US Patent 5,260,301: FK-506 Tacrolimus Solution Claims, Scope, Expiration, and Patent Landscape

US Patent 5,260,301 covers liquid pharmaceutical solutions containing FK-506, now known as tacrolimus, a polyoxyethylene hydrogenated castor oil surfactant, and a specified nonaqueous solvent. The patent’s core protection is formulation-based rather than compound-based. Its US patent term has expired, eliminating current US patent exclusivity under this patent. The claims remain relevant for historical freedom-to-operate analysis, formulation design, infringement review, and interpretation of tacrolimus product patents.

What does US Patent 5,260,301 protect?

The patent protects a tacrolimus solution in which three elements are present:

FK-506, or tacrolimus.
A pharmaceutically acceptable surfactant containing polyoxyethylene hydrogenated castor oil.
A pharmaceutically acceptable nonaqueous solvent selected from ethanol, propylene glycol, glycerin, or polyethylene glycol.

The independent composition claim is claim 1. Claim 8 independently covers a process for preparing the same type of solution by mixing the listed components.

The patent does not claim tacrolimus as a chemical compound. It does not claim every tacrolimus formulation, every surfactant-based formulation, or every injectable or oral dosage form. Its scope is limited by the combination of the active ingredient, surfactant class, and solvent class.

Key patent data

Item	Details
US patent	5,260,301
Active ingredient	FK-506, tacrolimus
Technology	Nonaqueous tacrolimus solution
Patent type	Formulation and manufacturing-process patent
Patent holder at issuance	Fujisawa Pharmaceutical Co., Ltd.
Filing period	Pre-1995 US patent application
Issue date	November 9, 1993
Statutory term	Generally 17 years from issue for this pre-1995 application
Calculated expiration	November 9, 2010
Current US patent status	Expired by term
Orange Book effect today	No current exclusionary effect from this patent

The patent’s title and bibliographic details should be read together with the official USPTO patent record and the issued claims. The date-based expiration analysis follows the pre-URAA term rule applicable to qualifying applications filed before June 8, 1995. [1,2]

How broad is claim 1 of US Patent 5,260,301?

Claim 1 is a combination claim. A product must contain all required claim elements to fall within its literal scope.

Element-by-element construction

Claim element	Scope
“A pharmaceutical solution”	Requires a liquid solution, rather than merely a suspension, emulsion, solid dosage form, or ointment
“FK 506”	Covers tacrolimus, historically identified as FK-506
“Pharmaceutically acceptable surface active agent”	Requires a pharmaceutically acceptable surfactant
“Comprising polyoxyethylene hydrogenated castor oil”	Requires a surfactant containing polyoxyethylene hydrogenated castor oil
“Pharmaceutically acceptable nonaqueous solvent”	Requires a solvent system characterized as nonaqueous
Specified solvent group	Ethanol, propylene glycol, glycerin, or polyethylene glycol

The term “comprising” generally permits additional ingredients. A solution could therefore contain preservatives, stabilizers, antioxidants, cosolvents, buffers, or other excipients without avoiding claim 1, provided the required ingredients remain present.

The claim is narrower than a claim to “tacrolimus plus any solubilizer.” A formulation using polysorbate, poloxamer, lecithin, sodium lauryl sulfate, or another surfactant would not literally satisfy the limitation requiring polyoxyethylene hydrogenated castor oil.

What dependent claims add to the patent scope?

Claims 2 through 7 narrow claim 1. They do not create independent protection for tacrolimus solutions that lack the elements of claim 1.

Claim 2: ingredient ratio

Claim 2 requires the weight ratio of FK-506 to the surfactant to be between 1:1 and 1:100.

This limitation is commercially relevant because it captures formulations containing substantially more surfactant than tacrolimus. A formulation with a ratio outside that range would not literally meet claim 2, although it could still fall within claim 1.

The claim does not specify:

Tacrolimus concentration in the final solution.
Total volume.
Solvent-to-drug ratio.
A particular route of administration.
A particular dosage strength.
A particular particle size or crystallinity.
A particular therapeutic indication.

Claims 3 through 5: solvent selection

Claims 3, 4, and 5 separately specify:

Propylene glycol.
Glycerin.
Polyethylene glycol.

These claims are narrower than claim 1 but overlap with it. They do not materially expand the solvent coverage because each listed solvent already appears in claim 1.

Claim 6: surfactant identity

Claim 6 specifies polyoxyethylene hydrogenated castor oil 60.

This claim provides a narrower species limitation within the broader surfactant language of claim 1. A formulation using a different grade or homolog of polyoxyethylene hydrogenated castor oil could fall within claim 1 but outside claim 6, depending on the technical identity of the material.

Claim 7: ethanol

Claim 7 specifies ethanol as the nonaqueous solvent. It is the ethanol counterpart to claims 3 through 5.

Claim 8: preparation process

Claim 8 covers mixing FK-506, the specified surfactant, and one of the listed nonaqueous solvents.

The issued text supplied in the question contains typographical variants such as “FX 506” and “caster oil.” The operative technical reading is FK-506 and polyoxyethylene hydrogenated castor oil, consistent with claim 1 and the patent subject matter.

Claim 8 is a process claim. It focuses on the act of preparing the solution, not solely on the final composition. A process that uses different materials, a different solvent system, or a different method may avoid literal infringement of claim 8 even if it produces a tacrolimus-containing liquid.

Does US Patent 5,260,301 cover Prograf or Protopic?

The patent has technical relevance to tacrolimus products but should not be treated as a blanket patent on Prograf or Protopic.

Prograf

Prograf is tacrolimus marketed primarily in oral capsules, granules, and injectable forms. The product’s regulatory and patent position has involved multiple patents covering dosage forms, compositions, methods of use, and manufacturing technology.

US Patent 5,260,301 could have been relevant to a tacrolimus solution containing polyoxyethylene hydrogenated castor oil and one of the listed solvents. It would not automatically cover:

Tacrolimus capsules.
Tacrolimus tablets.
Tacrolimus granules.
Aqueous tacrolimus products.
Tacrolimus products using a different surfactant.
Formulations lacking one of the claimed solvents.

Protopic

Protopic is a tacrolimus ointment. An ointment is materially different from the “pharmaceutical solution” required by claim 1. Unless the product is technically a solution meeting all claimed limitations, US Patent 5,260,301 would not ordinarily read on the ointment dosage form.

The distinction between a solution, suspension, emulsion, and ointment is important. Product classification depends on formulation composition and physical state, not only on the presence of tacrolimus.

When did US Patent 5,260,301 lose exclusivity?

US Patent 5,260,301 expired on November 9, 2010, based on its November 9, 1993 issue date and the 17-year term applicable to the pre-1995 filing regime. [1,2]

Milestone	Date
Patent issued	November 9, 1993
Expected statutory expiration	November 9, 2010
Current enforceability	Expired
Current generic-entry relevance	Historical only, absent a separate surviving patent

Patent expiration removes the right to enforce the expired patent against later products. It does not invalidate other tacrolimus patents with different claims or later expiration dates.

What was the relationship to the core tacrolimus patent estate?

The FK-506 compound estate was separate from the formulation estate.

Core compound protection

Tacrolimus was initially protected through patents directed to:

The FK-506 compound.
Related macrolide compounds.
Microbial production.
Immunosuppressive and therapeutic uses.
Pharmaceutical compositions.

The foundational compound and use patents were associated with Fujisawa and related entities. US Patent 5,260,301 should therefore be viewed as one formulation branch within a larger tacrolimus portfolio, not as the principal compound patent.

Formulation protection

Tacrolimus formulation patents generally addressed:

Oral solid dosage forms.
Injectable solutions.
Ointments.
Improved solubility.
Stability and preservation.
Controlled release.
Reduced irritation or toxicity.
Manufacturing and purification.

The 5,260,301 patent is unusually specific in its use of polyoxyethylene hydrogenated castor oil with a nonaqueous solvent. The claims do not cover all formulation strategies used in later tacrolimus products.

What formulation alternatives would fall outside the literal claims?

A competing formulation would generally avoid literal coverage if it omitted at least one required limitation. Examples include:

Formulation approach	Likely literal result under claim 1
Tacrolimus capsule with solid excipients	Outside “pharmaceutical solution”
Tacrolimus ointment	Outside solution limitation
Tacrolimus aqueous solution without the claimed surfactant	Outside required surfactant limitation
Tacrolimus solution using polysorbate instead of polyoxyethylene hydrogenated castor oil	Outside specified surfactant limitation
Tacrolimus solution using a solvent not listed in claim 1	Outside solvent Markush group
Tacrolimus suspension rather than solution	Outside solution limitation
Tacrolimus formulation without tacrolimus	Outside active-ingredient limitation
Tacrolimus solution using only water and no listed nonaqueous solvent	Outside claim 1

The word “comprising” means that additional ingredients do not necessarily avoid the claim. A design-around normally requires removal or alteration of a required limitation, not merely the addition of another excipient.

How strong was the patent estate for commercial enforcement?

The patent was technically narrow but commercially relevant during its term because it addressed solubilization of a poorly water-soluble immunosuppressant.

Strengths

It identified a defined surfactant-solvent platform for tacrolimus.
It included both composition and process claims.
The formulation claims used “comprising,” allowing additional ingredients.
The dependent claims supplied narrower positions around solvent choice, surfactant grade, and ratio.
The patent could have supported enforcement against a matching liquid formulation even if the competitor used a different brand or indication.

Limitations

The claims required a solution rather than any tacrolimus dosage form.
The solvent list was closed by the phrase “selected from the group consisting of.”
The surfactant limitation excluded many alternative solubilizers.
The patent did not claim the tacrolimus molecule itself.
The patent term ended in 2010.
The patent did not independently control later-developed dosage forms or delivery systems.

The closed Markush group is particularly important. Ethanol, propylene glycol, glycerin, and polyethylene glycol are included. A solvent outside that group would not literally satisfy the claim, subject to any applicable doctrine-of-equivalents analysis.

What was the Orange Book status of US Patent 5,260,301?

US Patent 5,260,301 is not a current source of Orange Book exclusivity. Its term expired in 2010.

The FDA Orange Book lists patents submitted by sponsors for approved drug products and identifies patent and exclusivity information associated with those products. A patent can be relevant to an approved product without being the only patent governing that product. Orange Book listing also does not extend an expired patent term. [3]

For tacrolimus products, Orange Book analysis must distinguish:

Product-specific listing.
Patent expiration.
Pediatric exclusivity.
New-drug exclusivity.
Paragraph IV certifications.
Unexpired formulation, method-of-use, or manufacturing patents.

US Patent 5,260,301 should not be treated as a current Orange Book barrier to an ANDA applicant.

Were there Paragraph IV challenges or settlements involving this patent?

Because US Patent 5,260,301 expired in 2010, it is not a current Paragraph IV obstacle. A Paragraph IV certification against this patent would have had practical relevance only while the patent was listed and unexpired.

The available claim information does not establish a specific Paragraph IV filing, ANDA litigation case, or settlement agreement directed to this patent. No litigation conclusion should be attributed to the patent merely because tacrolimus generics entered the market. Generic entry may have occurred after expiration of this patent or under separate patent certifications involving other tacrolimus patents.

Does the patent create biosimilar risk?

No. Tacrolimus is a small-molecule drug, not a biologic. Biosimilar concepts do not apply.

The relevant regulatory pathway is an abbreviated new drug application, or ANDA, for a generic tacrolimus product, not a biosimilar application under the Public Health Service Act. [3,4]

The principal competitive issues are therefore:

Pharmaceutical equivalence.
Bioequivalence.
Dosage-form matching.
Product-specific patent certifications.
Manufacturing capability.
FDA approval requirements.

What manufacturing and IP barriers did the patent create?

During its term, the patent could have constrained a manufacturer seeking to reproduce a matching tacrolimus solution using the claimed excipient platform.

The main technical barrier was solubilization. Tacrolimus has low aqueous solubility, so a liquid product may require:

A suitable surfactant.
A nonaqueous solvent.
Stable drug dispersion or solubilization.
Acceptable injection or oral tolerability.
Chemical stability over shelf life.
Control of impurities and degradation products.
Consistent mixing and fill-finish operations.

The patent did not prevent all manufacturing routes. A competitor could pursue a different dosage form, different surfactant, different solvent, solid dispersion, lipid system, suspension, or alternative delivery technology.

How does US Patent 5,260,301 compare with later tacrolimus formulation patents?

Issue	US 5,260,301	Later tacrolimus patents
Primary subject	Nonaqueous tacrolimus solution	Often dosage form, release, stability, or administration
Active ingredient	FK-506/tacrolimus	Tacrolimus or modified derivatives
Surfactant requirement	Polyoxyethylene hydrogenated castor oil	Varies by patent
Solvent requirement	Ethanol, propylene glycol, glycerin, or PEG	May use other solvent or excipient systems
Claim format	Composition plus preparation process	May include composition, method, device, or manufacturing claims
Current US term	Expired	Must be assessed patent by patent
Biosimilar relevance	None	None
Generic risk	Historical formulation risk	Depends on remaining claims and FDA listings

Key Takeaways

US Patent 5,260,301 covers a specific tacrolimus solution platform.
Claim 1 requires tacrolimus, polyoxyethylene hydrogenated castor oil, and one of four listed nonaqueous solvents.
Claim 2 adds a tacrolimus-to-surfactant ratio of 1:1 to 1:100 by weight.
Claims 3 through 7 narrow the solvent or surfactant selection.
Claim 8 covers preparation by mixing the required components.
The patent does not cover tacrolimus generally, every tacrolimus formulation, or every Prograf or Protopic product.
The patent expired on November 9, 2010.
It is not a current US patent barrier to generic tacrolimus entry.
Tacrolimus is a small molecule, so biosimilar analysis does not apply.
Current freedom-to-operate analysis must focus on surviving tacrolimus patents, FDA listings, manufacturing patents, and product-specific litigation.

FAQs

Does US Patent 5,260,301 cover a tacrolimus formulation using polysorbate 80?

Not literally under claim 1 if the formulation lacks polyoxyethylene hydrogenated castor oil. Polysorbate 80 is a different surfactant, although an equivalence analysis would depend on the facts and applicable law.

Can a generic manufacturer use propylene glycol with tacrolimus today?

The patent’s propylene glycol claims expired in 2010. A manufacturer must still assess other unexpired patents, FDA requirements, product quality, and regulatory exclusivity.

Does claim 2 require a specific tacrolimus concentration?

No. Claim 2 specifies the weight ratio between tacrolimus and the surfactant. It does not establish a particular concentration in the final dosage volume.

Is polyethylene glycol in claim 1 limited to one molecular weight?

The claim identifies polyethylene glycol generically and does not state a specific molecular weight. The specification and prosecution history would control any narrower construction based on molecular-weight terminology.

Could a tacrolimus suspension infringe claim 1?

A suspension would not ordinarily satisfy the express “pharmaceutical solution” limitation. The physical and pharmaceutical characterization of the product would control, along with any potential doctrine-of-equivalents analysis.

References

United States Patent and Trademark Office. (1993). US Patent No. 5,260,301, Pharmaceutical solution containing FK-506.
United States Code, 35 U.S.C. § 154. Patent term provisions for applications subject to the pre-URAA and transitional term rules.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations.
U.S. Food and Drug Administration. (2024). Generic drug facts and abbreviated new drug application requirements.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	2-51110	Mar 01, 1990

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	143598	⤷ Start Trial
Australia	642707	⤷ Start Trial
Australia	7194991	⤷ Start Trial
Canada	2037408	⤷ Start Trial
China	1028961	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 5,260,301