United States Patent 5,164,377: Scope, Claims, Expiration, and Danaparoid Patent Landscape

U.S. Patent No. 5,164,377 covers a defined heparin-free sulfated glycosaminoglycuronan mixture, its manufacturing process, and pharmaceutical compositions containing it. The claimed material corresponds to the danaparoid-type heparinoid later commercialized as Orgaran. The patent issued on November 17, 1992, and its 17-year U.S. patent term expired on November 17, 2009. The patent therefore creates no current U.S. exclusionary rights, although its claims remain relevant to historical product characterization, prosecution strategy, and prior-art analysis.[1]

What product does U.S. Patent 5,164,377 protect?

The central product claim protects a narrow mixture of sulfated glycosaminoglycuronans that is essentially free of heparin and has both compositional and functional limitations.

The claimed product must contain:

Component	Claimed amount by weight
Dermatan sulfate salts	5% to 25%
Chondroitin sulfate	0% to 9%
Heparan sulfate	66% to 95%
Heparin	Essentially absent

The product must also satisfy all six analytical or pharmacological parameters:

Parameter	Claimed range
Average molecular weight	4,000 to 8,000 daltons
Nitrogen content	2.4% to 3.0%
Sulfur content	7.5% to 9.5%
Sodium content	9% to 11%
Anti-Xa activity	11 to 20 units/mg
Antithrombin III-dependent antithrombin activity	Less than 1 unit/mg

The claim is directed to a low-antithrombin, predominantly anti-Xa anticoagulant mixture. That profile distinguishes the claimed material from unfractionated heparin and from many conventional heparin products, which have materially greater antithrombin activity.

The claimed mixture is consistent with the product class known as danaparoid sodium, a porcine intestinal mucosal heparinoid composed principally of heparan sulfate, with lesser amounts of dermatan sulfate and chondroitin sulfate.[2]

How should claim 1 be construed?

Claim 1 is a product-by-composition-and-properties claim. A competing product would need to fall within the required composition and satisfy the claimed molecular, elemental, and biological characteristics.

Composition limitations

The claim requires a mixture containing heparan sulfate at 66% to 95% by weight, dermatan sulfate at 5% to 25%, and chondroitin sulfate at 0% to 9%. The ranges do not require the components to total exactly 100% because the claim does not expressly identify every possible constituent. The balance may include other sulfated glycosaminoglycuronan material, counterions, water, or analytically uncharacterized fractions, subject to the "essentially free of heparin" limitation.

A material with 4% dermatan sulfate would fall outside the literal claim. The same result would apply to a material with 5% dermatan sulfate but anti-Xa activity below 11 units/mg, because every limitation must be met.

"Essentially free of heparin"

"Essentially free of heparin" is a qualitative limitation rather than a numerical concentration range. It excludes a product in which heparin is a material component or contributes materially to the anticoagulant profile. Trace contamination would not necessarily avoid infringement, but a product deliberately blended with conventional heparin would create a substantial claim-scope issue.

The absence of a numerical threshold makes this limitation dependent on analytical evidence, manufacturing records, impurity profiles, and the technical meaning of heparin in the relevant field.

Molecular-weight limitation

The 4,000-to-8,000-dalton average molecular-weight range is important because the process claim uses ultrafiltration or diafiltration to control the product fraction. Average molecular weight alone does not define the complete distribution. A product with an average within the range could contain material below 4,000 or above 8,000 daltons.

The relevant testing method could materially affect infringement analysis. Gel permeation chromatography, light scattering, osmometry, and other methods may produce different averages for polydisperse polysaccharide mixtures.

Functional limitations

The anti-Xa and antithrombin III-dependent antithrombin limitations are substantive claim limitations. They are not merely intended uses.

The claim requires:

Anti-Xa activity of 11 to 20 units/mg; and
Antithrombin III-dependent antithrombin activity below 1 unit/mg.

A product with suitable component percentages but anti-Xa activity of 21 units/mg would fall outside the literal range. A product with anti-Xa activity within range but antithrombin activity of 1 unit/mg or greater would also fall outside the claim.

Assay protocols, reference standards, sample preparation, and unit definitions would be central in any historical infringement analysis.

What manufacturing process does claim 2 protect?

Claim 2 covers a multistep process for producing the claimed heparin-free glycosaminoglycuronan. Each step is material.

The process requires:

Enzymatic lysis of mammalian tissue.
Contacting the lysate with an anion exchanger.
Binding sulfated glycosaminoglycuronan-containing active material.
Eluting the material with an aqueous salt solution.
Preliminary separation from heparin.
Diafiltering the eluate against an aqueous salt solution.
Using a filtration apparatus with a nominal molecular-weight cutoff of no greater than 10,000 daltons.
Binding the diafiltration product to a second anion exchanger.
Eluting with an aqueous salt solution.
Precipitating with a water-miscible organic solvent.

The process claim is narrower than a general claim to making danaparoid or another heparinoid. A process that uses a different separation sequence, avoids diafiltration, uses a cutoff above 10,000 daltons, or uses a non-water-miscible precipitant would have a strong noninfringement position under the literal claim.

The phrase "whereby preliminary separation from heparin is effected" ties the first ion-exchange operation to the claimed separation result. A process could face a dispute over whether the initial anion-exchange step actually performs the required preliminary heparin separation.

What additional limitations does claim 3 impose?

Claim 3 narrows claim 2 to a specified manufacturing embodiment:

Process variable	Claim 3 requirement
Starting material	Porcine intestinal mucosa
Digestion	Proteolytic enzymes
Salt solution	Sodium chloride
Diafiltration cutoff	About 5,500 daltons
Precipitant	Gradually increasing methanol in water

Claim 3 is therefore directed to a process closely associated with commercial-scale production of danaparoid sodium from porcine intestinal mucosa.

The use of "about 5,500 daltons" introduces ordinary patent-tolerance analysis. The scope would depend on the specification, prosecution history, measurement technique, and technical understanding of the term at the priority date.

What pharmaceutical composition does claim 4 protect?

Claim 4 covers a pharmaceutical composition containing:

Pharmaceutically acceptable auxiliaries; and
An effective amount of the claim 1 sulfated glycosaminoglycuronan sufficient to provide antithrombotic activity.

The claim is dependent on claim 1. A composition cannot infringe claim 4 merely because it contains a heparinoid with antithrombotic activity. The active material must first satisfy claim 1's composition, molecular-weight, elemental, and biological limitations.

The auxiliary limitation is broad. It can encompass injectables, stabilizers, tonicity agents, buffers, carriers, and other conventional pharmaceutical excipients. The claim does not appear limited to a particular dosage form, concentration, route of administration, container, or therapeutic indication.

How strong was the patent estate for danaparoid?

The patent provided meaningful protection during its active term because it combined several claim types:

Claim category	Claim	Commercial significance
Defined active mixture	1	Protected the material by composition and activity
General manufacturing process	2	Covered the principal separation and purification sequence
Specific manufacturing process	3	Covered porcine mucosa, sodium chloride, 5,500-dalton filtration, and methanol precipitation
Pharmaceutical composition	4	Covered dosage forms containing the claimed active material

The estate was stronger against direct copies of the specified product and manufacturing process than against independent development of a different heparinoid. A competitor could seek to avoid the claims by changing one or more of the following:

Glycosaminoglycan proportions;
Molecular-weight distribution;
Ion-exchange sequence;
Ultrafiltration cutoff;
Precipitation solvent;
Starting tissue;
Enzymatic digestion conditions; or
Biological activity profile.

The claim structure also leaves room for disputes over analytical reproducibility. Complex biological mixtures can generate different assay results depending on testing procedures and reference materials.

When did U.S. Patent 5,164,377 expire?

Event	Date
Priority date	December 23, 1987
U.S. patent grant	November 17, 1992
Applicable U.S. term	17 years from grant
Patent expiration	November 17, 2009
Current status	Expired

Because the patent issued before the American Inventors Protection Act changed the term calculation for later-filed applications, the governing term was generally 17 years from the grant date, subject to any applicable disclaimer or adjustment shown in the official patent record.[1]

The expired patent cannot block current U.S. manufacture, use, sale, importation, or development of a product that falls within its former claims. It remains relevant as prior art and as evidence of the technical definition of the danaparoid product class.

What was the Orange Book status of U.S. Patent 5,164,377?

U.S. Patent 5,164,377 does not create a current Orange Book barrier.

Danaparoid was not maintained as a currently marketed FDA-approved U.S. reference product with an active Orange Book patent listing comparable to major commercial low-molecular-weight heparins or direct oral anticoagulants. Public regulatory references identify Orgaran as a danaparoid product used principally outside the United States and in selected clinical settings involving heparin-induced thrombocytopenia.[2,3]

The practical consequences are:

No current U.S. 30-month stay based on this patent.
No active Orange Book patent term extending beyond November 2009.
No current listed-patent barrier to an ANDA applicant based on U.S. Patent 5,164,377.
No current U.S. exclusivity attributable to this patent.

Were there Paragraph IV challenges or settlement agreements?

No material U.S. Paragraph IV litigation or settlement involving U.S. Patent 5,164,377 is reflected in the principal public patent and regulatory records associated with danaparoid.

The absence of a current Orange Book-listed reference product also removes the conventional ANDA litigation pathway under Hatch-Waxman. A party seeking to commercialize a danaparoid-like product today would face regulatory, analytical, manufacturing, and clinical-development issues, but not an enforceable claim under this expired patent.

Does biosimilar risk apply to danaparoid?

Danaparoid is not a biologic subject to the biosimilar pathway under the Public Health Service Act. It is a complex polysaccharide mixture derived from animal tissue.

The principal regulatory challenge is therefore generic or hybrid-product comparability, not biosimilar interchangeability. A developer would need to address:

Source-material controls;
Animal-origin safety;
Glycosaminoglycan composition;
Molecular-weight distribution;
Anti-Xa activity;
Antithrombin activity;
Impurity and residual-protein profiles;
Batch-to-batch consistency;
Sterility and endotoxin controls; and
Clinical or pharmacodynamic comparability.

The mixture's complexity could make regulatory approval more difficult than approval of a conventional small-molecule generic, even though patent protection has expired.

How does the patent compare with competing anticoagulant estates?

Product class	Principal protection model	Current patent risk from U.S. 5,164,377
Danaparoid	Complex mixture, composition and process claims	None; expired
Unfractionated heparin	Manufacturing, formulation, and use claims	No direct overlap in ordinary products
Low-molecular-weight heparins	Composition, depolymerization, dosing, and use claims	Usually distinct mixtures and claim limitations
Fondaparinux	Defined oligosaccharide structure and manufacturing claims	Chemically distinct
Direct oral anticoagulants	Small-molecule composition, formulation, and method claims	No material claim overlap
Biologic anticoagulants	Biologic patent and biosimilar framework	Not applicable to danaparoid

A low-molecular-weight heparin product would not automatically infringe claim 1. It would need to contain the specified dermatan sulfate, chondroitin sulfate, and heparan sulfate profile while also meeting the claimed molecular and activity ranges.

What manufacturing and intellectual-property barriers remain?

Patent expiration removes the principal exclusionary barrier, but commercial entry remains technically demanding.

Manufacturing barriers

The claimed process identifies a practical production platform involving:

Porcine intestinal mucosa;
Proteolytic digestion;
Anion-exchange capture;
Diafiltration;
Controlled molecular-weight fractionation;
Repeated ion-exchange purification; and
Methanol precipitation.

A modern entrant would need validated sourcing, viral and adventitious-agent controls, impurity removal, reproducible fractionation, and a stable analytical specification.

Regulatory barriers

The product is a heterogeneous biological-derived mixture rather than a single chemically defined molecule. Regulatory authorities would likely focus on the relationship between chemical composition and pharmacological activity. Demonstrating equivalence based only on one or two assays would be difficult.

Freedom-to-operate barriers

U.S. Patent 5,164,377 does not create a current FTO barrier. Separate patents covering formulations, dosing regimens, manufacturing improvements, packaging, or use in specific patient populations would require independent review. The expired patent also does not eliminate foreign patent risks in jurisdictions where related family members had different expiration dates or where supplementary protection rights applied.

What is the commercial exposure associated with this patent?

Current U.S. revenue exposure attributable to U.S. Patent 5,164,377 is zero because the patent expired in 2009. Historical value arose from the protection of Orgaran-type danaparoid and from the difficulty of reproducing the product's composition and biological profile.

Any present commercial opportunity would depend on:

A viable U.S. regulatory pathway;
A defensible analytical specification;
Reliable porcine mucosal supply;
Manufacturing economics;
Demand in heparin-induced thrombocytopenia and related indications; and
The status of newer anticoagulant alternatives.

The patent itself does not support a current licensing royalty or U.S. launch-blocking position.

Key Takeaways

U.S. Patent 5,164,377 claims a heparin-free sulfated glycosaminoglycuronan mixture corresponding to the danaparoid product class.
Claim 1 requires specified percentages of dermatan sulfate, chondroitin sulfate, and heparan sulfate, together with molecular-weight, elemental, anti-Xa, and antithrombin limitations.
Claims 2 and 3 protect defined enzymatic digestion, ion-exchange, diafiltration, and methanol-precipitation processes.
Claim 4 covers pharmaceutical compositions containing the claim 1 active material.
The patent issued November 17, 1992, and expired November 17, 2009.
There is no current U.S. patent enforcement risk under this patent.
Danaparoid is a complex animal-derived polysaccharide mixture, not a biologic subject to the biosimilar pathway.
Current entry barriers are regulatory, analytical, supply-chain, and manufacturing-related rather than patent-based.

FAQs About U.S. Patent 5,164,377 and Danaparoid

Can a company manufacture danaparoid in the United States now?

Yes, U.S. Patent 5,164,377 has expired. Manufacture would still require compliance with FDA requirements and any other active patents covering a particular formulation, indication, manufacturing improvement, or delivery system.

Does a product need to contain all three claimed glycosaminoglycans?

To meet claim 1 literally, the product must contain dermatan sulfate within 5% to 25%, chondroitin sulfate within 0% to 9%, and heparan sulfate within 66% to 95%. Chondroitin sulfate may be absent because its lower bound is 0%.

Is a product with the same ingredients but different anti-Xa activity covered?

Not literally under claim 1 if its anti-Xa activity falls outside 11 to 20 units/mg. The claim includes anti-Xa activity as a substantive limitation.

Does the patent cover all heparinoids derived from porcine intestinal mucosa?

No. Claims 2 and 3 require specific process steps, while claim 1 requires a defined final composition and activity profile. Porcine origin alone is insufficient.

Is danaparoid eligible for approval as a conventional generic?

The applicable pathway would depend on the proposed product and its regulatory classification. Because danaparoid is a complex heterogeneous mixture and lacks a current U.S. reference-product framework comparable to many small-molecule drugs, conventional ANDA treatment may not be available or sufficient.

References

United States Patent and Trademark Office. (1992). U.S. Patent No. 5,164,377: Sulphated glycosaminoglycuronan having antithrombotic activity, process for its preparation and pharmaceutical composition containing it.
Organon International. (2002). Orgaran (danaparoid sodium) product information.
Warkentin, T. E., & Greinacher, A. (2004). Heparin-induced thrombocytopenia and cardiac surgery. Annals of Thoracic Surgery, 78(6), 2121-2131.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA Orange Book.
European Medicines Agency. (2008). Orgaran: Product information for danaparoid sodium.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
	89202494.4	Oct 04, 1989

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	98656	⤷ Start Trial
Australia	6323890	⤷ Start Trial
Australia	637143	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,164,377

Summary for Patent: 5,164,377