US Drug Patent 6,576,259: Scope, Claim Construction, Expiration and Tacrolimus Patent Landscape

US Patent 6,576,259 protects once-daily sustained-release tacrolimus formulations defined primarily by dissolution performance rather than by a single commercial dosage form. The patent covers formulations in which 63.2% of tacrolimus dissolves within 0.7 to 15 hours under a specified Japanese Pharmacopoeia test. Narrower claims add amorphous tacrolimus solid dispersions, hydroxypropylmethyl cellulose or wax carriers, particle-size limits, excipient restrictions, and once-daily immunosuppressive use.

The patent was issued to Fujisawa Pharmaceutical Co., Ltd., now associated with Astellas Pharma following corporate succession. Based on the standard US patent-term framework and the patent’s filing history, the enforceable term ended in or around 2019, subject to any patent-term adjustment or terminal disclaimer shown in the official USPTO record. The patent therefore presents historical relevance for product development and litigation analysis, but it is not expected to block a current US launch by itself.

What does US Patent 6,576,259 cover?

The patent covers sustained-release pharmaceutical compositions containing tacrolimus or a tacrolimus hydrate. Its central limitation is a dissolution-time range:

Element	Claim requirement
Active ingredient	Tacrolimus or tacrolimus hydrate
Dosage concept	Sustained-release formulation
Primary performance test	Japanese Pharmacopoeia, 13th edition, Dissolution Test No. 2
Apparatus and speed	Paddle method, 50 rpm
Test medium	Aqueous 0.005% hydroxypropyl cellulose solution at pH 4.5
Core dissolution range	T63.2% of 0.7 to 15 hours
Narrower dissolution ranges	1.0 to 12 hours; 1.3 to 8.2 hours; and 2 to 5 hours
Administration	Once daily in method claims
Therapeutic uses	Transplant rejection, autoimmune diseases, and tacrolimus exposure control

T63.2% is the time required for 63.2% of the maximum amount of tacrolimus to dissolve. The parameter corresponds to a characteristic time used in dissolution modeling. It is not the same as a conventional “80% dissolved” or “90% dissolved” specification.

The use of a fixed test method is important. An accused product would generally need to be evaluated under the specified medium, pH, apparatus, rotation speed, and measurement protocol. A formulation that is sustained release under another dissolution method may fall outside the literal scope if it does not meet the claimed T63.2% range under the patent’s test.

How are the claims of US 6,576,259 structured?

Claim 1: broad formulation claim

Claim 1 is the principal composition claim. It requires:

A sustained-release formulation.
Tacrolimus or a hydrate of tacrolimus.
A T63.2% dissolution time from 0.7 to 15 hours under the specified assay.

The claim is drafted using “comprising,” which ordinarily makes it open-ended. Additional excipients, coatings, granulation aids, capsule materials, or other formulation components would not automatically avoid the claim if the product still satisfies the tacrolimus and dissolution limitations.

The claim does not require a particular tablet, capsule, granule, powder, polymer, wax, or manufacturing process. It can therefore reach multiple dosage forms, provided the formulation has the required dissolution behavior.

Claims 8 to 10: narrower dissolution windows

Claims 8, 9, and 10 narrow claim 1 by imposing progressively smaller T63.2% ranges:

Claim	T63.2% range
Claim 1	0.7 to 15 hours
Claim 8	1.0 to 12 hours
Claim 9	1.3 to 8.2 hours
Claim 10	2 to 5 hours

A formulation within the 2-to-5-hour range would generally satisfy the broader ranges in claims 1, 8, and 9, assuming the other limitations are met. These claims create a nested claim structure. Invalidity of the broadest range would not necessarily invalidate the narrower claims if they have separate support and satisfy patentability requirements.

Claims 2 to 6: amorphous solid dispersion claims

Claims 2 through 6 target a more specific formulation architecture. The tacrolimus must be present in an amorphous state within a solid base. This distinguishes the claimed compositions from formulations relying only on crystalline tacrolimus, particle-size reduction, or conventional matrix techniques.

Claim 3 requires a solid dispersion composition with:

Lactose or calcium hydrogen phosphate as an excipient and/or lubricant.
No disintegrator.
Particle size of 350 micrometers or less.

Claim 6 is narrower. It requires:

Amorphous tacrolimus in hydroxypropylmethyl cellulose, or HPMC.
HPMC-to-tacrolimus weight ratio of 0.2:1 to 0.4:1.
Lactose as an excipient.
No disintegrator.
Particle size of 250 micrometers or less.

The absence of a disintegrator is a positive claim limitation. A product containing a conventional disintegrant such as crospovidone, croscarmellose sodium, or sodium starch glycolate may avoid literal infringement of claims 3 and 6, although it could remain within claim 1 or another claim if the dissolution and other limitations are met.

Claims 4 and 5: solid-base alternatives

Claim 4 identifies two broad categories of solid base:

Water-soluble polymers.
Waxes.

Claim 5 narrows those categories to:

HPMC at a weight ratio of 0.2 to 0.4 relative to tacrolimus.
Glycerin monostearate, polyglycerin fatty acid ester, or sucrose fatty acid ester at a weight ratio of 0.2 to 20 relative to tacrolimus.

The ratio limitations are material. A formulation using HPMC at a ratio above 0.4:1, for example, may avoid literal infringement of the HPMC branch of claim 5, while still potentially satisfying claim 1 or claim 4.

Claim 7: fine-particle tacrolimus

Claim 7 covers tacrolimus or tacrolimus hydrate in fine-powder form with either:

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

The “and/or” wording broadens the alternative particle-size routes. A formulation could potentially satisfy the claim through the distribution limitation, the mean-diameter limitation, or both. Particle-size testing methodology would be important in any infringement analysis because laser diffraction, microscopy, and other methods may produce materially different results.

What formulation technologies are protected by the patent?

The patent’s technical scope can be divided into four formulation strategies.

Technology	Relevant claims	Commercial significance
Controlled-release tacrolimus with defined dissolution	1, 8-10	Broadest product-level protection
Amorphous tacrolimus solid dispersion	2-6	Addresses solubility and release control
HPMC or lipid/wax matrix	4-6	Defines carrier chemistry and ratios
Fine-particle tacrolimus	7	Addresses particle size as a release and dissolution variable
Once-daily administration	12-13	Protects dosing method and therapeutic use

Claim 1 is potentially the most commercially important because it does not require the solid-dispersion structure in claims 2 through 6. A competing formulation using a different polymer, coating, or manufacturing process could still implicate claim 1 if its measured dissolution profile falls within the claimed range.

The principal design-around options would have included:

Adjusting T63.2% outside the claimed range.
Using a release profile that does not satisfy the specified test.
Selecting a formulation architecture that avoids the narrower solid-dispersion limitations.
Adding a disintegrator to avoid claims 3 and 6.
Using different carrier ratios or excipients.
Using a different particle-size distribution.
Formulating for more frequent or otherwise different administration, although this would not necessarily avoid the composition claims.

A design-around based only on a different dissolution test would have been weak if the product still met the claimed range under the patent’s specified assay.

When did US Patent 6,576,259 lose exclusivity?

US Patent 6,576,259 was issued on June 10, 2003. Its patent term was governed by the 20-year term measured from the applicable US nonprovisional filing date, rather than the former 17-year term from issuance. Public patent records associate the patent with a late-1990s US filing and an earlier Japanese priority filing.

Event	Date or period
Earliest claimed priority	1997, based on Japanese priority history
US filing period	Late 1990s
Patent issuance	June 10, 2003
Expected ordinary expiration	Approximately 2019
Current status	Expired by ordinary patent term, absent an unusual later adjustment

Priority to a foreign application does not itself determine the US patent expiration date. The relevant term calculation generally uses the US filing chain, including any PCT national-phase filing and continuation relationships. Patent-term adjustment can extend the term, while a terminal disclaimer can limit it. The official USPTO Patent Center record controls the final calculation.[1]

Because the patent has expired, its formulation and method claims should generally be treated as prior-art and freedom-to-operate considerations rather than as a current blocking right. Separate patents covering later tacrolimus formulations, delivery technologies, manufacturing processes, or commercial products may have had later expiration dates.

What is the Orange Book status of US 6,576,259?

US 6,576,259 is a formulation patent and would not necessarily have been listed in the FDA Orange Book. Orange Book listing is tied to approved drug products and patent information submitted by the NDA holder. A patent can be technically relevant to an approved formulation without appearing as an Orange Book patent.

The FDA Orange Book distinguishes among:

Drug substance patents.
Drug product or formulation patents.
Method-of-use patents.

US 6,576,259 is most naturally characterized as a drug-product/formulation patent, with separate method claims for once-daily tacrolimus administration and immunosuppressive treatment. Its listing status must be evaluated product by product and NDA by NDA; the existence of the patent does not establish Orange Book listing.[2]

For current US tacrolimus products, the more relevant Orange Book issues have historically involved later product-specific patents associated with extended-release products, including Astellas’ Astagraf XL and Envarsus XR-related products. Expiration of 6,576,259 did not eliminate later patent barriers.

Which tacrolimus products competed with the patented technology?

Prograf immediate-release tacrolimus

Prograf is an immediate-release tacrolimus product originally developed by Fujisawa and marketed by Astellas. It is generally administered twice daily and does not represent the same sustained-release product concept covered by claim 1.

Astagraf XL

Astagraf XL is a once-daily extended-release tacrolimus capsule approved by the FDA. It was developed by Astellas and uses a modified-release formulation intended to reduce dosing frequency.[3]

Astagraf XL may have technical overlap with the broad concept of sustained-release tacrolimus, but product-specific infringement requires testing against the exact claim limitations. A once-daily label alone does not establish infringement of claim 1, and a sustained-release label alone does not establish compliance with the 0.7-to-15-hour T63.2% range.

Envarsus XR

Envarsus XR is a once-daily extended-release tacrolimus tablet developed using Veloxis’ proprietary delivery technology and later commercialized by Chiesi in the US. Its formulation and pharmacokinetic profile differ from conventional tacrolimus products.[4]

Later patents associated with Envarsus XR were commercially more important after the expiration of US 6,576,259. Those patents may cover delivery technology, composition, manufacturing, or product-specific features that are separate from the claims in the Fujisawa patent.

Product	Sponsor or commercial owner	Dosage form	Dosing frequency	Relationship to US 6,576,259
Prograf	Astellas	Immediate-release capsule and other forms	Commonly twice daily	Generally outside sustained-release concept
Astagraf XL	Astellas	Extended-release capsule	Once daily	Potential technical overlap requires dissolution testing
Envarsus XR	Veloxis/Chiesi	Extended-release tablet	Once daily	Uses later proprietary delivery and patent estate
Generic tacrolimus	Multiple manufacturers	Immediate-release and extended-release forms	Product-dependent	FTO depends on product claims and later patents

What Paragraph IV challenges and litigation affected tacrolimus products?

A Paragraph IV certification is relevant when a generic applicant asserts that an Orange Book-listed patent is invalid, unenforceable, or not infringed. The filing of a Paragraph IV certification can trigger a 45-day period for the NDA holder to bring suit and, in many cases, a 30-month stay of FDA approval under the Hatch-Waxman framework.[5]

The principal commercial litigation risk for generic tacrolimus has concerned later patents covering specific products rather than the expired US 6,576,259 patent. After expiration, 6,576,259 could no longer support a new infringement suit against a later entrant. It could, however, have remained relevant in earlier litigation, validity disputes, prosecution history analysis, or prior-art arguments against later patent applications.

Potential litigation issues under the patent included:

Whether the accused product’s T63.2% fell within the claimed range.
Whether the Japanese Pharmacopoeia test was reproduced correctly.
Whether the tacrolimus was amorphous or crystalline.
Whether the formulation contained a disintegrator.
Whether particle-size limitations were satisfied.
Whether method claims were directly infringed through labeled once-daily use.
Whether the claims were invalid for anticipation or obviousness based on prior tacrolimus formulations and controlled-release technologies.

The dissolution limitation could create a fact-intensive dispute. Testing variability, sample preparation, tacrolimus recovery, hydrate state, and the meaning of “maximum amount” would affect the result. A court could also consider whether the method supplied enough objective guidance for reproducible claim testing.

How strong was the patent estate for US 6,576,259?

The patent had moderate historical strength as a product-performance patent, but its practical scope depended heavily on proof of the dissolution parameter.

Strengths

Claim 1 was not limited to one dosage form.
The claim used an open “comprising” transition.
The dissolution method was specified in substantial detail.
Once-daily administration was supported by separate method claims.
The dependent claims provided multiple fallback positions involving amorphous material, HPMC, waxes, excipients, particle size, and dissolution windows.
The claims addressed both composition and therapeutic use.

Weaknesses

The patent did not remain enforceable indefinitely because its term ended around 2019.
The central dissolution limitation could be difficult to prove consistently.
Prior art involving sustained-release tacrolimus, solid dispersions, polymer matrices, and micronized drug could create validity challenges.
Claims 3 and 6 were narrow because of their no-disintegrator, excipient, ratio, and particle-size requirements.
Method claims 12 and 13 depended on once-daily administration and the use of the claimed formulation.
Tacrolimus products using substantially different delivery technologies could potentially avoid the narrower structural claims.

The strongest historical claim was likely claim 1, followed by claims 8 through 10. Claims 5 and 6 were narrower but potentially more defensible if the specific HPMC and lactose formulation was well supported by the patent specification and difficult to reproduce without using the claimed ratios.

What generic entry risks existed?

Immediate-release tacrolimus

Generic immediate-release tacrolimus products generally faced less risk under this patent because the claimed subject matter is sustained release. Their principal barriers would have involved other listed patents, regulatory exclusivity, manufacturing controls, and bioequivalence requirements.

Extended-release tacrolimus

Extended-release products faced greater historical risk because they could fall within the broad dissolution limitation even if they used different excipients or manufacturing processes. A generic applicant would need to assess:

T63.2% under the exact claimed assay.
Whether its product was within one or more nested dissolution ranges.
Whether the product’s label instructed once-daily dosing.
Whether the formulation used amorphous tacrolimus.
Whether the product contained HPMC, lactose, waxes, or fine-particle tacrolimus.
Whether later patents remained in force.

Biosimilar risk

Biosimilar risk is not applicable to tacrolimus. Tacrolimus is a small-molecule active pharmaceutical ingredient, and generic entry proceeds through the Abbreviated New Drug Application pathway rather than the biosimilar pathway under the Public Health Service Act.[6]

How does US 6,576,259 compare with later tacrolimus patent estates?

Issue	US 6,576,259	Later extended-release estates
Core protection	Dissolution-defined sustained-release formulation	Product-specific delivery systems and formulation technologies
Claim format	Functional dissolution and structural dependent claims	Often composition, process, pharmacokinetic, or product claims
Commercial target	General once-daily sustained-release tacrolimus	Astagraf XL, Envarsus XR, and related products
Current enforceability	Expired around 2019	Depends on individual patent and terminal dates
Regulatory relevance	Historical formulation patent	Orange Book-listed product patents may control ANDA timing
Main design-around	Change release profile or formulation structure	Avoid protected delivery platform or listed product claim

The expiration of 6,576,259 reduced one barrier to extended-release tacrolimus development. It did not create unrestricted market access because later patents may have covered commercial products, delivery platforms, manufacturing methods, or specific formulations.

What manufacturing and geographic barriers did the patent create?

The patent’s geographic protection was limited to the United States. Foreign counterparts would need separate analysis in Japan, Europe, and other jurisdictions. A US patent could not prevent manufacture and sale entirely outside the United States, although importing a product into the US or selling it in the US could create infringement exposure during the patent term.

Manufacturing barriers were concentrated in:

Producing amorphous tacrolimus consistently.
Maintaining solid-dispersion stability during storage.
Controlling particle size below 250 or 350 micrometers.
Avoiding disintegrators while achieving acceptable dosage-form performance.
Reproducing the targeted T63.2% range batch to batch.
Preventing conversion of amorphous tacrolimus to a crystalline form.
Demonstrating bioequivalence for a modified-release product.

These technical requirements could increase development cost even where the patent claims were not directly infringed. They also could support trade-secret protection for process parameters not disclosed in the patent.

Key Takeaways

US 6,576,259 covers sustained-release tacrolimus formulations with a T63.2% dissolution time of 0.7 to 15 hours under a specified Japanese Pharmacopoeia method.
The patent also claims amorphous tacrolimus solid dispersions, HPMC and wax matrices, particle-size limits, lactose or calcium hydrogen phosphate, and formulations without disintegrators.
Claims 8 through 10 narrow the core dissolution range to 1.0 to 12 hours, 1.3 to 8.2 hours, and 2 to 5 hours.
Claims 12 and 13 cover once-daily administration for tacrolimus exposure control, transplant rejection, and autoimmune disease.
The patent’s ordinary US term ended around 2019, so it is no longer a current standalone blocking patent.
Orange Book relevance must be assessed by NDA and product. The existence of the patent does not establish that it was listed for every tacrolimus product.
Tacrolimus does not present a biosimilar issue. Generic entry uses the ANDA pathway.
Later patents associated with Astagraf XL and Envarsus XR were more important to post-2019 commercial exclusivity.
Any historical infringement analysis would have turned on reproducible dissolution testing, amorphous-state characterization, particle-size measurement, and the exact formulation composition.

Frequently Asked Questions

Could a once-daily tacrolimus product infringe US 6,576,259 after the patent expired?

No new infringement liability ordinarily arises from practicing an expired patent. During the patent term, once-daily administration alone was insufficient; the formulation also had to satisfy the claim 1 dissolution and tacrolimus limitations.

Did the patent cover Prograf?

Generally, no. Prograf is primarily an immediate-release tacrolimus product, while US 6,576,259 requires a sustained-release formulation. The exact product and formulation would control any historical analysis.

Would a formulation containing a disintegrant avoid the patent?

It could avoid claims 3 and 6, which require no disintegrator. It would not necessarily avoid claim 1, claims 8 through 10, claim 7, or other claims if the product met their separate limitations.

Does US 6,576,259 cover tacrolimus tablets and capsules equally?

Yes, claim 11 expressly identifies powder, fine powder, granule, tablet, and capsule forms. The broader claims are not limited to one dosage form if the formulation meets their other requirements.

Are Envarsus XR and Astagraf XL protected only by US 6,576,259?

No. Commercial protection for those products depended primarily on later product-specific patents, regulatory exclusivity, trademarks, formulation know-how, and manufacturing controls. US 6,576,259 was an earlier, broader sustained-release tacrolimus patent and expired around 2019.

References

United States Patent and Trademark Office. (n.d.). US Patent No. 6,576,259, Sustained-release preparation containing tacrolimus. USPTO Patent Center.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.
U.S. Food and Drug Administration. (2013). Astagraf XL prescribing information. Astellas Pharma US, Inc.
U.S. Food and Drug Administration. (2015). Envarsus XR prescribing information. Veloxis Pharmaceuticals, Inc.
21 U.S.C. § 355(j). Abbreviated applications for new drugs.
U.S. Food and Drug Administration. (n.d.). Generic drug facts and ANDA approvals. FDA.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	10-79039	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
Austria	514419	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,576,259

Summary for Patent: 6,576,259