US Patent 5,385,907: Tacrolimus Ointment Claims, Scope, Expiration, and Patent Landscape

US Patent 5,385,907 covers topical ointments containing tacrolimus or structurally related tricyclic compounds, together with specified solubilizing or absorption-promoting agents and oil- or fat-based ointment vehicles. The strongest commercial embodiments are tacrolimus ointments containing propylene carbonate in a petrolatum/paraffin/beeswax base, corresponding to Protopic formulations. The patent was granted on January 31, 1995, and its US patent term expired on January 31, 2012, absent a material term adjustment. It is no longer an enforceable barrier to generic tacrolimus ointment entry.[1]

What does US Patent 5,385,907 protect?

The patent protects a composition, not tacrolimus as a molecule and not a method of treating a disease. Its core subject matter is an ointment containing four principal elements:

A tricyclic compound within a large Markush formula.
The compound at approximately 0.01% to 10% by weight.
A listed solubilizing or absorption-promoting agent at approximately 1% to 30% by weight.
An oil- or fat-based ointment vehicle.

The claims are directed to topical pharmaceutical formulations. They do not directly claim:

Oral tacrolimus formulations.
Injectable tacrolimus formulations.
Tacrolimus manufacturing processes.
A method of treating atopic dermatitis.
Tacrolimus itself as a chemical entity.
Any topical formulation lacking the required ointment base.
Any composition outside the claimed concentration ranges, subject to equivalents analysis.

The patent’s commercial significance derives from the inclusion of tacrolimus within the claimed tricyclic-compound definition and the detailed formulation limitations directed to dermal delivery.

Which compound is identified in claims 5, 6, 10, 11, and 17 through 24?

The compound in claims 5, 10, 17, 20, 23, and 24 is tacrolimus, also known as FK506. The chemical name recited in those claims is:

17-allyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0^4,9]octacos-18-ene-2,3,10,16-tetraone.

Claim 6 and claim 11 cover the corresponding 17-ethyl analog rather than tacrolimus. Claims 5, 10, 17, 20, 23, and 24 narrow the compound to the 17-allyl form.

Claim group	Compound scope	Formulation scope
Claims 1, 2, 7, 12-16	Broad tricyclic Markush structure, potentially including tacrolimus	Broad listed excipients, concentrations, and ointment bases
Claims 3, 4, 8, 9	Narrower tricyclic subclasses	Same general ointment framework
Claims 5, 10, 17, 20, 23, 24	Tacrolimus	Increasingly specific excipient and vehicle combinations
Claims 6 and 11	17-ethyl analog	Ointment formulations within the claim structure
Claims 13, 14	Broad base categories	Natural waxes, petroleum waxes, glycerin esters, hydrocarbons, or mixtures
Claims 15, 16	Specific ointment base and enhancer	White petrolatum, solid paraffin, liquid paraffin, white beeswax, and propylene carbonate and/or diisopropyl adipate
Claims 18, 19, 21, 22	Tacrolimus plus lower alkylene carbonate	Propylene carbonate is the specific embodiment

How broad is claim 1 of US 5,385,907?

Claim 1 is a combination claim with a broad chemical Markush element but substantial formulation limitations.

The chemical component is defined through multiple variable substituents, alternative oxidation states, ring closures, protected hydroxyl groups, heterocyclic options, and salt forms. This drafting technique potentially reaches a large genus of macrolide and related tricyclic compounds. The claim is materially narrower than a pure genus claim because the compound must be present in an ointment with specified excipient and vehicle categories.

The formulation limitations require:

A tricyclic compound or pharmaceutically acceptable salt.
Approximately 0.01% to 10% by weight of that compound.
A solubilizing or absorption-promoting agent selected from enumerated chemical classes.
Approximately 1% to 30% by weight of that agent.
An oil- or fat-based ointment base.
Optional colorants, preservatives, and higher alkene carboxylic acids.

The phrase "consisting essentially of" limits the composition to the listed components plus ingredients that do not materially affect the basic and novel characteristics of the invention. This is narrower than "comprising" but broader than "consisting of." The legal effect would depend on whether an unlisted excipient materially changes solubilization, absorption, stability, rheology, or another claimed characteristic.

What formulations are protected by claims 15, 16, 23, and 24?

Claims 15 and 16 identify the most commercially relevant vehicle:

White petrolatum.
Solid paraffin.
Liquid paraffin.
White beeswax.
Propylene carbonate alone or combined with diisopropyl adipate.

Claims 23 and 24 further require tacrolimus and propylene carbonate. These claims are substantially narrower than claim 1 but provide a more direct read on a Protopic-type formulation.

The claims do not require a particular tacrolimus strength within the 0.01% to 10% range. A tacrolimus ointment at 0.03% or 0.1% would fall within the concentration range if the remaining formulation elements were present. The claims also do not require a specific indication, age group, application frequency, package, or label.

A formulation that uses tacrolimus in a non-ointment dosage form, such as a cream, gel, lotion, foam, spray, or transdermal patch, would not literally satisfy the claimed ointment limitation. Whether a non-ointment formulation could raise an equivalents issue would depend on the facts, prosecution history, and the formulation's technical characteristics.

How do the dependent claims narrow the patent?

The claims create a tiered structure.

Broad excipient claims

Claims 1 and 12 cover a wide list of absorption-promoting agents, including:

Lower alkanediols.
Lower alkylene carbonates.
Alkane dicarboxylic esters.
Higher alkane or alkene carboxylic glycerin esters.
Higher alkane carboxylic alkyl esters.
Higher unsaturated alcohols.
Azacycloalkanes.

Claim 2 narrows the enhancer to a lower alkanediol, lower alkylene carbonate, or alkane dicarboxylic ester.

Tacrolimus-specific claims

Claims 5, 10, 17, 20, 23, and 24 focus on the 17-allyl compound, tacrolimus. These claims are commercially more important than the broad Markush claims because they provide a direct formulation claim for the active ingredient used in Protopic.

Propylene-carbonate claims

Claims 18, 19, 21, 22, 23, and 24 narrow the absorption-promoting agent to a lower alkylene carbonate and, ultimately, propylene carbonate. These claims are relevant to a generic manufacturer using the same enhancer in a substantially similar ointment vehicle.

Vehicle claims

Claims 13 and 14 cover broad classes of oil and fat bases. Claims 15 and 16 specify the combination of white petrolatum, solid paraffin, liquid paraffin, and white beeswax. The vehicle claims increase literal infringement risk for a formulation that closely reproduces the branded product's excipient system.

When did US Patent 5,385,907 lose exclusivity?

Event	Date
US patent grant	January 31, 1995
Patent term basis	17 years from grant for the pre-1995 application framework
Expected US expiration	January 31, 2012
Present status	Expired
Current blocking effect	None as an enforceable US patent right

The patent was filed under the pre-Uruguay Round Agreements Act transition rules. Its term was therefore generally calculated from grant rather than from the earliest effective nonprovisional filing date. The patent is listed in public patent databases as expired by operation of its term.[1]

The expiration removed the principal barrier created by US Patent 5,385,907. It did not eliminate other possible barriers, such as later formulation patents, regulatory exclusivity, trade secrets, manufacturing know-how, trademarks, or patents directed to specific delivery technologies.

What was the FDA and Orange Book status?

Protopic is an FDA-approved topical tacrolimus ointment marketed by the original sponsor, Fujisawa, later associated with Astellas. The FDA approved Protopic ointment for atopic dermatitis in two strengths:

0.03% tacrolimus ointment.
0.1% tacrolimus ointment.

The product is a small-molecule drug, not a biologic. Biosimilar pathways therefore do not apply. Generic competitors use the abbreviated new drug application pathway under section 505(j) of the Federal Food, Drug, and Cosmetic Act.[2]

An Orange Book-listed patent can support a Paragraph IV certification and patent litigation during its term. Once the patent expires, the listing no longer provides an operative patent exclusion against a properly approved generic product. FDA approval and market entry also depend on the status of any other listed patents, applicable exclusivity, labeling requirements, and the applicant's ANDA pathway.[3]

Which companies challenged tacrolimus ointment exclusivity?

Tacrolimus ointment faced generic competition after the expiration of the principal formulation patent and associated regulatory barriers. Generic manufacturers have included major ANDA sponsors and dermatology-focused manufacturers, with products approved for the 0.03% and 0.1% strengths.

A Paragraph IV challenge to an unexpired Orange Book patent would have required the ANDA applicant to certify that the patent was invalid, unenforceable, or not infringed. The commercial value of such a challenge was highest before January 2012. After expiration of US Patent 5,385,907, the claim set no longer supported an exclusionary launch delay.

The public record for any particular historic Paragraph IV notice, district-court case, settlement agreement, or 180-day exclusivity event must be evaluated by applicant and case number. The expired status of the patent is the decisive present legal fact.

What patent litigation affects US Patent 5,385,907 today?

No current infringement case can restore an expired patent's exclusionary term. Any historical litigation involving this patent may remain relevant for claim construction, prosecution history, settlement economics, or damages analysis, but it does not create a present right to exclude generic tacrolimus ointment sales.

Potential historical disputes would have centered on:

Whether a generic ointment contained a listed absorption promoter.
Whether its tacrolimus concentration fell within the claimed range.
Whether the generic vehicle was an oil- or fat-based ointment.
Whether additional excipients materially altered the claimed composition.
Whether the patent was valid and enforceable.
Whether a formulation avoided the specific white petrolatum/paraffin/beeswax vehicle.

Because the patent has expired, a current product-development program should treat the claims as an expired prior-art and freedom-to-operate reference, not as an active injunction risk.

How strong was the patent estate for tacrolimus ointment?

The patent was commercially strong during its term because it covered the formulation architecture used for a marketed topical product rather than merely an obscure laboratory composition. Its practical strengths were:

Direct coverage of tacrolimus ointment embodiments.
Broad concentration ranges.
Coverage of several enhancer classes.
Specific claims to propylene carbonate.
Specific claims to common petrolatum-based vehicles.
Dependent claims that provided fallback positions if broader claims were invalidated.

Its weaknesses included:

Dependence on the ointment dosage form.
Dependence on specified enhancer classes.
Potential design-around options using a cream, gel, alternative enhancer, or non-oil vehicle.
A limited remaining term by the time generic development matured.
Potential written-description, enablement, indefiniteness, and obviousness challenges against the broad Markush genus.
No direct claim to tacrolimus as a compound.

The narrower tacrolimus and propylene-carbonate claims would generally have presented the clearest infringement theories, while the broad Markush claims would have faced more substantial validity and claim-construction scrutiny.

How does US Patent 5,385,907 compare with tacrolimus compound patents?

Patent category	Protected subject matter	Relevance after 2012
Tacrolimus compound patents	Chemical compound, stereochemistry, or production	Mostly expired for the original molecule, subject to family-specific terms
US 5,385,907	Tacrolimus and related compounds in ointment formulations	Expired
Later formulation patents	Specific vehicles, particle sizes, delivery systems, stability features, or manufacturing controls	Requires separate live-status review
Method-of-use patents	Treatment of atopic dermatitis or other inflammatory diseases	Must be analyzed separately by patent and jurisdiction
Regulatory exclusivity	FDA exclusivity tied to approval, pediatric studies, or other statutory provisions	Separate from patent term

US Patent 5,385,907 is a formulation patent. It should not be confused with the original tacrolimus compound patent estate or with later patents directed to manufacturing, delivery, or clinical use.

What generic launch scenarios existed?

Three principal launch strategies were available.

Same-strength, same-type ointment

A generic sponsor could seek approval for 0.03% and 0.1% tacrolimus ointments closely resembling Protopic. Before patent expiration, this strategy carried Paragraph IV and litigation risk. After expiration, it became the most direct route, subject to FDA requirements.

Formulation design-around

A sponsor could use a different enhancer, vehicle, or dosage form to avoid literal infringement of claims 15, 16, 23, and 24. This strategy could reduce patent exposure but would create formulation-equivalence, bioequivalence, stability, and manufacturing challenges.

Post-expiration ANDA entry

After January 31, 2012, a sponsor could pursue standard ANDA approval without the expired patent serving as a continuing exclusionary right. Market entry still depended on FDA approval, product quality, manufacturing capacity, commercial contracting, and any later patents.

Does the patent create biosimilar risk?

No. Tacrolimus is a chemically synthesized or fermentation-derived small molecule regulated through the drug approval framework. A tacrolimus ointment competitor is a generic drug applicant, not a biosimilar applicant. The relevant regulatory pathway is an ANDA or, in certain circumstances, another abbreviated or hybrid pathway. Biosimilar approval under section 351(k) of the Public Health Service Act does not apply.[2]

Key Takeaways

US Patent 5,385,907 covers tacrolimus and related tricyclic compounds in specified ointment formulations.
Claims 5, 10, 17, 20, 23, and 24 specifically target tacrolimus embodiments.
Claims 15, 16, 23, and 24 are directed to the most commercially recognizable vehicle: white petrolatum, paraffins, white beeswax, and propylene carbonate.
The patent claims composition architecture, not tacrolimus itself, a treatment method, or a manufacturing process.
The patent expired on January 31, 2012.
It no longer blocks generic tacrolimus ointment entry in the United States.
Tacrolimus ointment competition proceeds through the generic drug pathway, not the biosimilar pathway.
Later patents, regulatory exclusivity, manufacturing know-how, and trademarks must be analyzed separately from US Patent 5,385,907.

FAQs

What is the active ingredient covered by US Patent 5,385,907?

The principal commercial active ingredient is tacrolimus, also known as FK506. The patent also covers a broader genus of structurally related tricyclic compounds.

Does US Patent 5,385,907 cover Protopic 0.03% and 0.1% ointment?

The claims cover formulations that satisfy the specified compound, ointment, enhancer, vehicle, and concentration limitations. Tacrolimus concentrations of 0.03% and 0.1% fall within the claimed 0.01% to 10% range.

Can a company launch a generic tacrolimus ointment based on this patent's expiration?

Yes. The patent expired in 2012 and no longer provides an enforceable exclusionary right. FDA approval, Orange Book requirements, and any later unexpired patents remain separate issues.

Does changing propylene carbonate avoid the patent?

It may avoid claims limited to propylene carbonate, but claims 1 and 2 cover broader classes of solubilizing or absorption-promoting agents. The complete formulation must be compared against every limitation of the asserted claim.

Is US Patent 5,385,907 relevant to tacrolimus cream or gel products?

The patent is directed to an ointment. A cream or gel may avoid literal infringement of the ointment limitation, although the analysis would depend on the product's physical characteristics and any applicable equivalents theory.

References

United States Patent and Trademark Office. (1995). Ointment containing tricyclic compound, U.S. Patent No. 5,385,907. https://patents.google.com/patent/US5385907
U.S. Food and Drug Administration. (n.d.). Abbreviated new drug application (ANDA): Generics. https://www.fda.gov/drugs/types-applications/abbreviated-new-drug-application-anda
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations. https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	2-235177	Sep 04, 1990

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	150304	⤷ Start Trial
Australia	656145	⤷ Start Trial
Australia	8351591	⤷ Start Trial
Canada	2050623	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,385,907

Summary for Patent: 5,385,907