US Patent 8,551,522: Tacrolimus Sustained-Release Claims, Scope and Patent Landscape

US Patent 8,551,522 covers sustained-release tacrolimus formulations defined primarily by dissolution kinetics, solid-state structure, polymer content, and particle size. The broadest claim reaches either an amorphous tacrolimus solid dispersion or a fine-powder tacrolimus formulation, provided the formulation produces a T63.2% dissolution time of 0.7 to 15 hours under the specified Japanese Pharmacopoeia test. The patent is most relevant to once-daily tacrolimus products, including formulations competing with Astellas' Astagraf XL and Veloxis' Envarsus XR.

What does US Patent 8,551,522 claim?

Claim 1 is the only independent claim. It has two alternative technical pathways:

Claim 1 pathway	Required elements
Solid-dispersion pathway	Tacrolimus or tacrolimus hydrate in an amorphous state in a water-soluble polymer
Fine-powder pathway	Tacrolimus or tacrolimus hydrate present as fine powder within specified particle-size limits
Common requirement	Sustained-release formulation with T63.2% of 0.7 to 15 hours
Dosage-form scope	Not limited to a particular dosage form
Solid-dispersion polymer ratio	0.2 to 0.4 parts polymer per 1 part tacrolimus
Solid-dispersion restriction	No disintegrator in the solid dispersion composition

The specified polymers are hydroxypropylmethyl cellulose, methyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, and polyethylene glycol.

The claim is drafted with "comprising," which generally makes it open-ended. A formulation containing the claimed elements may fall within the claim even if it also contains additional excipients, coatings, release modifiers, or manufacturing aids.

How is the T63.2% limitation measured?

T63.2% is the time required for 63.2% of the maximum dissolved tacrolimus amount to enter solution. Claim 1 requires measurement under the following conditions:

Parameter	Claimed condition
Pharmacopoeial method	Japanese Pharmacopoeia, 13th edition, Dissolution Test No. 2
Apparatus	Puddle method as stated in the claim; the standard terminology is generally "paddle" method
Agitation	50 rpm
Test medium	Aqueous 0.005% hydroxypropyl cellulose solution
pH	4.5
Measured substance	Tacrolimus or tacrolimus hydrate
Required T63.2%	0.7 to 15 hours

This dissolution limitation is central to infringement analysis. A competing product cannot be assessed solely by its label, dosage frequency, or general description as "extended release." The product would need to be tested using the claim-specific medium, pH, agitation speed, apparatus, and calculation method.

The use of maximum dissolved amount rather than a fixed percentage of labeled dose can affect the result. Laboratory protocols should therefore define how incomplete recovery, assay variability, hydrate content, and the dissolution endpoint are handled.

What formulations are protected by the solid-dispersion claims?

The solid-dispersion pathway requires tacrolimus to be present in an amorphous state within a specified water-soluble polymer. The polymer-to-tacrolimus ratio must be 0.2:1 to 0.4:1 by weight.

Claim 1 therefore does not cover every amorphous tacrolimus formulation. A formulation may avoid this pathway if it has:

A polymer-to-tacrolimus ratio below 0.2:1 or above 0.4:1;
A polymer outside the five listed polymer classes;
Tacrolimus that is not amorphous in the polymer matrix;
A solid dispersion composition containing a disintegrator, if the disintegrator is part of that defined composition; or
A T63.2% outside the claimed dissolution range.

The "no disintegrator" limitation applies expressly to the solid-dispersion composition. It does not automatically apply to every component of a finished dosage form under the fine-powder alternative.

What additional excipients are covered?

Claim 2 adds lactose or calcium hydrogen phosphate as an excipient and/or lubricant. This claim narrows claim 1 and is not an independent protection for a formulation lacking the claim 1 dissolution and structural requirements.

Claim 3 requires hydroxypropylmethyl cellulose, or HPMC, as the water-soluble polymer.

Claim 4 adds two further limitations:

Lactose is present as an excipient in the solid dispersion; and
The solid dispersion composition has a particle size of 250 micrometers or less.

The particle-size limitation in claim 4 concerns the solid dispersion composition. It should not automatically be equated with the tacrolimus particle-size limitations in claim 1's separate fine-powder pathway.

What particle sizes are protected?

The fine-powder alternative covers tacrolimus or tacrolimus hydrate having:

A particle-size distribution within 0.1 to 50 micrometers; and/or
A mean particle diameter within 0.2 to 20 micrometers.

The "and/or" wording creates a potentially broad alternative. On its face, a formulation may satisfy the limitation through the specified distribution, the specified mean diameter, or both.

Particle-size testing will be technically important. Laser diffraction, microscopy, and other methods can produce different D10, D50, D90, or mean-diameter results. A product-development or litigation protocol should identify:

The particle-size measurement technique;
Sample dispersion conditions;
Whether agglomerates are broken apart;
The meaning of "particle-size distribution within the range";
Whether the measurement applies to tacrolimus particles before granulation or to the final dosage form; and
Whether the claimed measurement is made on tacrolimus alone or on a composite formulation.

How do dependent claims narrow US 8,551,522?

Claim	Added limitation
1	Broad independent claim; T63.2%, solid dispersion or fine powder
2	Lactose or calcium hydrogen phosphate
3	HPMC polymer
4	HPMC, lactose, and solid dispersion particle size of 250 micrometers or less
5	Powder, granule, tablet, or capsule
6	T63.2% of 1.0 to 12 hours
7	T63.2% of 1.3 to 8.2 hours
8	T63.2% of 2 to 5 hours
9	Claim 2 dosage forms
10	Claim 3 dosage forms
11	Claim 4 dosage forms
12	Claim 6 dosage forms
13	Claim 7 dosage forms

Claims 6 through 8 create progressively narrower dissolution windows. Claim 8 is the narrowest T63.2% limitation, requiring a dissolution time from 2 to 5 hours.

Claims 5 and 9 through 13 are dosage-form claims. They do not independently remove the structural and dissolution limitations inherited from claim 1 or the relevant parent claim.

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

US 8,551,522 has meaningful technical breadth but several claim-construction and proof constraints.

Strengths

The patent combines multiple infringement parameters:

Active ingredient identity;
Amorphous solid-state form;
Polymer identity;
Quantified polymer ratio;
Absence of a disintegrator;
Particle-size characteristics;
Dissolution kinetics;
Excipients; and
Dosage form.

The dissolution limitation can capture formulations that use different manufacturing processes but produce the same release profile. The fine-powder alternative also provides a potential route to coverage without requiring the claimed amorphous polymer matrix.

The claims are directed to formulation architecture rather than a particular brand name. They may therefore be relevant to a product even if the product uses a different capsule shell, coating, filling process, or commercial label.

Weaknesses and design-around opportunities

The claims contain narrow numerical boundaries. A developer could investigate:

T63.2% below 0.7 hours or above 15 hours;
A polymer ratio outside 0.2:1 to 0.4:1;
A non-listed polymer;
Crystalline rather than amorphous tacrolimus;
A formulation with a disintegrator in the solid dispersion;
Tacrolimus particles outside the claimed size ranges;
A different release mechanism that does not meet the dissolution endpoint; or
A formulation in which the relevant excipient is not part of the claimed composition.

A design-around must be tested against the full claim, including possible equivalents arguments. Changing one variable may not eliminate risk if the resulting product still satisfies another claim pathway or if the change has no substantial technical effect.

How does US 8,551,522 compare with once-daily tacrolimus products?

Product	Sponsor or commercial originator	FDA dosage concept	Relevance to US 8,551,522
Prograf	Astellas	Immediate-release tacrolimus capsules and injection	Primarily a comparator; immediate release does not inherently satisfy the sustained-release limitation
Astagraf XL	Astellas	Once-daily extended-release tacrolimus capsules	Directly relevant because of its extended-release tacrolimus architecture
Envarsus XR	Veloxis Pharmaceuticals, now associated with Chiesi	Once-daily extended-release tacrolimus tablets using MeltDose technology	Competing extended-release technology; claim coverage depends on actual composition, particle attributes, and dissolution results
Generic immediate-release tacrolimus	Multiple manufacturers	Immediate-release capsules	Generally lower direct risk unless the product meets the claimed T63.2% and formulation limitations
Generic extended-release tacrolimus	Manufacturer-specific	Once-daily extended-release product, where approved	Requires product-by-product Orange Book and laboratory analysis

A label describing a product as once daily is not enough to establish infringement. Astagraf XL and Envarsus XR use different formulation platforms, and the claim analysis must distinguish capsule-based extended release from tablet-based delivery systems.

What is the FDA regulatory status of the relevant products?

The key FDA milestones are:

FDA product	NDA	FDA milestone
Prograf	050708	Original tacrolimus product
Astagraf XL	204096	Approved in 2013
Envarsus XR	207046	Approved in 2015

The FDA's Orange Book identifies approved products, patents submitted by NDA holders, and applicable exclusivity information. Orange Book listing does not itself establish that every listed patent will be infringed by every competing product. The relevant question is whether the generic or follow-on product's composition and labeled use fall within an asserted claim.

For a generic extended-release tacrolimus application, a Paragraph IV certification would be the principal Hatch-Waxman mechanism for challenging an unexpired listed patent. The NDA holder or patent owner could then file an infringement action within 45 days, potentially triggering a statutory stay of approval of up to 30 months under the Hatch-Waxman framework. The commercial effect depends on the patent's actual listing, expiration date, certification type, litigation outcome, and any settlement terms.

When does US 8,551,522 lose exclusivity?

The patent number and claim text alone do not establish the final enforceable expiration date. The relevant calculation requires the patent's earliest effective nonprovisional or international filing date, patent-term adjustment, patent-term extension, terminal disclaimer, and any applicable regulatory extension.

For a US patent governed by the modern 20-year term, the baseline is generally 20 years from the earliest effective nonprovisional filing date, subject to statutory adjustments under 35 U.S.C. §§ 154 and 156. The issue date, October 8, 2013, is not the term endpoint.

Patent exclusivity and FDA exclusivity are separate. A product can lose FDA market exclusivity while a formulation patent remains enforceable, or a patent can expire while other Orange Book-listed patents continue to delay approval or launch.

What patent litigation and settlement risks apply?

The principal litigation risk is claim-by-claim proof of the formulation characteristics. A patent owner would likely seek evidence concerning:

Tacrolimus solid-state characterization;
Polymer identity and loading;
Presence or absence of a disintegrator;
Particle-size distribution;
Dissolution profiles under the specified test;
Manufacturing batch records; and
Bioequivalence or product-development data submitted to FDA.

A Paragraph IV case involving this patent would likely focus on noninfringement and validity. Potential validity issues could include anticipation or obviousness based on earlier tacrolimus sustained-release formulations, written-description support for the numerical ranges and alternative structures, enablement of the full dissolution and particle-size scope, and definiteness of the measurement terms.

Settlement agreements may include delayed generic entry, licenses, authorized-generic provisions, manufacturing restrictions, or geographic limits. Their commercial effect cannot be inferred from a patent listing alone.

What manufacturing and geographic barriers exist?

The patent is limited to the United States. Equivalent patent families may exist in Japan, Europe, Canada, Australia, and other markets, but foreign claims must be analyzed independently. Differences in prosecution can produce materially different scope.

Manufacturing barriers are strongest where a product depends on:

Maintaining amorphous tacrolimus during processing and storage;
Achieving a narrow polymer ratio;
Controlling particle-size distribution;
Preventing recrystallization;
Reproducing dissolution in the specified hydroxypropyl cellulose medium; and
Producing consistent release across capsule or tablet batches.

A supplier can create additional freedom-to-operate issues through patents covering tacrolimus crystallization, amorphous dispersions, granulation, coating, modified-release matrices, or manufacturing controls.

Key Takeaways

US 8,551,522 is a formulation patent, not a patent covering tacrolimus generally.
Claim 1 requires both a specific sustained-release dissolution profile and either a defined amorphous solid dispersion or a defined fine-powder formulation.
The solid-dispersion route requires a listed polymer, an amorphous tacrolimus state, a 0.2:1 to 0.4:1 polymer ratio, and no disintegrator in the solid dispersion.
The fine-powder route uses particle-size limitations of 0.1 to 50 micrometers and/or a mean diameter of 0.2 to 20 micrometers.
Claims 6 through 8 narrow the dissolution window, with claim 8 requiring T63.2% of 2 to 5 hours.
Astagraf XL and Envarsus XR are the principal commercial extended-release tacrolimus comparators.
A Paragraph IV challenge would require a product-specific analysis of the formulation, dissolution behavior, Orange Book listing, and patent term.
Patent expiration cannot be reliably determined from the claim text or issue date alone.

FAQs About US Patent 8,551,522

Does US 8,551,522 cover all once-daily tacrolimus products?

No. Once-daily dosing does not by itself satisfy the claims. The product must meet the claimed dissolution and formulation or particle-size limitations.

Can a formulation avoid claim 1 by using a different polymer?

Potentially. The solid-dispersion pathway expressly lists five polymer classes. A different polymer may avoid that pathway, but the product must still be assessed under the fine-powder alternative and the doctrine of equivalents.

Does claim 4 cover tacrolimus particles smaller than 250 micrometers?

Not necessarily. Claim 4 refers to the particle size of the solid dispersion composition. That is distinct from the tacrolimus particle-size limitations in claim 1.

Is a tablet outside the scope because the patent discusses capsules?

No. Claims 5 and 9 through 13 expressly include tablets, as well as powders, granules, and capsules.

Does a Paragraph IV certification automatically invalidate US 8,551,522?

No. A Paragraph IV certification is an assertion that the patent is invalid, unenforceable, or will not be infringed. The patent remains enforceable unless it expires, is disclaimed, or is held invalid or unenforceable.

References

Astellas Pharma Inc. (2013). United States Patent No. 8,551,522: Sustained-release formulation comprising tacrolimus. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations. FDA Orange Book.
U.S. Food and Drug Administration. (2013). Astagraf XL prescribing information. FDA.
U.S. Food and Drug Administration. (2015). Envarsus XR prescribing information. FDA.
U.S. Food and Drug Administration. (n.d.). Prograf prescribing information. FDA.
United States Code, 35 U.S.C. §§ 154, 156.
United States Code, 21 U.S.C. § 355(j).

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	10-079039	Mar 26, 1998
Japan	10-182963	Jun 29, 1998

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	023299	⤷ Start Trial
Austria	269075	⤷ Start Trial
Austria	464900	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 8,551,522

Summary for Patent: 8,551,522