United States Patent 8,586,084: Tacrolimus Extended-Release Claims, Scope and Patent Landscape

U.S. Patent No. 8,586,084 protects methods of suppressing organ-transplant rejection by administering an extended-release tacrolimus formulation with defined dissolution performance. The patent is centered on delayed and controlled tacrolimus release, reduced food-effect variability, and delivery toward the distal duodenum. Its principal commercial relevance is Envarsus XR, an extended-release tacrolimus product approved by the FDA for prophylaxis of organ rejection in kidney-transplant patients.

The patent does not broadly cover all tacrolimus products. Its claims require a specific combination of therapeutic use, extended-release formulation characteristics, and, in several claims, particular formulation ingredients or dissolution results.

What does U.S. Patent 8,586,084 cover?

The patent covers a method of suppressing rejection after organ transplantation by orally administering extended-release tacrolimus that releases no more than 62% of its tacrolimus content within 15 hours under a specified USP Paddle dissolution test.

Feature	Claim requirement
Active ingredient	Tacrolimus
Administration	Oral
Dosage form	Extended-release pharmaceutical composition
Therapeutic use	Suppression of organ-transplant rejection
Core dissolution limit	No more than 62% released within 15 hours
Dissolution method	USP Paddle, 50 rpm
Dissolution medium	900 mL aqueous medium with 0.005% hydroxypropylcellulose
Medium pH	pH 4.5
Dependent organ claims	Kidney and liver
Additional formulation options	Poloxamer, polyethylene glycol, cellulose derivatives, solid carriers, tacrolimus-containing particles, compressed tablets
Pharmacokinetic requirement	Fed/fasted AUC ratio of at least 0.9 in claim 6
Release profile	pH-independent release in claim 7

The independent claims are method claims rather than broad composition claims. This distinction matters for generic entry. A formulation may fall within the technical description of the patent but avoid direct infringement if it is not marketed or used for the claimed transplant-rejection indication, subject to the scope of the approved label and induced-infringement principles.

How do claims 1 through 15 define the patent scope?

Claim 1: The principal dissolution-based method claim

Claim 1 requires five central elements:

A patient has received an organ transplant.
The purpose is to suppress a rejection reaction.
The patient orally receives tacrolimus.
Tacrolimus is in an extended-release composition.
The formulation releases no more than 62% of tacrolimus within 15 hours under the specified test.

The dissolution condition is a quantitative limitation. It is not enough for a product to be marketed as "extended release." The accused formulation must meet the specified release threshold when tested under the claimed conditions.

The test details are material:

Paddle apparatus
50 revolutions per minute
900 mL aqueous dissolution medium
0.005% hydroxypropylcellulose
pH 4.5
15-hour measurement point

Differences in apparatus, medium, pH, agitation speed, sampling time, or calculation method could affect infringement analysis. A generic manufacturer would ordinarily need validated comparative dissolution data under the exact claim conditions.

Claims 2 and 3: Kidney and liver transplants

Claim 2 narrows the method to kidney transplantation. Claim 3 narrows it to liver transplantation.

The kidney claim has the greatest commercial importance because Envarsus XR's FDA-approved indication is prophylaxis of organ rejection in kidney transplant patients receiving combination immunosuppressive therapy. The liver claim may have less direct product-label exposure unless the product is promoted or used for that indication.

Claims 4 and 5: Stricter dissolution thresholds

Claims 4 and 5 narrow claim 1 by requiring:

No more than 60% release within 15 hours; or
No more than 50% release within 15 hours.

These claims create fallback positions if the broader 62% limitation is challenged. A product releasing 50% or less would satisfy the numerical limitations of claims 1, 4, and 5, assuming the other limitations are met. A product releasing between 50% and 60% could fall within claims 1 and 4 but not claim 5. A product releasing between 60% and 62% could fall within claim 1 but not claims 4 or 5.

Claims 6 and 7: Food effect and pH-independent release

Claim 6 requires an AUCfed/AUCfasted ratio of at least 0.9. This limitation targets reduced pharmacokinetic variation between fed and fasted conditions.

Claim 7 requires pH-independent release. The claim does not specify a numerical pH range or a particular test protocol. That can create claim-construction and analytical issues because pH independence must be demonstrated through an appropriate comparative release study.

These claims are commercially important because conventional tacrolimus formulations can exhibit clinically relevant absorption variability. The patent links extended release to a more consistent exposure profile rather than only to a slower dissolution rate.

Claims 8 through 12: Vehicle and carrier limitations

These claims narrow the formulation architecture:

Claim 8 requires tacrolimus dispersed or dissolved in a hydrophilic or water-miscible vehicle.
Claim 9 specifies poloxamer.
Claim 10 specifies poloxamer and polyethylene glycol.
Claim 11 requires a polyethylene glycol-to-poloxamer weight ratio between about 1:3 and about 10:1.
Claim 12 requires a solid carrier.

These limitations may capture formulations using hydrophilic solubilization systems before compression or granulation. Claim 11 is especially relevant to formulation reverse engineering because the ratio is expressly claimed.

Claims 13 through 15: Release agents, particles and tablets

Claim 13 lists potential modifying release agents, including:

Hydroxypropyl methylcellulose
Hydroxypropyl cellulose
Methylcellulose
Sodium carboxymethylcellulose
Hydroxyethyl cellulose
Poloxamers
Polyoxyethylene stearates
Polycaprolactone
Polyvinylpyrrolidone
PVP-polyvinyl acetate copolymers
Polymethacrylic polymers
Polyvinyl alcohol
Polyethylene oxide
Mixtures of these materials

Claim 14 requires tacrolimus-containing particles. Claim 15 requires a compressed tablet.

The dependent claims provide multiple technical routes into the patent. A formulation that avoids one excipient may still implicate another dependent claim if it meets the relevant composition and dissolution limitations.

What do claims 16 and 17 add?

Claims 16 and 17 are separately anchored to a poloxamer-containing vehicle.

Claim 16 requires:

Tacrolimus dispersed or dissolved in a vehicle;
One or more release-modifying agents;
A vehicle containing poloxamer;
Release of no more than 62% within 15 hours under the claimed test; and
Delayed release to the distal duodenum, reducing gastrointestinal side effects and CYP3A4 metabolism.

Claim 17 adds:

A solid carrier; and
Polyethylene glycol with a molecular weight of approximately 1,000 to 35,000.

The distal-duodenum and CYP3A4 language is significant. It describes the pharmacological rationale for the formulation and may create an additional limitation in claim 16. Whether this language is treated as a binding structural, functional, or intended-result limitation would depend on claim construction and the factual record.

The text supplied for claim 16 contains the phrase "a therapeutically effective amount of effective amount of tacrolimus." That appears to be a drafting duplication. The issued patent, prosecution history, certificate of correction, and court claim construction would control the legally operative wording.

When does U.S. Patent 8,586,084 expire?

The patent has a 20-year term measured from the relevant nonprovisional or international filing date, subject to patent-term adjustment and any legally applicable correction. Public patent records associate the patent family with a December 2006 priority date and a 2027 statutory term horizon. The expected base expiration is December 2027, subject to the exact term calculation recorded by the USPTO.

Milestone	Date or status
Earliest reported priority	December 21, 2006
U.S. patent	8,586,084
Patent type	Utility patent
Principal subject	Extended-release tacrolimus transplant-rejection methods
Expected base term horizon	December 2027
Patent-term adjustment	Must be confirmed from the USPTO patent-term calculation
Patent-term extension	No extension is assumed in this analysis

The FDA Orange Book listing, if applicable to a specific NDA and product, is the controlling commercial reference for listed patent information. Patent expiration and Orange Book delisting are separate issues. A patent can remain legally enforceable while an Orange Book listing is removed or challenged.

What is the Orange Book status of the patent?

Envarsus XR is approved under FDA NDA 206406. The product contains tacrolimus in an extended-release tablet and is indicated for prophylaxis of organ rejection in kidney transplant recipients.[2]

Patent-listing analysis should distinguish among:

The patent appearing in the Orange Book;
The claims actually covering the approved product;
The expiration date reported by FDA;
Any pediatric exclusivity or other regulatory exclusivity;
Paragraph IV certifications filed by ANDA applicants.

An Orange Book listing does not establish that every claim in the patent covers the product. It indicates that the NDA sponsor identified the patent as claiming the drug, a method of using the drug, or a formulation associated with the approved product under FDA listing rules.

The central regulatory risk is therefore claim-product overlap, not merely the presence of the patent in the Orange Book.

What generic entry risks exist for Envarsus XR?

A generic applicant seeking approval for extended-release tacrolimus could challenge the patent through an ANDA certification. The most relevant Paragraph IV theories would likely involve:

Non-infringement of the dissolution threshold.
Absence of a claimed excipient or vehicle.
A different release mechanism.
Failure to meet the fed/fasted AUC limitation.
Lack of pH-independent release.
A different approved indication or label.
Invalidity based on anticipation, obviousness, indefiniteness, written description, or enablement.

The dissolution limitation creates a measurable design-around target. A generic developer could attempt to release more than 62% within 15 hours under the precise test conditions. That strategy would not necessarily avoid all related patents, including other Envarsus formulation or manufacturing patents.

The method-of-use format also creates litigation complexity. An ANDA label directed only to non-infringing uses may reduce risk, but tacrolimus extended-release products are inherently associated with transplant immunosuppression. Physicians' foreseeable use and product instructions would be relevant to induced-infringement analysis.

How strong is the patent estate for extended-release tacrolimus?

The patent is technically meaningful but does not operate alone. The broader Envarsus estate has included patents directed to formulation design, release behavior, and related product characteristics. A generic entrant would need to assess the complete family and Orange Book portfolio rather than only U.S. Patent 8,586,084.

Risk category	Assessment
Composition coverage	Moderate; claims are primarily method claims with formulation limitations
Dissolution coverage	Strong where the product meets the exact 62%, 60%, or 50% thresholds
Excipient coverage	Moderately broad because claim 13 lists many release agents
Product-use coverage	Strong for kidney-transplant use if the product satisfies the release limitation
Design-around potential	Meaningful through release profile, vehicle, excipient, or label changes
Testing burden	High because infringement depends on a specified dissolution protocol
Invalidity exposure	Concentrated on obviousness and the technical significance of the release and food-effect limitations
Biosimilar exposure	Not applicable; tacrolimus is a small-molecule drug

The patent's strength is highest when a competing product matches both the claimed release profile and the claimed transplant-rejection use. It is weaker against a formulation that has a materially different release curve and does not satisfy the numerical limitation.

What patent litigation and settlements affect the product?

Publicly available records should be reviewed for any ANDA litigation naming the patent owner, Envarsus marketing authorization holder, or an extended-release tacrolimus applicant. The critical documents are:

FDA Paragraph IV notice records where available;
District court complaints and docket entries;
Patent Trial and Appeal Board proceedings;
Settlement agreements and consent judgments;
FDA approval dates for competing extended-release tacrolimus products.

No litigation outcome should be inferred solely from the patent's Orange Book presence. A settlement may permit an agreed generic launch date without invalidating or cancelling the patent. Conversely, the absence of a reported court decision does not establish that no Paragraph IV notice was served.

How does U.S. Patent 8,586,084 compare with immediate-release tacrolimus patents?

Issue	U.S. 8,586,084	Immediate-release tacrolimus products
Product concept	Extended-release tacrolimus	Conventional immediate-release tacrolimus
Principal commercial example	Envarsus XR	Prograf and generic tacrolimus capsules
Release profile	Controlled, delayed release	Rapid or conventional release
Core patent metric	Percentage released at 15 hours	Usually not the same extended-release threshold
Food-effect objective	AUCfed/AUCfasted of at least 0.9 in claim 6	Greater exposure variability may be associated with conventional products
Organ indication	Transplant rejection suppression	Transplant rejection suppression
Biosimilar pathway	Not applicable	Not applicable
Main generic issue	Formulation and method overlap	Conventional ANDA substitution and product patents

Immediate-release tacrolimus generics do not automatically practice the extended-release claims. The patent is directed to a distinct dosage-form technology, even though both products contain the same active ingredient and are used in transplant patients.

What manufacturing and geographic barriers remain?

The patent is limited territorially to the United States. Parallel rights in Europe, Canada, Japan, and other jurisdictions must be assessed separately because claim scope, prosecution history, term, and validity can differ.

Manufacturing risk may arise from:

Hydrophilic tacrolimus dispersion;
Poloxamer and polyethylene glycol processing;
Particle formation;
Controlled compression;
Uniform dose distribution;
Reproducible 15-hour dissolution;
Stability of tacrolimus under manufacturing and storage conditions.

A manufacturer can avoid literal composition limitations yet still produce a release profile falling within the method claims. Batch-to-batch dissolution control is therefore central to both regulatory equivalence and patent-risk management.

What is the commercial exposure from the patent?

Envarsus XR competes in a high-value transplant-maintenance market where switching costs, physician familiarity, therapeutic monitoring, and reimbursement influence adoption. The patent's revenue relevance depends on:

Envarsus XR net sales;
Duration of remaining patent protection;
Timing of generic or authorized-generic entry;
Whether competing products achieve therapeutic equivalence;
Whether a generic can avoid the claimed release profile;
Any settlement-imposed launch date.

A generic launch before the patent's expected 2027 term horizon would likely require a successful challenge, a non-infringing formulation, a settlement, or a licensing arrangement. The economic effect would be greater if the entrant were substitutable at the pharmacy level and lower if transplant centers continued prescribing Envarsus XR based on pharmacokinetic or clinical preferences.

Key Takeaways

U.S. Patent 8,586,084 is a method patent for extended-release tacrolimus used to suppress organ-transplant rejection.
The core limitation is release of no more than 62% of tacrolimus within 15 hours under a specified USP Paddle dissolution test.
Dependent claims narrow the invention to kidney or liver transplantation, stricter release limits, reduced food effect, pH-independent release, poloxamer and polyethylene glycol vehicles, cellulose-based release agents, particles, and compressed tablets.
The patent is most relevant to Envarsus XR and its extended-release tacrolimus formulation.
The expected statutory term horizon is December 2027, subject to the USPTO's final patent-term calculation.
Generic risk centers on Paragraph IV challenges to dissolution, formulation, method-of-use, obviousness, and claim construction.
Tacrolimus is a small-molecule drug, so biosimilar analysis does not apply.
The patent has meaningful commercial value but should be assessed with the full Envarsus patent family, Orange Book records, prosecution history, and any ANDA litigation.

Frequently Asked Questions

Does U.S. Patent 8,586,084 cover all tacrolimus products?

No. It covers specific extended-release tacrolimus methods meeting the claimed therapeutic and dissolution requirements. Immediate-release tacrolimus products generally do not satisfy the core extended-release limitation.

Can a generic tacrolimus manufacturer avoid the patent by changing the excipients?

Potentially. A changed excipient system may avoid dependent claims, but the generic could still infringe claim 1 if its product meets the claimed release threshold and is used for transplant-rejection suppression.

Is Envarsus XR protected by a biologic exclusivity period?

No. Tacrolimus is a small-molecule immunosuppressant. Envarsus XR proceeds through the NDA pathway, not the biologic license application and biosimilar pathways.

Does a Paragraph IV certification automatically invalidate the patent?

No. Paragraph IV is an assertion that the patent is invalid, unenforceable, or will not be infringed. The patent remains enforceable unless cancelled, invalidated, expired, or otherwise resolved.

Why is the 15-hour dissolution test important?

The 15-hour test converts the extended-release concept into a measurable claim limitation. A competing formulation's release percentage under the exact test conditions can determine whether the core claims are implicated.

References

United States Patent and Trademark Office. (2013). U.S. Patent No. 8,586,084: Extended release formulations of tacrolimus.
U.S. Food and Drug Administration. (2015). Envarsus XR prescribing information.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
U.S. Food and Drug Administration. (2024). Drugs@FDA: Envarsus XR, NDA 206406.

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

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

Details for Patent: 8,586,084

Summary for Patent: 8,586,084