United States Patent 5,134,127: Scope, Claims, Expiration and Cyclodextrin Patent Landscape

U.S. Patent No. 5,134,127 covers purified sulfoalkyl ether cyclodextrin compositions, drug-cyclodextrin complexes, pharmaceutical formulations and delayed-release compositions. Its broadest commercial relevance is sulfobutyl ether beta-cyclodextrin, commonly known as SBECD or Captisol. The patent issued on July 28, 1992, and its 17-year term expired on July 28, 2009. It has no current blocking effect on SBECD manufacture, formulation or commercialization.[1][2]

The patent remains important as a foundational disclosure because later patents, manufacturing know-how, regulatory filings and contractual licenses may have created separate commercial barriers. Those later rights must be analyzed independently from U.S. Patent 5,134,127.

What technology does U.S. Patent 5,134,127 protect?

The patent protects chemically modified cyclodextrins in which one or more hydroxyl groups are substituted with a sulfoalkyl ether group:

A cyclodextrin ring with n equal to 4, 5 or 6.
Sulfoalkyl substituents having a C2-C6 alkylene spacer.
Pharmaceutically acceptable counterions, such as sodium.
Purification sufficient to remove or limit underivatized cyclodextrin.
Drug complexes and pharmaceutical compositions containing those derivatives.
Delayed-release compositions.

The commercially important embodiment is the sodium salt of sulfobutyl ether beta-cyclodextrin, or SBECD-Na. “Beta-cyclodextrin” corresponds to the seven-glucose-unit cyclodextrin most commonly used in Captisol products. The claim language uses a structural variable system rather than the commercial term SBECD.

The patent therefore covers more than one named compound. It covers a composition class defined by substitution pattern, spacer length, cyclodextrin ring size, counterion and impurity profile.

What is the commercial relationship between the claims and Captisol?

Captisol is a branded form of SBECD developed and commercialized through the CyDex and Ligand organizations. The patent claims encompass SBECD compositions when the commercial material satisfies the claimed structural and purity limitations.

The claims do not require a particular drug. Claim 8 covers a drug complex with the claimed derivative, while claim 13 identifies a broad list of example drugs, including diazepam, dexamethasone, digoxin, ibuprofen, ketoprofen, nitroglycerin, phenytoin, prednisolone and warfarin.

The presence of a drug in the claim does not make every product containing that drug infringing. The product must also contain the claimed cyclodextrin derivative and satisfy the relevant purity and structural limitations.

How many independent claims does U.S. Patent 5,134,127 contain?

The supplied claim set has four independent claims: claims 1, 8, 14 and 16.

Independent claim	Protected subject matter	Key limitation
Claim 1	Purified cyclodextrin derivative composition	TLC absence of underivatized cyclodextrin
Claim 8	Drug complex with cyclodextrin derivative	No more than 5 wt.% underivatized cyclodextrin
Claim 14	Pharmaceutical composition with carrier and drug complex	No more than 5 wt.% underivatized cyclodextrin
Claim 16	Delayed-release pharmaceutical composition	Purified cyclodextrin derivative and drug complex

Claims 2-7 narrow claim 1 by specifying substitution at R1-R3 and, in some cases, at R4, R6 and R8. Claims 9-13 narrow claim 8. Claims 15 and 17-45 add carrier, ring-size, alkylene-chain, substitution-degree and impurity limitations.

What does claim 1 cover?

Claim 1 is the principal composition claim. It requires:

A purified cyclodextrin derivative composition.
A cyclodextrin ring represented by n equal to 4, 5 or 6.
Each substituent position to be either:
- O-, representing an unsubstituted hydroxyl-derived position; or
- O-(C2-C6 alkylene)-SO3-, representing a sulfoalkyl ether group.
At least one of R1 and R2 to contain the sulfoalkyl ether group.
Pharmaceutically acceptable cations associated with the sulfonate groups.
Absence of underivatized cyclodextrin as measured by thin-layer chromatography.

The claim is broad in three respects.

First, it covers multiple cyclodextrin ring sizes. Second, it covers C2-C6 alkylene spacers, not only the C4 spacer used in SBECD. Third, it does not require a specific degree of substitution, provided the required substitution pattern is present.

How important is the TLC purity limitation?

The TLC limitation is material. Claim 1 is not simply a claim to any sulfoalkyl ether cyclodextrin. It requires a purified composition showing an absence of underivatized cyclodextrin by the specified analytical method.

This creates an analytical infringement issue. A product could contain the correct derivative but avoid claim 1 if it does not meet the stated TLC result. Conversely, a claim challenge could focus on whether “absence” means literal non-detection, whether the TLC method is sufficiently defined, and whether the specification provides an objective reproducible test.

Claims 26-35 add quantitative impurity limitations, including less than 5% and less than 2% underivatized cyclodextrin or beta-cyclodextrin. Those dependent claims are narrower and more readily tested by quantitative analytical methods.

What do claims 8, 14 and 16 protect?

Claim 8: drug-cyclodextrin complexes

Claim 8 covers a composition in which a drug is complexed to the claimed cyclodextrin derivative and the composition contains no more than 5 wt.% underivatized cyclodextrin.

This claim reaches a finished drug complex, an active pharmaceutical ingredient formulation intermediate or a pharmaceutical formulation, depending on how “composition” and “complexed” are construed. It is narrower than claim 1 because it requires a drug complex but is broader in not requiring the claim 1 TLC “absence” language.

Claim 14: pharmaceutical compositions

Claim 14 adds a pharmaceutically acceptable carrier. Claim 15 narrows the carrier to one suitable for parenteral administration.

The claim potentially covers injectable compositions containing a drug-SBECD complex, including products in which the cyclodextrin improves aqueous solubility or enables intravenous delivery. The claim does not require a particular dosage, route other than the dependent parenteral limitation, release profile or disease indication.

Claim 16: delayed-release formulations

Claim 16 covers a delayed-release pharmaceutical composition containing a drug complexed to the purified cyclodextrin derivative. It does not include the explicit 5 wt.% impurity ceiling found in claims 8 and 14.

The claim is potentially relevant to oral, depot or other modified-release dosage forms. A product would need to satisfy both the cyclodextrin-complex limitation and the delayed-release limitation. A conventional immediate-release injectable product would generally not meet the delayed-release requirement.

What chemical variations are covered by the dependent claims?

The dependent claims create several commercially relevant subgroups.

Claim group	Structural limitation
Claims 2, 9	R1, R2 and R3 are sulfoalkyl ether groups
Claims 3, 18, 19	C2-C6 spacer narrowed to specific methylene lengths
Claims 4	R1-R3 use C3 or C4 spacers
Claims 5-7, 10-12	Additional substitution at R4, R6 and R8
Claims 17, 36, 41	n equals 5
Claims 18, 37, 42	C3 alkylene spacer
Claims 19, 38, 43	C4 alkylene spacer
Claims 20-25, 39-40, 44-45	Average substitution levels
Claims 26-35	Less than 5% or less than 2% underivatized material

The claims directed to an average of approximately 1, 3.6, 4.7 or 7 sulfoalkyl groups per cyclodextrin molecule cover composition distributions. They do not necessarily require every molecule in the batch to have exactly that number of substituents.

That distinction is important for SBECD. Commercial SBECD is generally a heterogeneous mixture of substitution isomers and degrees of substitution rather than a single molecular species. Average substitution, impurity content and analytical characterization are therefore central to claim mapping.

When did U.S. Patent 5,134,127 lose exclusivity?

Event	Date
Earliest priority date	May 27, 1988
U.S. patent issuance	July 28, 1992
Original patent term	17 years from issue
Expiration	July 28, 2009
Current status	Expired

Because the patent issued before the effective transition to the modern 20-year-from-earliest-effective-filing-date regime, its term was governed by the pre-1995 patent-term rules. The patent expired in 2009 under the 17-year term measured from issuance.[1][2]

Patent-term extension under 35 U.S.C. §156 is generally associated with approved drug products and regulated active ingredients. An excipient composition patent such as this one would not ordinarily receive a product-specific extension. No current enforceable exclusivity remains under U.S. Patent 5,134,127.

What is the Orange Book status of U.S. Patent 5,134,127?

U.S. Patent 5,134,127 is not an Orange Book patent listing for SBECD.

The FDA Orange Book lists patents and exclusivity associated with approved drug products, not every patent covering an excipient, manufacturing process or drug-delivery technology. SBECD is an excipient used in approved products, including certain injectable formulations, but the excipient patent itself is not a listed-drug patent that supports a Paragraph IV certification.[3]

A generic applicant challenging a drug product containing SBECD would analyze:

Patents listed for the reference listed drug.
Drug-specific formulation patents.
Method-of-use patents.
Any applicable pediatric exclusivity.
FDA product-specific guidance.
Separate third-party rights relating to SBECD supply or manufacturing.

The applicant would not ordinarily file a Paragraph IV certification against U.S. Patent 5,134,127 because the patent is expired and is not an Orange Book-listed patent for a reference product.

Which companies are connected to the SBECD patent landscape?

The foundational technology was associated with the University of Kansas and was later commercialized through CyDex Pharmaceuticals. Ligand Pharmaceuticals acquired CyDex and has promoted Captisol as a drug-development and formulation platform.[4][5]

The relevant commercial participants include:

Company or organization	Role
University of Kansas	Originator and early patent owner associated with cyclodextrin technology
CyDex Pharmaceuticals	Commercial developer of Captisol and related cyclodextrin technology
Ligand Pharmaceuticals	Current owner and licensor of the Captisol platform
Drug sponsors	Developers of approved products using SBECD as an excipient
Generic manufacturers	Potential users or purchasers of SBECD for drug-product manufacture
Excipient manufacturers	Suppliers of SBECD or comparable sulfoalkyl ether cyclodextrins

Licensing arrangements are commercially important even after patent expiration. A supplier may control a trademark, quality specification, regulatory package, technical support program or proprietary manufacturing process without holding an enforceable claim under Patent 5,134,127.

What later patents may still create barriers after the 2009 expiration?

The patent landscape should be separated into five categories.

Later composition patents

Later patents may claim narrower SBECD compositions, defined substitution distributions, impurity limits, counterion profiles or physical properties. Those claims can remain relevant if they have later expiration dates and cover the exact commercial material.

Manufacturing patents

Manufacturing claims may cover:

Selective sulfoalkylation.
Control of substitution degree.
Removal of residual beta-cyclodextrin.
Ion-exchange or neutralization steps.
Drying and isolation.
Batch consistency.
Analytical release specifications.

For a generic SBECD manufacturer, process patents may be more important than the expired composition patent. A process that uses a patented reaction sequence can create infringement exposure even when the final composition is off-patent.

Formulation patents

Drug sponsors may claim a specific combination of an active ingredient and SBECD, including:

Concentration ranges.
pH.
Buffer systems.
Reconstitution conditions.
Freeze-dried cakes.
Container systems.
Infusion stability.
Osmolality.
Administration schedules.

These patents are product-specific and can remain enforceable after the foundational cyclodextrin patent expires.

Method-of-use patents

Method claims may cover use of a drug-SBECD complex for a specific disease, patient population, dosage regimen or route of administration. Such patents can affect commercial launch even where the excipient itself is unpatented.

Contractual and regulatory barriers

Captisol licensing agreements, trademarks, quality agreements and regulatory-support arrangements can affect supply and commercialization. They are not patent rights, but they may influence the practical ability of a competitor to use the same excipient platform.

Does U.S. Patent 5,134,127 create biosimilar risk?

No material biosimilar risk arises from this patent.

SBECD is a small-molecule excipient, not a biologic. Biosimilar applicants do not rely on the Biologics Price Competition and Innovation Act pathway to address SBECD. The relevant competitive pathways are abbreviated new drug applications, 505(b)(2) applications and full new drug applications, depending on the active ingredient and formulation.

For biologic products that use SBECD as an excipient, biosimilar competition would concern the reference biologic, its manufacturing process, formulation and listed patents. Patent 5,134,127 would not independently block a biosimilar filing because it is expired.

What generic launch risks exist for drugs using SBECD?

The expired patent removes one potential barrier, but it does not eliminate product-specific launch risk.

Risk category	Impact on generic entry
Orange Book drug patents	May require Paragraph IV litigation or a section viii carve-out
Formulation patents	Can delay an identical formulation
Method-of-use patents	May require labeling restrictions
SBECD supplier access	Can affect commercial scale and regulatory consistency
Manufacturing patents	May require a non-infringing process
Excipient qualification	Requires impurity, safety and stability data
Clinical formulation differences	May prevent simple ANDA reliance
Inactive Ingredient Database status	Supports regulatory precedent but does not establish patent freedom

FDA’s Inactive Ingredient Database provides regulatory precedent for SBECD in approved dosage forms and routes. That database does not determine patent scope, infringement or freedom to operate.[6]

For an injectable generic, the commercial assessment should focus on whether the proposed product uses the same SBECD grade, concentration, buffer, reconstitution system and administration conditions as the reference product. The expired patent itself is not the principal launch risk.

How strong is the patent estate for the claimed technology?

U.S. Patent 5,134,127 had strong historical breadth but weak present-day exclusionary value because it expired in 2009.

Factor	Assessment
Chemical breadth	Broad
Product coverage	Broad for drug-cyclodextrin complexes
Purity limitations	Material and potentially limiting
Commercial relevance	High for SBECD
Current enforceability	None under this patent
Orange Book relevance	None
Biosimilar relevance	None
Manufacturing barrier	Only if supported by later process patents
Licensing relevance	Potentially significant despite patent expiration
Generic entry effect	Removes foundational composition barrier

The patent was strategically important because it claimed the derivative, purified composition, drug complex and pharmaceutical formulation in one family. Its expiration shifts competitive control from the foundational composition claims to later patents, manufacturing expertise, regulatory data and supply relationships.

What litigation or settlement issues affect the patent?

U.S. Patent 5,134,127 cannot support a new U.S. infringement action because it expired in 2009. Any historical litigation or settlement involving the patent would have to be evaluated against the patent’s expiration, the asserted claims, the accused product and the settlement’s contractual terms.

Current disputes involving SBECD are more likely to concern:

Later patents.
Drug-specific formulation patents.
Supply contracts.
Trademark use.
Regulatory equivalence.
Quality specifications.
Trade secrets associated with manufacturing.

A historical settlement can retain commercial significance if it includes field-of-use restrictions, supply commitments, sublicensing provisions or other obligations that survive patent expiration. Those contractual provisions are separate from the patent claims.

What geographic coverage did the patent have?

U.S. Patent 5,134,127 provided rights only in the United States. Equivalent protection in Europe, Japan, Canada or other jurisdictions depended on separate national filings and the status of those corresponding patents.

A U.S. expiration did not automatically terminate foreign rights. For international freedom-to-operate analysis, the relevant questions are:

Whether a corresponding application was filed.
Whether a patent issued.
The effective filing and priority dates.
Patent-term adjustments or extensions.
National maintenance fees.
Claim amendments.
Local court or patent-office status.

The U.S. patent should therefore be treated as expired domestic protection, not as evidence that the global SBECD estate expired everywhere at the same time.

Key Takeaways

U.S. Patent 5,134,127 covers purified sulfoalkyl ether cyclodextrins, drug complexes, pharmaceutical compositions and delayed-release formulations.
Its broadest commercial embodiment is sodium sulfobutyl ether beta-cyclodextrin, or SBECD.
The claims cover C2-C6 sulfoalkyl spacers, multiple cyclodextrin ring sizes, variable substitution patterns and pharmaceutically acceptable cations.
Purity is central, with claims directed to TLC absence of underivatized cyclodextrin and quantitative limits below 5% or 2%.
The patent issued July 28, 1992, and expired July 28, 2009.
It is not an Orange Book-listed patent and cannot support a current Paragraph IV challenge.
Biosimilar risk is not relevant to this excipient patent.
Current commercial risk lies in later formulation and manufacturing patents, product-specific drug patents, licensing terms, regulatory know-how and supply access.
The expired patent does not establish worldwide freedom to operate because foreign counterpart rights must be assessed separately.

FAQs

Can a company manufacture SBECD without infringing U.S. Patent 5,134,127?

Yes. The patent expired on July 28, 2009. Manufacturing can still implicate later composition, process or product patents.

Does Captisol remain patent-protected?

The original patent does not provide current protection. Captisol may remain protected through later patents, trademarks, proprietary manufacturing processes, regulatory materials and commercial contracts.

Does a drug product containing SBECD require a Paragraph IV certification?

Not against U.S. Patent 5,134,127. An ANDA applicant must assess the patents listed for the specific reference drug, not every expired excipient patent.

Are C3 and C4 sulfoalkyl cyclodextrins both covered by the patent?

Yes. The claims expressly cover C2-C6 alkylene spacers, with dependent claims identifying C3 and C4 embodiments. The patent is especially relevant to C4 SBECD.

Can a generic drug use a different SBECD supplier?

Potentially. Supplier substitution requires regulatory qualification, comparable quality and impurity control, and a separate freedom-to-operate review of supplier processes and later patents.

References

United States Patent and Trademark Office. (1992). U.S. Patent No. 5,134,127, Cyclodextrin derivatives. U.S. Department of Commerce.
United States Code, 35 U.S.C. §154. Patent term provisions applicable to patents issuing before the 1995 term transition.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
Ligand Pharmaceuticals Incorporated. (2024). Annual report on Form 10-K.
CyDex Pharmaceuticals, Inc. (n.d.). Captisol sulfobutyl ether beta-cyclodextrin technology.
U.S. Food and Drug Administration. (2024). Inactive Ingredient Database.

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
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,134,127

Summary for Patent: 5,134,127