the particle to a receptor-recognizing tissue.

Claims 24 through 32 identify:

• Antibodies;
• Anti-melanoma antibodies;
• Anti-heart-myosin antibodies for infarcted heart tissue;
• Anti-T-cell antibodies for lymphoma;
• Antibodies against carcinoembryonic antigens for colonic tumors;
• Anti-ovarian-cancer-cell antibodies;
• Carbohydrates; and
• Hormones.

These claims attempt to cover molecularly targeted MRI contrast agents. Their practical scope depends on whether the biological ligand is covalently coupled to the polymer and whether the particle is directed in vivo to tissue recognizing that ligand.

What do claims 32 through 37 cover?

Claims 32 through 37 cover reticuloendothelial-system manipulation rather than only contrast-agent composition.

RES blocking and serum-lifetime extension

Claim 32 covers administering a blocking agent before or together with a superparamagnetic MR contrast agent. The blocking agent must competitively bind RES receptors that would otherwise remove the contrast agent from circulation.

Claims 33 and 34 narrow the blocking agent to a paramagnetic agent, including paramagnetic iron oxide used with biodegradable superparamagnetic iron oxide.

The commercial objective is to reduce rapid uptake by macrophages in the liver and spleen, thereby extending circulation time and potentially improving blood-pool imaging.

Blood-flow detection

Claim 35 covers:

1. Administration of a dispersoid recognized by RES receptors;
2. Subsequent administration of a competing superparamagnetic MR contrast agent;
3. MR imaging of blood in a body section; and
4. Detection of blood-flow presence or absence.

Claims 36 and 37 narrow the blocking agent to a paramagnetic agent and identify biodegradable superparamagnetic iron oxide as the contrast agent.

These claims are technically distinct from ordinary organ imaging. They require a competitive receptor-blocking sequence and a blood-flow determination.

What do claims 38 and 39 cover?

Claims 38 and 39 cover reducing anemia through parenteral administration of biodegradable superparamagnetic iron-oxide dispersoids.

Claim 38 requires an individual particle with:

• Iron-oxide crystals of 10 to 500 Å;
• Overall mean diameter of 10 to 5,000 Å;
• Surface area greater than 75 m²/g;
• Magnetic saturation of 5 to 90 EMU/g; and
• Magnetic squareness below 0.1.

Claim 39 adds the polycarboxylic-acid buffer and the relaxivity and concentration limitations.

These claims are technically significant because they extend beyond diagnostic imaging into therapeutic iron administration. Their relevance to later intravenous iron products depends on whether the product satisfies all particle and magnetic limitations. A conventional iron-carbohydrate complex would not automatically fall within the claims merely because it is administered parenterally to treat iron-deficiency anemia.

When did US Patent 4,827,945 lose exclusivity?

The patent issued on May 9, 1989. For a US patent governed by the pre-1995 term rule, the ordinary term was 17 years from issue. On that basis, the patent expired on May 9, 2006. [1, 2]

Event	Date
US patent grant	May 9, 1989
Ordinary patent term	17 years from issuance
Expected expiration	May 9, 2006
Current status	Expired by term

The patent cannot support a new US infringement action after expiration. It can still affect patentability of later applications as prior art, subject to the applicable filing-date and prior-art rules.

What FDA products are most closely associated with this patent?

The patent's technology is most closely associated with biodegradable superparamagnetic iron-oxide products, including ferumoxides and related dextran-coated or polymer-associated particles.

Product or agent	Active material	Regulatory status	Relationship to the patent technology
Feridex I.V.	Ferumoxides, superparamagnetic iron oxide	FDA-approved MRI contrast agent; later discontinued in the United States	Closely aligned with biodegradable SPIO liver and RES imaging
Resovist	Ferucarbotran	Approved in certain non-US markets; not broadly commercialized in the United States	Related SPIO platform with carbohydrate coating
Combidex or ferumoxtran-10	Dextran-coated SPIO	Investigational or limited-market status	Related lymph-node and RES imaging technology
Feraheme	Ferumoxytol, iron-carbohydrate nanoparticle	FDA-approved for iron-deficiency anemia	Therapeutically related iron-oxide nanoparticle, but not an FDA-approved MRI contrast indication

Feridex I.V. was approved for hepatic MRI applications involving abnormal liver tissue. Its product profile corresponds closely to the patent's claims involving biodegradable superparamagnetic iron oxide, polymer association, and reticuloendothelial-system imaging. [3]

Feraheme was approved for iron-deficiency anemia, which overlaps conceptually with claims 38 and 39. Its approved use is as an intravenous iron-replacement product, not as an MRI contrast agent. The product's regulatory labeling emphasizes iron-replacement pharmacology and hypersensitivity risks rather than diagnostic imaging. [4]

What is the Orange Book status of this patent?

US Patent 4,827,945 is not a current Orange Book exclusivity barrier. Its term expired in 2006, and Feridex I.V. is no longer a current US commercial product with active market exclusivity.

The Orange Book records patents and exclusivity information for approved drug products, but listing status does not extend an expired patent term. FDA's Orange Book framework also distinguishes between approved products, discontinued products, patent listings, and regulatory exclusivity. [5]

For current development programs, the relevant question is not whether this patent once covered ferumoxides. The relevant questions are whether later patents cover:

• The specific iron-carbohydrate or dextran structure;
• Particle size distribution;
• Surface chemistry;
• Manufacturing processes;
• Sterilization and formulation;
• Clinical imaging indications;
• Dosage and administration protocols; or
• Therapeutic iron-replacement uses.

Are there Paragraph IV challenges associated with US Patent 4,827,945?

A Paragraph IV certification would have been relevant only while the patent was listed and unexpired for an applicable FDA product. Because US Patent 4,827,945 expired in 2006, it is no longer a meaningful Paragraph IV barrier for an ANDA or 505(b)(2) applicant.

The patent's claims are method claims. Under the Hatch-Waxman framework, a generic applicant would generally evaluate whether the reference product's labeling induces use of the claimed methods and whether any listed method-of-use patent remains enforceable. [6]

The practical risk profile is:

Issue	Current effect
Paragraph IV notice against the expired patent	No meaningful ongoing exclusionary effect
30-month stay based solely on this patent	Not available as a current patent-term strategy
Historical litigation value	Potentially relevant to older product launches
Prior-art value	High for later SPIO, iron-oxide, and MRI-agent applications
Current launch barrier	None from this patent alone

Which companies challenged or commercialized related technology?

The principal commercial participants in the relevant technology area have included:

• Advanced Magnetics, later associated with AMAG Pharmaceuticals;
• Schering AG and Bayer-related entities involved in ferucarbotran and related contrast products;
• Nycomed and later GE Healthcare interests in MRI contrast technologies;
• Berlex and Bayer entities in the MRI contrast market; and
• Manufacturers of iron-carbohydrate products, including ferumoxytol developers.

The competition was divided between diagnostic SPIO products and therapeutic intravenous iron products. The two categories share particle-engineering concepts but have different regulatory objectives, clinical endpoints, labeling, and patent strategies.

How strong was the patent estate?

Historical strength

The patent was historically strong in concept coverage because it combined:

• Broad in vivo MRI method claims;
• Defined superparamagnetic behavior;
• Defined particle and crystal dimensions;
• Polymer-associated embodiments;
• Specific buffer systems;
• Organ and tissue indications;
• Targeted biological ligands;
• RES blocking;
• Blood-flow imaging; and
• Anemia treatment.

This structure gave the patent multiple infringement theories against a product using the claimed particle platform across different indications.

Limitations affecting claim strength

The patent also contains limitations that could have constrained enforcement:

1. The magnetic saturation and squareness ranges require technical testing.
2. Relaxivity thresholds depend on measurement conditions, field strength, temperature, and concentration methodology.
3. “Biodegradable” and “ultimately biodegraded” require factual proof concerning biological fate.
4. The light-scattering diameter limitation can vary with aggregation state and test protocol.
5. Claims 32 through 37 require RES-receptor competition, which may be difficult to establish without pharmacokinetic or mechanistic evidence.
6. Claims 23 through 31 require covalent ligand coupling and in vivo tissue recognition.
7. Method claims require proof of the accused administration and imaging use.

The patent was therefore broad at the platform level but technically evidence-intensive in litigation.

What patent barriers remain after expiration?

The expired patent does not eliminate freedom-to-operate risks for modern products. Later patent families may cover:

• Ferumoxytol compositions and iron-carbohydrate chemistry;
• Dextran or modified-dextran coatings;
• Crosslinking and surface functionalization;
• Particle-size control;
• Injectable formulations;
• Sterile manufacturing;
• Long-circulating nanoparticle designs;
• MRI-specific diagnostic indications;
• Targeted antibodies or peptides;
• Iron-deficiency-anemia dosing regimens; and
• New contrast-agent combinations.

A current developer should separate the expired platform claims from later improvement patents. The relevant FTO analysis must examine US continuations, divisionals, continuation-in-part applications, terminal disclaimers, patent-term adjustments, and patents listed for the specific reference product.

What generic launch scenarios exist?

Generic MRI contrast agent

A generic or 505(b)(2) applicant could potentially pursue a biodegradable SPIO MRI product without obtaining rights under US Patent 4,827,945. The principal barriers would be clinical-development cost, discontinued reference-product status, manufacturing complexity, and the absence of a large current US market.

Follow-on intravenous iron product

A follow-on ferumoxytol or iron-carbohydrate product would face a different landscape. The expired patent would not be the main issue. Later composition, manufacturing, formulation, and clinical-use patents would require separate review. FDA approval would also depend on the applicable pathway and reference-product availability. [4, 5]

Non-US launch

Patent analysis must be performed jurisdiction by jurisdiction. US expiration does not establish expiration elsewhere. Foreign counterparts may have expired at different times, been abandoned, lapsed for nonpayment, or received supplementary protection or other term extensions. A global launch requires country-level review of the patent family and national registers.

Key Takeaways

• US Patent 4,827,945 is a foundational platform patent for biodegradable superparamagnetic metal-oxide MRI contrast agents.
• Its strongest commercial concepts are polymer-associated iron oxide, dextran-coated particles, RES imaging, liver and spleen imaging, and targeted contrast agents.
• Claims 32 through 37 cover RES blocking, serum-lifetime extension, and blood-flow detection.
• Claims 38 and 39 extend the patent to anemia-reduction methods using biodegradable superparamagnetic iron oxide.
• The patent issued May 9, 1989, and its ordinary term expired May 9, 2006.
• It is no longer a current US exclusionary right and should not block a present-day US launch.
• Later patents, rather than this patent, are the principal FTO risk for ferumoxytol, iron-carbohydrate products, modern SPIO agents, and targeted nanoparticle formulations.
• The patent remains important prior art for MRI contrast, nanomedicine, iron therapy, and biodegradable magnetic-particle technologies.

FAQs About US Patent 4,827,945

Is US Patent 4,827,945 still enforceable?

No. Its ordinary US patent term expired May 9, 2006.

Did US Patent 4,827,945 cover Feridex?

Its claims cover technical characteristics and uses closely associated with Feridex-type biodegradable superparamagnetic iron-oxide MRI agents. Product-specific infringement would require analysis of the marketed formulation, labeling, and claimed method.

Does the patent cover ferumoxytol?

Not automatically. Ferumoxytol may share certain iron-oxide and biodegradation concepts, but infringement would require every limitation of an asserted claim, including the specified magnetic, particle, relaxivity, and use limitations.

Can an expired patent still affect a new MRI contrast-agent application?

Yes. It can operate as prior art against later patent claims, even though it cannot provide current infringement protection.

Are biosimilar rules relevant to this patent?

Generally no. Superparamagnetic iron-oxide and iron-carbohydrate products are regulated as drug products rather than biologic products for which the principal US pathway is biosimilar approval under section 351(k). The relevant pathway may instead be an ANDA, 505(b)(2) application, or a full NDA, depending on the product and reference.

References

1. United States Patent and Trademark Office. (1989). U.S. Patent No. 4,827,945.
2. 35 U.S.C. § 154. Patent term and patent rights.
3. U.S. Food and Drug Administration. (n.d.). Feridex I.V. prescribing information.
4. U.S. Food and Drug Administration. (n.d.). Feraheme (ferumoxytol injection) prescribing information.
5. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
6. U.S. Food and Drug Administration. (n.d.). Guidance for industry: 180-day exclusivity when multiple ANDA applicants submit substantially complete ANDAs with paragraph IV certifications.

Drugs Protected by US Patent 4,827,945

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 4,827,945

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