US Patent 5,376,645: Scope, Claims, Expiration and Cyclodextrin Patent Landscape

US Patent 5,376,645 covered pharmaceutical compositions containing sulfobutyl ether cyclodextrin derivatives, particularly mixtures of sulfobutyl ether beta-cyclodextrin and underivatized cyclodextrin. The patent also covered drug-cyclodextrin complexes and orally administered pharmaceutical compositions.

The patent issued on December 27, 1994. Its 17-year term for a pre-1995 application expired on December 27, 2011. The patent therefore has no current blocking effect against generic, branded, or biosimilar products. Its commercial importance was historical: it helped establish intellectual-property protection for sulfobutyl ether cyclodextrins, including the excipient technology later commercialized as Captisol. [1]

What technology does US Patent 5,376,645 protect?

The patent protects compositions containing a sulfated cyclodextrin derivative with the following core characteristics:

Limitation	Scope
Cyclodextrin ring size	n = 4, 5, or 6
Principal derivative	O-(C2-C6 alkylene)-SO3- substituted cyclodextrin
Required substitution	At least one of R1 and R2 must be an O-(C2-C6 alkylene)-SO3- group
Counterions	Pharmaceutically acceptable cations
Composition format	Derivative composition, drug complex, or oral pharmaceutical composition
Residual parent cyclodextrin	Less than, or not more than, approximately 50%; narrower claims require less than 40% or 25%
Drug-complex claims	Broad list of drugs, including steroids, NSAIDs, barbiturates, antibiotics, vitamins and cardiovascular agents
Preferred cyclodextrin	n = 5, corresponding to beta-cyclodextrin
Preferred linker	C3 or C4 alkylene
Degree of substitution	Approximately 1, 3.6, 4.7 or 7 substituents per cyclodextrin molecule

The patent is directed to composition technology rather than a single active pharmaceutical ingredient. The protected derivative is commonly described as sulfobutyl ether beta-cyclodextrin, or SBECD, when the cyclodextrin is beta-cyclodextrin and the linker is a four-carbon butylene group.

The claims do not require a single chemically uniform derivative. Several claims expressly cover compositions containing cyclodextrin derivatives with an average number of substituents per molecule. That language is important because industrial SBECD is generally a distribution of substitution levels rather than one discrete molecular species.

How do claims 1 through 23 define the cyclodextrin composition?

Claims 1 through 23 are composition claims directed to the cyclodextrin derivative itself and its composition profile.

Independent claim 1

Claim 1 requires:

A cyclodextrin derivative with a ring size corresponding to n = 4, 5 or 6.
Substituents that are either unmodified O- positions or O-(C2-C6 alkylene)-SO3- groups.
At least one required sulfated alkylene ether substituent at R1 or R2.
Pharmaceutically acceptable cations.
Less than about 50% underivatized cyclodextrin.

The claim is broad in several respects. It allows different ring sizes, different linker lengths, different substitution positions, and different pharmaceutically acceptable counterions. It is narrower than a claim to any sulfated cyclodextrin because it imposes the R1/R2 positional requirement and a limit on residual underivatized cyclodextrin.

The composition limitation is central. A material containing the claimed derivative but more than approximately 50% underivatized cyclodextrin would fall outside the literal scope of claim 1.

Dependent claims 2 through 6

These claims narrow substitution patterns:

Claims 2 and 3 require substitution at R1, R2 and R3.
Claim 3 limits the linker to a three- or four-carbon chain.
Claims 4 through 6 address additional substitution at R4, R6 and R8.
Claims 4 through 6 require R5, R7 and R9 to remain O-.
Claim 6 requires substitution at R4, R6 and R8.

These limitations target defined positional substitution patterns on the cyclodextrin ring. They are narrower than the generic composition in claim 1 and would have been relevant to products manufactured with a controlled substitution pattern.

Claims 7 through 15

Claims 7 through 15 focus on beta-cyclodextrin and average substitution levels.

Claims	Ring size	Linker	Average number of sulfated ether groups
7	n = 5	Not limited	Not limited
8, 10-12	n = 5	C3	About 1, 3.6 or 7
9, 13-15	n = 5	C4	About 1, 4.7 or 7

The claims use average substitution levels rather than a single degree of substitution. This is consistent with a mixture of beta-cyclodextrin derivatives having different substitution numbers.

Claims 16 through 23

These claims impose tighter purity or composition limits:

Less than 40% underivatized cyclodextrin.
Less than 25% underivatized cyclodextrin.
In several claims, less than 40% or 25% beta-cyclodextrin specifically.

The progression from 50% to 40% to 25% creates nested composition positions. Historically, these limitations could distinguish higher-purity derivative preparations from partially derivatized mixtures.

What do claims 24 through 46 protect?

Claims 24 through 46 cover drug complexes containing the cyclodextrin derivative.

Claim 24 requires:

A drug;
A cyclodextrin derivative within the claimed structural formula; and
Not more than approximately 50 weight percent underivatized cyclodextrin.

The drug is not limited to one active ingredient. Claim 29 lists a wide range of compounds, including:

Amobarbital, pentobarbital and phenobarbital;
Ampicillin, methicillin, penicillin and chloramphenicol;
Aspirin, ibuprofen, flurbiprofen and ketoprofen;
Diazepam, nitrazepam and other benzodiazepines;
Dexamethasone, prednisolone, progesterone and testosterone;
Digoxin, digitoxin and reserpine;
Griseofulvin, metronidazole and mitomycin;
Vitamins A, D3, E and K3;
Warfarin and nitroglycerin.

The claim set therefore reaches drug-cyclodextrin complexes across several therapeutic classes. It does not require a particular dosage form, route of administration, therapeutic indication or drug-to-cyclodextrin ratio unless imposed by a dependent claim or the specification.

Claims 30 through 34 narrow the complex to beta-cyclodextrin, C3 or C4 linkers, and specified average substitution levels. Claims 35 through 46 impose the less-than-40% and less-than-25% residual beta-cyclodextrin limits.

Why the residual cyclodextrin limitation matters

A product containing SBECD is not automatically within the claims. Literal claim coverage requires the composition to satisfy the residual underivatized cyclodextrin limitation. Analytical testing would likely focus on:

The percentage of underivatized beta-cyclodextrin;
The identity and distribution of substituted species;
Average degree of substitution;
The alkylene linker length;
The counterion;
The presence and identity of the complexed drug.

The patent does not claim every pharmaceutical use of SBECD. It claims compositions that meet defined chemical and compositional parameters.

What does claim 47 protect?

Claim 47 is an oral pharmaceutical composition claim. It requires:

A pharmaceutically acceptable orally suitable carrier;
A clathrate complex;
A drug complexed to the claimed cyclodextrin derivative; and
Not more than 50% underivatized cyclodextrin.

This claim adds a route and dosage-form-related limitation that is absent from most earlier claims. A product would need to be formulated for oral administration and contain the required clathrate complex.

The claim is not directed to parenteral formulations, ophthalmic products, inhaled products or topical products unless the product also satisfies the oral-administration requirement.

What are the principal claim-construction issues?

Several terms would have been material in an infringement or validity analysis.

"Cyclodextrin derivative"

The claims cover derivatives of cyclodextrins with n = 4, 5 or 6. In conventional nomenclature, these correspond broadly to alpha-, beta- and gamma-cyclodextrin ring sizes, although the patent’s formula and specification control the precise interpretation.

"O-(C2-C6 alkylene)-SO3-"

This limitation requires an alkylene spacer of two to six carbon atoms between the cyclodextrin oxygen and the sulfonate group. It excludes linkers outside the C2-C6 range.

C3 and C4 linkers receive special treatment in the dependent claims. C4 sulfobutyl ether derivatives are the commercially significant subgroup associated with SBECD.

"Pharmaceutically acceptable cation"

The claims are not limited to sodium. Depending on the specification and technical context, the term may encompass other pharmaceutically acceptable counterions. A sodium, potassium, ammonium or other salt form would require analysis against the patent’s intrinsic disclosure and ordinary meaning.

"Less than about 50%" and "not more than about 50%"

Claims 1 through 23 use "less than about 50%," while claims 24 through 47 use "not more than about 50 wt. %." The distinction could matter at the boundary, although the use of "about" introduces an analytical tolerance issue.

Average degree of substitution

Claims 10 through 15 and 33 through 34 refer to average substitution levels. The relevant measurement method, sampling, and calculation would be important. A supplier could not establish noninfringement merely by showing that no individual molecule has exactly 3.6 or 4.7 substituents, because the claims address an average across the composition.

When did US Patent 5,376,645 expire?

US Patent 5,376,645 expired on December 27, 2011, based on the 17-year patent term applicable to the pre-1995 application and its December 27, 1994 issue date. [1]

Event	Date
Patent issued	December 27, 1994
Original statutory term	17 years from issue
Expiration	December 27, 2011
Current enforceability	Expired
Current blocking right	None

The patent cannot presently support a new infringement action for conduct occurring after expiration. It may remain relevant as prior art, as historical evidence of the SBECD technology, and in analyses of later patents claiming improved manufacturing, purity, formulations or specific drug products.

What is the Orange Book status of US Patent 5,376,645?

US Patent 5,376,645 is not a currently enforceable Orange Book patent covering a marketed drug product. The patent claims an excipient and drug-cyclodextrin compositions rather than a specific FDA-approved active pharmaceutical ingredient.

The FDA Orange Book lists patents submitted by NDA sponsors for approved drug products. An expired composition patent of this type would not create a current Orange Book barrier to an ANDA applicant. Orange Book-listed method-of-use patents also have no practical current blocking effect if they expired in 2011. [2]

Were there Paragraph IV challenges to this patent?

Paragraph IV challenges are generally relevant when an unexpired patent is listed for an approved drug and an ANDA applicant certifies that the patent is invalid, unenforceable or not infringed.

US Patent 5,376,645 expired before the modern commercial expansion of several major SBECD-containing products. Its expiration eliminates any current Paragraph IV barrier. A historical ANDA certification involving this patent would not delay present generic entry because the patent term has ended.

The patent also was not a conventional active-ingredient patent for a single approved drug. A Paragraph IV dispute would therefore have depended on whether a sponsor listed it against a specific NDA and whether the proposed generic product practiced the composition claims.

Which FDA-approved products use SBECD technology?

SBECD is used as a solubilizing excipient in several approved products. Examples include:

Product	Active ingredient	Manufacturer or sponsor	SBECD relevance
Vfend	Voriconazole	Pfizer	Intravenous formulation uses SBECD
Noxafil injection	Posaconazole	Merck	Intravenous formulation uses SBECD
Veklury	Remdesivir	Gilead Sciences	Injectable formulation uses SBECD
Cresemba intravenous	Isavuconazonium sulfate	Astellas	Intravenous formulation uses SBECD-related solubilization technology
Bridion	Sugammadex	Merck	Cyclodextrin-based active ingredient, but not necessarily an SBECD product

FDA labeling identifies excipients and formulation composition for approved products. [3-6] The presence of SBECD in a product does not establish infringement of US 5,376,645 because the patent has expired and later patents may cover different aspects of the product.

How did licensing affect the commercial value of the patent?

The technology associated with sulfobutyl ether cyclodextrins was developed through the University of Kansas and commercialized through CyDex Pharmaceuticals. CyDex developed Captisol, a branded sulfobutyl ether beta-cyclodextrin excipient, and entered licensing and supply relationships with drug developers.

Ligand Pharmaceuticals acquired CyDex in 2011. Ligand later commercialized Captisol through supply, licensing and development agreements with pharmaceutical companies. [7]

The commercial value shifted over time from the original composition patent to:

Captisol trademarks and know-how;
Manufacturing controls;
Purity and impurity specifications;
Regulatory documentation;
Drug-specific formulation patents;
Supply agreements;
Later patents covering improved production or specific pharmaceutical products.

Patent expiry did not eliminate the commercial value of the excipient platform. It removed exclusivity under US 5,376,645 while leaving regulatory, manufacturing and contractual barriers potentially relevant.

How strong is the patent estate today?

The estate represented by US 5,376,645 is legally weak as a current exclusivity asset because the patent expired in 2011.

Category	Current assessment
Core composition patent	Expired
Drug-complex claims	Expired
Oral formulation claim	Expired
Orange Book blocking power	None from this patent
Generic entry risk from this patent	None
Biosimilar risk	Not applicable
Historical platform importance	High
Manufacturing know-how value	Potentially significant
Later patent risk	Must be assessed separately
Regulatory and supply-chain risk	Potentially relevant

The main surviving barriers are not based on this patent. They may arise from later patents covering a particular dosage form, drug product, process, impurity profile, particle size, manufacturing method or combination formulation.

What generic launch scenarios exist?

For a product that uses SBECD or a comparable sulfated cyclodextrin, three broad launch scenarios apply:

Generic product using the same excipient

A generic sponsor can use SBECD without infringing US 5,376,645 because the patent expired. The sponsor must still satisfy FDA requirements for pharmaceutical equivalence, bioequivalence, quality and manufacturing controls.

Alternative cyclodextrin formulation

A sponsor may use another cyclodextrin or solubilizer. This can avoid later formulation patents but may require new toxicology, stability and bioequivalence work.

Product-specific patent risk

The principal remaining risk may be a later patent covering the active ingredient’s formulation, intravenous delivery, dosing regimen, stability profile or manufacturing process. Those patents must be analyzed independently from the expired SBECD patent.

What manufacturing and geographic barriers remain?

The US patent has no live US exclusivity. Geographic analysis must separate patent status from regulatory and commercial conditions.

Jurisdiction	Position based on US 5,376,645
United States	Expired December 27, 2011
Europe	US expiration does not determine European status
Japan	US expiration does not determine Japanese status
China	US expiration does not determine Chinese status
Canada	US expiration does not determine Canadian status
Other jurisdictions	Local family members require separate review

Manufacturing barriers may remain through process know-how, validated production capacity, quality standards, customer qualification and regulatory filings. These are commercial barriers, not continuing rights under the US patent.

Key Takeaways

US Patent 5,376,645 covered sulfated alkylene ether cyclodextrin compositions, drug complexes and oral pharmaceutical compositions.
The principal commercial embodiment was sulfobutyl ether beta-cyclodextrin, commonly known as SBECD.
Claims require defined substitution patterns and limits on underivatized cyclodextrin.
Claims 10 through 15 and 33 through 34 use average degrees of substitution.
Claim 29 lists a broad range of drugs but does not create a current monopoly over those active ingredients.
The patent expired on December 27, 2011.
It has no current Orange Book blocking effect and cannot support a current Paragraph IV barrier.
SBECD-containing products may still face later formulation, process, method-of-use, regulatory or supply-chain constraints.
The patent remains important as historical prior art and as the foundation of the Captisol commercial platform.

FAQs

Does US Patent 5,376,645 cover Captisol today?

No. The patent covered compositions corresponding to the Captisol technology, but it expired on December 27, 2011. Captisol may still be protected commercially by trademarks, know-how, supply agreements or later patents.

Can a generic manufacturer use SBECD without licensing this patent?

Yes, this patent no longer requires a license for activities occurring after expiration. A generic manufacturer must still assess later patents, regulatory requirements and contractual restrictions.

Does the patent cover all cyclodextrin drug complexes?

No. It covers complexes that satisfy the claimed sulfated cyclodextrin structure, substitution requirements and residual underivatized cyclodextrin limits. It does not cover every cyclodextrin, every drug complex or every solubilizer.

Is SBECD a biologic patent or biosimilar issue?

No. SBECD is an excipient and cyclodextrin derivative. Biosimilar patent procedures do not apply to the excipient itself, although a biologic product could independently contain or use a cyclodextrin excipient.

Can a later patent still block an SBECD-containing product?

Yes. A later patent may claim the active ingredient, formulation, manufacturing process, dosing regimen, impurity profile, delivery system or a specific combination. US 5,376,645 does not resolve those later-patent issues.

References

United States Patent and Trademark Office. (1994). U.S. Patent No. 5,376,645: Sulfobutyl ether cyclodextrin derivatives and pharmaceutical compositions containing same. https://patents.google.com/patent/US5376645A/en
U.S. Food and Drug Administration. (2025). Approved drug products with therapeutic equivalence evaluations, Orange Book. https://www.fda.gov/drugs/drug-approvals-and-databases/orange-book
U.S. Food and Drug Administration. (2024). VFEND (voriconazole) prescribing information. Pfizer. https://www.accessdata.fda.gov/drugsatfda_docs/label/
U.S. Food and Drug Administration. (2024). NOXAFIL (posaconazole) prescribing information. Merck. https://www.accessdata.fda.gov/drugsatfda_docs/label/
U.S. Food and Drug Administration. (2024). VEKLURY (remdesivir) prescribing information. Gilead Sciences. https://www.accessdata.fda.gov/drugsatfda_docs/label/
U.S. Food and Drug Administration. (2024). CRESEMBA (isavuconazonium sulfate) prescribing information. Astellas Pharma. https://www.accessdata.fda.gov/drugsatfda_docs/label/
Ligand Pharmaceuticals Incorporated. (2011). Annual report pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934. https://investor.ligand.com/financial-information/sec-filings

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	170742	⤷ Start Trial
Austria	217325	⤷ Start Trial
Australia	4779993	⤷ Start Trial
Australia	646020	⤷ Start Trial
Australia	672814	⤷ Start Trial
Australia	7236491	⤷ Start Trial
Canada	2074186	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,376,645

Summary for Patent: 5,376,645