US Patent 8,486,993: Tacrolimus Solid-Composition Claims, Scope, Validity Risks, and Patent Landscape

US Patent 8,486,993 covers solid tacrolimus compositions using at least two hydrophilic or water-miscible vehicles, one of which must be a poloxamer. The claims also reach agglomerated particle formulations, a spray-and-mechanical-working manufacturing process, organ-transplant rejection methods, and extended-release compositions defined by a W50 pharmacokinetic parameter.

The broadest practical limitation is the required vehicle system: tacrolimus must be dispersed or dissolved in at least two hydrophilic or water-miscible vehicles with melting points of at least 30°C, and one vehicle must be a poloxamer. Poloxamer 188 is separately claimed.

What does US Patent 8,486,993 protect?

The patent protects a formulation architecture rather than tacrolimus itself. Its principal elements are:

Claim element	Scope
Active ingredient	Tacrolimus
Dosage form	Solid pharmaceutical composition
Carrier	Solid carrier
Vehicle system	At least two hydrophilic or water-miscible vehicles
Thermal limitation	Vehicles have melting points of at least 30°C
Mandatory excipient	One vehicle is a poloxamer
Tacrolimus concentration	0.01% to 15% w/w
Particle limitation	Claims 3-6 require agglomerated particles with dgw of 100-1,000 micrometers
Manufacturing limitation	Claims 5-6 require spraying, mechanical working, and compression
Therapeutic use	Suppression of transplanted-organ rejection
Modified release	Claims 9-14 require a release-modifying agent and, in narrower claims, W50 of at least 12 or 14 hours

The claims use “comprising,” which generally makes them open-ended. A product may contain additional excipients, coatings, binders, lubricants, disintegrants, stabilizers, or release-control materials and still fall within the claim if every required element is present.[1]

How broad is independent claim 1?

Claim 1 is the principal composition claim. It requires five material limitations:

A solid pharmaceutical composition.
A solid carrier.
Tacrolimus.
A mixture of at least two hydrophilic or water-miscible vehicles.
At least one vehicle that is a poloxamer.

The tacrolimus concentration must be between 0.01% and 15% by weight. The claimed vehicles must have melting points of at least 30°C.

The claim does not require:

A particular tablet size.
A particular dissolution profile.
A particular tacrolimus polymorph.
A particular solid carrier.
Poloxamer 188 specifically.
A specified particle size.
A particular administration route.
An extended-release profile.
A particular transplant indication.

Claim 1 therefore has potentially broad coverage over immediate-release and modified-release solid tacrolimus products, provided the vehicle and concentration limitations are met.

What does “at least two vehicles” require?

The formulation must contain a vehicle mixture rather than a single hydrophilic vehicle. One of the vehicles must be a poloxamer. The second vehicle could be another hydrophilic or water-miscible material, subject to the claim’s melting-point requirement.

Potentially relevant materials may include polyethylene glycols, hydrophilic surfactants, other poloxamers, or related pharmaceutical solubilizers. Whether a specific excipient qualifies depends on its composition, grade, melting behavior, and use in the actual formulation.

A formulation containing poloxamer 188 plus a second qualifying vehicle is the clearest literal case. A formulation containing only one poloxamer vehicle would generally fail the “mixture of at least two” limitation unless the poloxamer system itself is properly characterized as containing multiple qualifying vehicles.

What additional protection does claim 2 provide?

Claim 2 narrows claim 1 by requiring poloxamer 188. It does not remove the other limitations of claim 1.

A product must still have:

Tacrolimus at 0.01% to 15% w/w.
A solid carrier.
At least two hydrophilic or water-miscible vehicles.
Vehicles with melting points of at least 30°C.
A solid pharmaceutical composition.

Claim 2 has greater formulation specificity but a narrower design-around target. Substitution of poloxamer 188 with another poloxamer may avoid claim 2 while remaining within claim 1.

What formulations are protected by claims 3 and 4?

Claims 3 and 4 add an agglomerated-particle requirement. The composition must contain agglomerated particles having a geometric weight mean diameter, or dgw, of 100 to 1,000 micrometers.

This limitation matters because the claim is directed to a particulate intermediate or final dosage-form structure, not simply to the presence of tacrolimus and a poloxamer-containing vehicle mixture.

Requirement	Claim 3
Solid carrier	Required
Tacrolimus	Required
At least two qualifying vehicles	Required
Poloxamer	Required
Tacrolimus concentration	Approximately 0.01% to 15% w/w
Agglomerated particles	Required
dgw	100-1,000 micrometers

A formulation may avoid claims 3 and 4 if its particles fall outside the stated dgw range or if it does not contain agglomerated particles. That does not necessarily avoid claim 1, which has no particle-size limitation.

Particle-size testing would therefore be central to any infringement analysis. The testing method, sampling plan, particle-shape assumptions, and calculation of dgw can affect the result.

What process is protected by claims 5 and 6?

Claims 5 and 6 are process-defined composition claims. They require a solid composition prepared by:

Spraying a solid carrier with tacrolimus dispersed or dissolved in a mixture of two qualifying hydrophilic or water-miscible vehicles.
Mechanically working the sprayed material to form agglomerated particles with a dgw of 100 to 1,000 micrometers.
Compressing the agglomerated particles.
Maintaining tacrolimus at approximately 0.01% to 15% w/w.
Including a poloxamer, with poloxamer 188 required by claim 6.

The process claim creates manufacturing-record exposure. A tablet manufacturer may infringe even if the final tablet’s composition is difficult to distinguish analytically, if the claimed process was used and the resulting product satisfies the claim limitations.

Relevant evidence would include:

Spray-granulation records.
In-process batch instructions.
Equipment settings.
Feed-solution composition.
Granulation and milling records.
Particle-size certificates.
Compression records.
Supplier specifications for poloxamer and other vehicles.

A manufacturer using dry blending, direct compression, fluid-bed coating, hot-melt extrusion, or another process may avoid claims 5 and 6 if it does not practice the required sequence. It could still face composition claims 1-4.

What do claims 7 and 8 cover?

Claims 7 and 8 cover methods of suppressing transplanted-organ rejection by administering an effective amount of a composition falling within claim 1 or claim 5.

The method claims do not claim tacrolimus treatment generally. They are tied to the claimed formulation. A generic tacrolimus product that does not meet the composition limitations would not infringe merely because it is administered to a transplant recipient.

Potentially relevant organ-transplant uses include kidney, liver, heart, lung, pancreas, and other solid-organ transplantation. The supplied claims do not limit the method to a particular organ, dosing schedule, trough concentration, or patient subgroup.

What do claims 9 through 14 add?

Claims 9-14 address modified-release versions of the composition.

Claims 9 and 12 require a release-modifying agent. Claims 10, 11, 13, and 14 add W50 requirements:

Claim	Added limitation
9	Claim 1 composition with a release-modifying agent
10	W50 of at least 12 hours
11	W50 of at least 14 hours
12	Claim 5 composition with a release-modifying agent
13	W50 of at least 12 hours
14	W50 of at least 14 hours

W50 is defined in the claims as the period during which plasma concentration is at least 50% of Cmax. These claims introduce a pharmacokinetic limitation that may require clinical or controlled pharmacokinetic testing.

The W50 limitation creates several legal and technical issues:

The test population may affect the result.
Food status may affect tacrolimus exposure.
Dose normalization may be necessary.
Cmax variability may materially change the calculated W50.
Sampling intervals may influence the measured duration.
The release-modifying agent must be identified as part of the claimed composition, but the claim does not specify one particular agent.

Claims 11 and 14 are narrower than claims 10 and 13 because they require W50 of at least 14 hours.

When does US Patent 8,486,993 lose exclusivity?

The patent issued on July 23, 2013.[2] The statutory patent term is generally 20 years from the earliest effective nonprovisional filing date, subject to patent-term adjustment, patent-term extension, terminal disclaimers, and other term events.[3]

The issue date alone does not establish the expiration date. A reliable expiration analysis requires the patent’s earliest priority and nonprovisional filing data, any terminal disclaimer, patent-term adjustment, and any patent-term extension. The patent’s enforceability also depends on maintenance-fee payment and post-grant proceedings.

Patent expiration should be distinguished from FDA exclusivity. Patent protection and regulatory exclusivity may expire on different dates.

Is US Patent 8,486,993 an Orange Book patent?

A patent is Orange Book-listed only if it is submitted by the NDA holder and accepted by FDA as claiming the approved drug, formulation, composition, or method of use under FDA listing rules.[4]

The patent claims are technically relevant to tacrolimus solid dosage forms, but the claims supplied do not establish:

Whether the patent is listed in the Orange Book.
Which NDA product it covers.
Whether it is listed against Prograf, Astagraf XL, Envarsus XR, or another tacrolimus product.
Whether FDA has delisted it.
Whether its listing has been disputed.

Orange Book status must be checked against the current FDA patent listing for the specific tacrolimus NDA. A patent may be commercially relevant without being Orange Book-listed, particularly where the patent is asserted in litigation or licensed as a manufacturing technology.

How does this patent compare with competing tacrolimus patent estates?

Tacrolimus products fall into several technical groups:

Product or technology category	Typical patent focus
Immediate-release tacrolimus capsules	Capsule composition, manufacturing, crystallinity, formulation excipients
Prolonged-release tacrolimus	Release-control matrix, dissolution profile, dosing interval, pharmacokinetics
MeltDose-type formulations	Solid dispersion, enhanced bioavailability, particle engineering, manufacturing
Tacrolimus granules or pediatric products	Granulation, suspension behavior, dose flexibility
Generic tacrolimus	Bioequivalence, formulation design, ANDA certification, Paragraph IV risk
Transplant treatment methods	Dosing regimens, conversion methods, therapeutic drug monitoring

US 8,486,993 is strongest where a competing product uses the claimed combination of tacrolimus, a poloxamer-containing vehicle mixture, a solid carrier, and the claimed concentration range. It is less relevant to a formulation based on a different solubilization mechanism, a single vehicle, a non-poloxamer surfactant system, or a process that does not produce the claimed agglomerated particles.

What generic entry risks exist?

A generic applicant seeking approval for an affected tacrolimus product could face several certification paths:

Paragraph I: no relevant patent information listed.
Paragraph II: listed patent has expired.
Paragraph III: approval is sought after patent expiration.
Paragraph IV: the patent is invalid, unenforceable, or not infringed.[5]

For this patent, a Paragraph IV strategy could target:

Failure to use a poloxamer.
Use of a single qualifying vehicle.
Vehicle melting point below 30°C.
Tacrolimus concentration outside the claimed range.
Failure to use the claimed agglomerated particle structure.
dgw outside 100-1,000 micrometers.
Different manufacturing sequence.
Absence of the claimed release-modifying agent.
Failure to achieve W50 of 12 or 14 hours.
Invalidity based on anticipation or obviousness.

The broadest claim, claim 1, is likely the principal barrier. Claims 3-6 create narrower technical barriers that may be easier to avoid through formulation or process redesign.

What are the principal validity risks?

Anticipation and obviousness

The patent’s validity may depend on whether earlier tacrolimus formulation references disclosed the required combination of:

A solid carrier.
Tacrolimus.
At least two qualifying hydrophilic or water-miscible vehicles.
A poloxamer.
Vehicle melting points of at least 30°C.
The claimed concentration range.

For claims 3-6, the prior art would need to address the agglomerated-particle and manufacturing limitations. For claims 10, 11, 13, and 14, prior art would also need to disclose or render obvious the W50 performance requirement.

Definiteness and enablement

Potential issues include the boundaries of:

“Hydrophilic.”
“Water-miscible.”
“Melting point.”
“Mechanically working.”
“Agglomerated particles.”
“Geometric weight mean diameter.”
“Effective amount.”
W50 measurement methodology.

The enforceability of the W50 claims may depend heavily on whether the patent specification provides sufficient testing protocols and representative examples across the full claimed scope.

What licensing and litigation conclusions follow?

The claims alone do not establish a licensing agreement, settlement, Paragraph IV notice, ANDA litigation, or current enforcement action. Those events are separate from the patent document and must be confirmed through assignment records, FDA listings, PACER, and reported settlement documents.

From a commercial perspective, the patent is most relevant to:

Tacrolimus extended-release developers.
Generic manufacturers developing poloxamer-containing formulations.
Contract manufacturers using spray granulation or agglomeration.
Licensees commercializing solid-dispersion or particle-engineering technology.
NDA holders assessing Orange Book listing or patent-term exposure.

Tacrolimus is a small molecule. Biosimilar risk does not apply. The relevant competitive threat is generic or hybrid regulatory approval, not a biosimilar pathway.

Key Takeaways

US Patent 8,486,993 targets tacrolimus solid formulations, not tacrolimus as an active ingredient.
Claim 1 requires at least two qualifying hydrophilic or water-miscible vehicles and a poloxamer.
Claim 2 specifically requires poloxamer 188.
Claims 3 and 4 add agglomerated particles with a dgw of 100-1,000 micrometers.
Claims 5 and 6 require a spray, mechanical-working, and compression process.
Claims 9-14 cover release-modified formulations with W50 thresholds of at least 12 or 14 hours.
The strongest design-around routes are removal of the poloxamer, use of one vehicle, a different vehicle melting profile, alternative particle engineering, or a different manufacturing process.
Orange Book listing, patent expiration, assignment, maintenance status, and litigation cannot be established from the claims alone.
Generic risk is formulation-specific and depends on the actual excipient system, particle structure, manufacturing process, and ANDA certification.

FAQs

Does a tacrolimus tablet infringe US Patent 8,486,993 merely because it is extended release?

No. Extended release alone is insufficient. The product must satisfy the relevant composition, vehicle, concentration, particle, process, and, for narrower claims, W50 limitations.

Can a formulation avoid claim 2 by replacing poloxamer 188?

Yes, potentially. Replacing poloxamer 188 may avoid claim 2, but another poloxamer could still implicate claim 1 if all of its limitations are met.

Does a product with particles below 100 micrometers avoid the patent?

It may avoid claims 3-6 if the claimed agglomerated-particle limitation is not met. It may still fall within claim 1, which has no particle-size requirement.

Is a tacrolimus generic a biosimilar under FDA law?

No. Tacrolimus is a small-molecule drug. Generic applicants generally use the ANDA pathway, not the biosimilar pathway.

Does a Paragraph IV certification automatically invalidate the patent?

No. Paragraph IV is an applicant’s legal position that the patent is invalid, unenforceable, or not infringed. The patent remains enforceable unless it expires, is disclaimed, is cancelled, or is held invalid or unenforceable.

References

United States Patent and Trademark Office. (2024). Manual of Patent Examining Procedure: Claim interpretation and transitional terms. U.S. Department of Commerce.
United States Patent and Trademark Office. (2013). US Patent No. 8,486,993. U.S. Department of Commerce.
United States Code. (2024). 35 U.S.C. §§ 154, 156, and 253. Legal Information Institute, Cornell Law School.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration. (2024). Abbreviated new drug application submissions: Patent certification and the Paragraph IV process. U.S. Department of Health and Human Services.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Denmark	2003 01232	Aug 29, 2003
Denmark	2003 01837	Dec 11, 2003
Denmark	2004 00079	Jan 21, 2004
Denmark	2004 00463	Mar 23, 2004

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	473003	⤷ Start Trial
Austria	531368	⤷ Start Trial
Australia	2004267909	⤷ Start Trial
Australia	2004267910	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 8,486,993

Summary for Patent: 8,486,993