United States Drug Patent 5,583,131: Claim Scope, Plerixafor Coverage, and Patent Landscape

US Patent No. 5,583,131 is the foundational U.S. patent covering bicyclam and related bis-macrocyclic compounds with anti-HIV activity. Its claim set includes broad pharmaceutical-composition coverage, specific bicyclam chemical entities, metal complexes, acid-addition salts, and several substituted aromatic or heteroaromatic linkers. The patent is most closely associated with plerixafor, also known as AMD3100 and marketed by Genzyme/Sanofi as Mozobil.

The patent issued on December 10, 1996. Its ordinary United States patent term ended December 10, 2013, subject to any applicable regulatory or pediatric extension. The patent therefore does not currently block generic manufacture or use in the United States. The patent remains commercially important because it defined the original chemical and intellectual-property platform for CXCR4 antagonists.

What drug does US Patent 5,583,131 protect?

US 5,583,131 protects a class of linked cyclic polyamines, particularly bis-macrocycles connected through aromatic or heteroaromatic methylene bridges.

The principal structure is:

Z-R-A-R'-Y

where:

Z and Y are identical cyclic polyamine moieties;
each cyclic polyamine has 10 to 15 ring members;
each ring contains 3 to 6 amine nitrogens;
the ring nitrogens are separated by at least two carbon atoms;
the ring heteroatoms are limited to amine nitrogens;
A is an aromatic or heteroaromatic moiety other than quinoline;
R and R' are methylene groups attached to ring nitrogen atoms;
the relevant amine nitrogens are otherwise unsubstituted.

The lead structure associated with the patent is the bicyclam compound:

1,1'-[1,4-phenylenebis(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane

This compound is commonly known as AMD3100 or plerixafor. Plerixafor is a small-molecule CXCR4 antagonist used with granulocyte colony-stimulating factor to mobilize hematopoietic stem cells for collection before autologous transplantation. The FDA approved Mozobil on December 15, 2008, for patients with non-Hodgkin lymphoma or multiple myeloma undergoing stem-cell collection. The approved indication is not HIV treatment, even though the patented compounds were originally claimed as anti-HIV agents (FDA, 2008).

What are the main claim categories in US 5,583,131?

The claims divide into two principal categories:

Pharmaceutical compositions containing the claimed bis-macrocyclic compounds.
The compounds themselves, including specific salts and metal complexes.

Claim group	Claims	Primary subject matter	Commercial relevance
Broad composition genus	1	Pharmaceutical composition containing a linked cyclic polyamine active against HIV	Core platform claim
Macrocycle-size limitation	2	14-membered rings with four ring nitrogens	Directly targets bicyclam structures
Specific composition claims	3-16	Named aromatic, heteroaromatic, and macrocycle variants	Species-level composition protection
Specific compound claims	17-35	Named salts, substituted analogs, and metal complexes	Chemical-entity protection
Plerixafor-relevant species	4, 5, 23 and related claims	Para-phenylene-linked bicyclam and its metal complexes	Most important historical coverage

Claim 1 is the broadest claim. Claims 2 through 16 narrow the composition by specifying ring architecture or named active ingredients. Claims 17 through 35 identify individual chemical compounds or complexes.

The patent does not claim a conventional tablet, capsule, injectable formulation, excipient system, dosage regimen, manufacturing process, or treatment method in the claim language supplied by the user.

How broad is claim 1?

Claim 1 has substantial chemical breadth but several structural limitations.

Structural limitations

The claim requires both cyclic polyamine termini to be identical. This excludes compounds in which the two macrocycles differ in ring size, nitrogen count, substitution pattern, or ring connectivity.

The macrocycles must have:

10 to 15 total ring members;
3 to 6 ring nitrogens;
at least two carbon atoms between adjacent amine nitrogens;
no ring heteroatoms other than amine nitrogens.

The claim therefore reaches bicyclam, bis-triazacyclododecane, and related bis-polyaza macrocycles, but it does not cover every polyamine, crown ether, piperazine, diaza-crown, or mixed heteroatom macrocycle.

Linker limitations

The two macrocycles must be connected by an aromatic or heteroaromatic group through methylene substituents:

macrocycle-N-CH2-A-CH2-N-macrocycle

The claim excludes:

quinoline as the central aromatic or heteroaromatic moiety;
nonaromatic aliphatic linkers;
direct carbon-carbon attachment between the macrocycle and aromatic ring;
linkers using oxygen, sulfur, carbonyl, or additional nitrogen instead of methylene;
unsymmetrical macrocycle pairs.

Nitrogen-substitution limitation

The ring amine nitrogens are required to be otherwise unsubstituted. This is an important design-around limitation. N-alkylated, N-acylated, N-benzylated, or otherwise substituted analogs may fall outside claim 1, depending on the exact location and nature of the substitution.

The limitation does not necessarily exclude protonation or formation of an acid-addition salt. The dependent claims expressly identify acid-addition salt forms.

Which claims most directly cover plerixafor?

The claims most closely associated with plerixafor are the para-phenylene-linked bicyclam claims.

Claim	Relevant subject matter
2	Two 14-membered macrocycles, each with four ring nitrogens
4	1,1'-[1,4-phenylenebis(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane in acid-addition salt form
5	Bis-zinc complex of the para-phenylene-linked bicyclam
6	Bis-copper complex of the para-phenylene-linked bicyclam
23	Bis-zinc complex as a compound claim
33-35	Related substituted para-phenylene analogs

The core plerixafor structure is the free-base bicyclam. Commercial plerixafor is supplied as the hydrochloride salt. Claims 4 and related claims expressly identify the acid-addition salt form, while claim 1 provides broader composition coverage.

What chemical structures are covered by claims 3 through 35?

The named species cover several linker families.

Phenylene-linked bicyclams

Claims 3 and 4 cover meta- and para-phenylene-linked bicyclams. The para-phenylene structure is the principal plerixafor-related species.

Claims 17, 18, 19, 20, 32, 33, and 34 add substituted aromatic analogs, including:

nitro-substituted phenylene;
tetrachlorophenylene;
tetrafluorophenylene;
naphthylene;
dimethylphenylene;
dichlorophenylene;
bromophenylene.

Biphenyl and heteroaromatic linkers

Claims 7, 24, 13, 28, 14, and 29 cover:

biphenylene-linked compounds;
bipyridine-linked compounds;
phenanthroline-linked compounds.

These structures introduce additional aromatic nitrogen atoms into the linker but preserve the macrocyclic polyamine termini.

Pyridine and thiophene linkers

Claims 10, 11, 12, 25, 26, and 27 cover:

2,6-pyridine-linked compounds;
3,5-pyridine-linked compounds;
2,5-thiophene-linked compounds.

Smaller triazacyclododecane macrocycles

Claims 21, 22, 30, and 31 cover compounds containing 1,5,9-triazacyclododecane units. These claims broaden the portfolio beyond the 14-membered tetraazacyclotetradecane bicyclam series.

Metal complexes

Claims 5, 6, and 23 cover bis-zinc and bis-copper complexes. These claims are chemically distinct from ordinary acid-addition salts. A metal complex may have different coordination, formulation, pharmacology, and regulatory characteristics from plerixafor hydrochloride.

How do the composition claims differ from the compound claims?

Claims 1 through 16 are composition claims. They require a pharmaceutical composition containing the relevant active compound and, in claim 1, require that the composition be active against HIV.

Claims 17 through 35 are drafted as compound claims but depend on claim 1 as supplied. That drafting creates a formal category issue because a compound cannot literally depend on a pharmaceutical-composition claim without importing composition language. The original patent text and prosecution history control the legal effect of that dependency. The claims supplied contain apparent transcription errors, including:

“1'1'” instead of “1,1'”;
“phenyleneis” instead of “phenylenebis”;
“1,4,7,1 1” instead of “1,4,7,11”;
“trlazacyclododecane” instead of “triazacyclododecane”;
inconsistent punctuation and spacing.

Those errors should be resolved against the issued patent and certificate history before relying on a claim construction.

What formulations are protected by US 5,583,131?

The patent claims pharmaceutical compositions but does not, based on the supplied claims, require a particular dosage form or formulation technology.

The claims therefore potentially reach compositions containing a covered active ingredient in forms such as:

injectable solutions;
sterile aqueous preparations;
oral tablets;
capsules;
powders;
suspensions;
acid-addition salt formulations;
compositions containing metal complexes.

The patent does not expressly require:

a specific excipient;
a particular pH;
a concentration range;
a delivery device;
a sustained-release matrix;
a liposomal formulation;
a specific route of administration.

That distinction matters for later formulation patents. A later patent could protect an injectable concentration, stabilizer system, container, manufacturing process, or dosing regimen even though the original compound patent has expired. Such later rights would need separate claim-by-claim analysis.

Did the patent claim a method of treating HIV or cancer?

Not in the claims supplied.

Claim 1 describes a pharmaceutical composition active against HIV. It does not recite administering the composition to a patient. The claim set therefore differs from a method-of-treatment patent that would require steps such as administering plerixafor to mobilize stem cells or treating an HIV-infected patient.

The later clinical use of plerixafor for hematopoietic stem-cell mobilization is based on its CXCR4-antagonist pharmacology, not on the original HIV-composition claim language. The patent’s original therapeutic field and Mozobil’s approved field are therefore different.

When did US Patent 5,583,131 lose exclusivity?

The patent issued on December 10, 1996. For a U.S. patent subject to the pre-Uruguay Round patent-term rules, the ordinary term was 17 years from issuance. The ordinary expiration date was therefore:

December 10, 2013

The FDA’s Orange Book listed US 5,583,131 for Mozobil. FDA’s product information identifies plerixafor injection as a prescription drug approved under NDA 022311 (FDA, 2008; FDA, n.d.).

A pediatric exclusivity extension, if applicable to the listed product and patent, could extend enforceability beyond the ordinary patent expiration date. The commercially relevant protection period for the original U.S. product was nevertheless centered on December 2013, not on a current patent term.

What was the Orange Book status of plerixafor?

Mozobil was approved as a new molecular entity under NDA 022311. US 5,583,131 was the principal Orange Book patent associated with the product’s original chemical protection.

Regulatory item	Status
Product	Mozobil
Active ingredient	Plerixafor
Developer/marketer	Genzyme, later part of Sanofi
FDA approval	December 15, 2008
NDA	022311
Dosage form	Injection
Original U.S. patent	US 5,583,131
Ordinary patent expiration	December 10, 2013
Regulatory category	Small molecule, not biologic
Biosimilar pathway	Not applicable

Because plerixafor is a small molecule, follow-on products use the abbreviated new drug application pathway rather than the biosimilar pathway under section 351(k) of the Public Health Service Act.

Were there Paragraph IV challenges to plerixafor?

A Paragraph IV certification would be the relevant ANDA mechanism for challenging an unexpired Orange Book patent. Once US 5,583,131 expired, the patent no longer presented a live patent barrier to a new ANDA applicant.

The supplied record does not identify a specific Paragraph IV notice, ANDA filer, or litigation docket. No complete litigation conclusion can be drawn from the claims alone. The practical legal position is clear, however: a Paragraph IV challenge to the original compound patent would have been relevant before December 2013; after expiration, the patent could not support a conventional patent-infringement exclusion against a generic launch.

Which companies challenged or commercialized plerixafor?

The commercial history is more concentrated than the patent landscape.

Company	Role
AnorMED	Developed AMD3100/plerixafor
Genzyme	Acquired AnorMED and commercialized Mozobil
Sanofi	Acquired Genzyme and inherited the product franchise
Generic applicants	Relevant after loss of the original compound patent
Biosimilar developers	Not applicable because plerixafor is a small molecule

The original patent was associated with the early bicyclam anti-HIV research program. Commercial value later shifted to stem-cell mobilization after the CXCR4 mechanism and clinical utility were established.

How strong is the patent estate for plerixafor?

Historical strength

The patent was strong during its enforceable period because it combined:

a broad structural genus;
specific bicyclam species;
acid-addition salts;
metal complexes;
multiple aromatic and heteroaromatic linkers;
composition and compound claim formats.

The para-phenylene-linked bicyclam claims were particularly important because they captured the core plerixafor structure and its salt forms.

Current strength

The original patent has no remaining ordinary U.S. exclusionary value after expiration. Its current value is historical and evidentiary:

it defines the original chemical platform;
it may remain relevant in freedom-to-operate histories;
it may appear in prior-art analyses;
it can help identify related patent families and later CXCR4 patents.

An expired patent cannot block a current generic launch, although it can remain relevant to validity, priority, inventorship, and prior-art disputes involving later patents.

What design-around strategies would avoid the literal scope?

A competitor seeking to avoid literal infringement could consider structural changes to one or more required elements:

Use nonidentical macrocycles at the two ends.
Substitute one or more macrocyclic nitrogen atoms.
Replace a methylene bridge with another linker.
Use an aliphatic or nonaromatic central linker.
Introduce oxygen or sulfur into the macrocycle.
Use a quinoline central linker, which claim 1 expressly excludes.
Use macrocycles outside the 10-to-15-member range.
Use ring systems with adjacent nitrogen atoms or fewer than three or more than six ring nitrogens.
Use a monocyclic CXCR4 antagonist rather than a linked bis-macrocycle.

These strategies would still require analysis of later patents and the doctrine of equivalents. They do not revive the expired patent, but they remain relevant to historical claim construction and to later patent families directed to CXCR4 antagonists.

What manufacturing and intellectual-property barriers remain?

The original patent does not claim a manufacturing process in the claims provided. Generic manufacturers therefore face process-development rather than composition-patent barriers.

Relevant technical issues include:

synthesis of the bis-macrocyclic core;
control of regioisomers and constitutional isomers;
removal of metal contaminants;
salt formation and crystallization;
impurity profiling;
sterile injectable manufacture;
stability of the injectable product;
analytical methods for release testing;
bioequivalence for the injection.

For an ANDA, the key regulatory burden is demonstration of pharmaceutical equivalence and bioequivalence, together with manufacturing compliance. Plerixafor’s injectable dosage form can make manufacturing and analytical control more demanding than an ordinary immediate-release tablet, but those issues are distinct from patent exclusivity.

How does plerixafor compare with competing CXCR4 antagonists?

Product or class	Chemical type	Regulatory position	Relationship to US 5,583,131
Plerixafor	Bis-macrocyclic bicyclam	FDA-approved stem-cell mobilizer	Core commercial species associated with the patent
AMD11070	Small-molecule CXCR4 antagonist	Investigational history	Structurally distinct from the claimed bicyclam platform
Other CXCR4 antagonists	Diverse small molecules, peptides, and biologics	Mostly investigational or indication-specific	May avoid the literal bicyclam limitations
CXCR4 antibodies	Biologic	Separate biologics pathway	Outside the small-molecule claim structure

The patent does not create biosimilar exposure because plerixafor is not a biologic. Competitive risk is therefore driven by generic small-molecule entry and alternative CXCR4-directed products, not by biosimilar substitution.

What is the revenue exposure from expiration?

US 5,583,131 was the principal historical U.S. compound patent for Mozobil. Its expiration removed the primary composition-based barrier to generic competition. The impact on revenue depends on:

the number of approved ANDA applicants;
generic launch timing;
hospital and transplant-center purchasing;
injectable manufacturing capacity;
price erosion;
continued use in lymphoma and myeloma mobilization;
international patent and regulatory status.

No current revenue figure can be attributed to the patent without product sales and market-share data. The patent’s direct revenue protection in the United States ended with expiration, subject to any applicable extension.

What is the geographic coverage of the patent family?

US 5,583,131 provides U.S. rights only. Equivalent protection in Europe, Canada, Japan, and other jurisdictions depends on separately issued national or regional patents and their individual expiration dates.

Patent families for pharmaceutical inventions often include:

a priority filing;
an international PCT application;
national-phase applications;
divisional applications;
continuation applications;
related process or use patents.

The U.S. expiration date cannot be used as a substitute for foreign expiration analysis. A generic launch strategy must be assessed jurisdiction by jurisdiction, particularly in Europe, Canada, Japan, Australia, and emerging markets.

Key Takeaways

US 5,583,131 covers linked bis-macrocyclic polyamines, especially bicyclam compounds.
Plerixafor is the principal commercial compound associated with the patent.
Claim 1 requires identical cyclic polyamine termini connected through methylene groups to an aromatic or heteroaromatic linker.
The claim excludes quinoline linkers and limits macrocycle size, nitrogen count, nitrogen spacing, and nitrogen substitution.
Claims 3 through 16 focus on pharmaceutical compositions; claims 17 through 35 identify specific compounds and complexes.
The patent does not claim a specific injectable formulation, dosing regimen, manufacturing process, or stem-cell-mobilization method in the supplied claim set.
The ordinary U.S. patent term ended December 10, 2013.
Plerixafor is a small molecule, so generic competition proceeds through ANDAs, not biosimilar applications.
Any current U.S. patent risk must come from later patents, not from the expired US 5,583,131 compound patent.
Foreign rights require separate national patent-family review.

FAQs

Is plerixafor still protected by US Patent 5,583,131?

No. The ordinary U.S. patent term ended December 10, 2013. Any later U.S. protection must be evaluated under separate patents.

Does US 5,583,131 cover plerixafor hydrochloride?

Yes, the para-phenylene-linked bicyclam species and acid-addition salt forms are expressly identified in the claim set supplied.

Can a generic manufacturer rely on the expiration of US 5,583,131?

Yes, expiration removes the original patent’s exclusionary effect. The manufacturer must still address any later patents, FDA requirements, and product-specific regulatory obligations.

Is plerixafor subject to biosimilar competition?

No. Plerixafor is a small molecule. Follow-on products use the ANDA pathway rather than the biosimilar pathway.

Does the patent cover all CXCR4 antagonists?

No. It covers a defined structural class of linked cyclic polyamines. Structurally unrelated CXCR4 antagonists can fall outside its literal scope.

References

Food and Drug Administration. (2008). Mozobil (plerixafor injection) prescribing information. U.S. Department of Health and Human Services.
Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book. U.S. Department of Health and Human Services.
U.S. Patent No. 5,583,131. (1996). Bis-macrocyclic compounds, pharmaceutical compositions, and uses thereof. United States Patent and Trademark Office.
Sanofi. (n.d.). Mozobil product information. Sanofi U.S.
U.S. Food and Drug Administration. (2017). Orange Book patent and exclusivity information. U.S. Department of Health and Human Services.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	91/26677	Dec 16, 1991

PCT Information
PCT Filed	December 16, 1992	PCT Application Number:	PCT/GB92/02334
PCT Publication Date:	June 24, 1993	PCT Publication Number:	WO93/12096

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0619813	⤷ Start Trial	CA 2009 00052	Denmark	⤷ Start Trial
European Patent Office	0619813	⤷ Start Trial	C300425	Netherlands	⤷ Start Trial
European Patent Office	0619813	⤷ Start Trial	SPC038/2009	Ireland	⤷ Start Trial
European Patent Office	0619813	⤷ Start Trial	10C0002	France	⤷ Start Trial
European Patent Office	0619813	⤷ Start Trial	SPC/GB10/004	United Kingdom	⤷ Start Trial
Austria	273964	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 5,583,131