US Patent 7,994,214: Tacrolimus Solid-Dispersion Claims, Expiry, Orange Book Status and Generic Risk

US Patent 7,994,214 protects a tacrolimus solid pharmaceutical composition built around a solvent-free or solvent-minimized solid dispersion of tacrolimus in high-molecular-weight polyethylene glycol, typically PEG 6000, combined with a poloxamer and deposited on a solid carrier. Its strongest commercial relevance is to modified-release and bioavailability-enhanced tacrolimus tablets, including formulations developed from the Veloxis MeltDose platform.

The patent’s principal technical limitation is not tacrolimus alone. Infringement generally requires the claimed combination of:

Tacrolimus;
PEG with average molecular weight of at least 1,500;
A poloxamer;
A solid carrier or particulate structure;
Tacrolimus concentration between 0.01% and 15% by weight; and
For narrower claims, specified particle size, PEG-to-poloxamer ratio, dissolution, enteric protection, pharmacokinetics, or manufacturing steps.

The patent has a projected US patent-term expiry in December 2025, subject to the patent’s recorded term adjustment and any terminal disclaimer. Its practical blocking value therefore depends heavily on later family patents, Orange Book listings, formulation differences and the timing of an abbreviated new drug application.

What technology does US Patent 7,994,214 protect?

The patent protects a formulation architecture designed to improve tacrolimus dissolution and oral exposure. Tacrolimus is poorly water-soluble and has variable oral absorption. The claimed formulation disperses or dissolves tacrolimus in PEG and poloxamer, then converts that mixture into particles or agglomerates using a solid carrier.

The core independent claim is claim 1:

Claim element	Scope
Active ingredient	Tacrolimus
PEG	Average molecular weight of at least 1,500
Surfactant/polymer	A poloxamer
Physical form	Solid pharmaceutical composition containing particles
Carrier	Solid carrier
Tacrolimus loading	0.01% to 15% w/w

The claim does not require a particular tablet shape, capsule, brand, release profile or indication. A composition can fall within claim 1 before being compressed into a tablet. Claims 17 through 45 extend protection to oral dosage forms, tablets, particle geometry, release-modifying excipients and manufacturing methods.

The patent’s commercial theory is that tacrolimus can be processed into a stable solid dispersion without relying on a conventional organic solvent. The resulting particles can be compressed into a tablet with improved dissolution and a lower dose than an immediate-release tacrolimus capsule.

How are the US 7,994,214 claims structured?

Core composition claims

Claims 1 through 16 define the particulate formulation. Claim 1 is the principal composition claim. Claims 2 and 3 distinguish between:

A mixture of solid dispersion and solid solution; and
A fully dissolved solid solution at ambient temperature.

Claims 4 through 6 limit melting point and tacrolimus concentration. Claims 7 through 9 impose dissolution targets:

Claim	Dissolution limitation
7	At least 50% released within 30 minutes
8	At least 75% released within 40 minutes
9	At least 90% released within 60 minutes

Claims 10 through 12 focus on the preferred excipient combination. The PEG-to-poloxamer ratio is between 1:3 and 10:1, with poloxamer 188 and PEG 6000 specifically identified.

Claims 15 and 16 limit particle size. The broad range is 10 to 2,000 micrometers, while the narrower range is 50 to 300 micrometers.

Dosage-form claims

Claims 17 through 35 cover solid oral dosage forms. They include:

Unit dosage forms;
Tablets;
Silica, silicates and silicon dioxide;
Release-modifying agents;
HPMC and other water-miscible polymers;
Ethyl cellulose and other water-insoluble polymers;
Hydrophilic or hydrophobic oils;
Enteric coatings;
Extended-release profiles; and
Pharmacokinetic equivalence to the Prograf capsule approved under NDA 050708.

Claim 34 is commercially significant because it combines a pharmacokinetic limitation with dose reduction. The claimed dosage form must produce an AUC or Cmax between 80% and 125% of the FDA-approved Prograf capsule while using no more than approximately 85% of the comparator dose.

That limitation is difficult to assess from formulation composition alone. It requires comparative clinical or pharmacokinetic evidence and raises claim-construction issues concerning the reference product, dose normalization, patient population and statistical method.

Manufacturing claims

Claims 36 through 39 cover the manufacturing process:

Disperse or dissolve tacrolimus in PEG and poloxamer;
Spray the mixture onto a solid carrier;
Produce the solid pharmaceutical composition;
Perform the process without an organic solvent.

Claims 44 and 45 are narrower. They require spraying, mechanically working the product to form agglomerated particles, and compressing those particles into a tablet.

These claims create a separate infringement path. A product may avoid a composition claim but still implicate a process claim if the manufacturer uses spray layering and mechanical agglomeration within the specified parameters.

What are the strongest claims in US Patent 7,994,214?

The strongest commercial claims are likely claims 1, 36, 41, 43 and 44, although their value differs by accused product.

Claim	Commercial relevance	Principal vulnerability
1	Broadest combination claim for the particulate formulation	Prior-art combination of tacrolimus, PEG, poloxamer and carrier
36	Spray-on manufacturing process	Process may be difficult to prove from the finished product
41	Solvent-free particulate formulation	Broad language and potential written-description issues
43	Agglomerated particles with size and PEG/poloxamer ratio	Narrower but more technically identifiable
44	Spray, mechanical working and compression	Strong process specificity; requires evidence of manufacturing steps
34	Reduced-dose pharmacokinetic performance	Clinical proof and claim-construction complexity
31-33	Enteric dosage form with limited early release	Potential enablement and infringement-testing issues

Claim 1 has the largest literal scope, but claims 43 and 44 may provide better enforcement leverage where particle size, excipient ratio and manufacturing records can be established.

What formulation limitations must a competing tacrolimus product satisfy?

A competing product presents the greatest literal infringement risk if it contains the following combination:

Tacrolimus dispersed or dissolved in PEG 1500 or higher;
A poloxamer, especially poloxamer 188;
Tacrolimus at 0.01% to 15% w/w;
A particulate solid carrier;
Particle size within the claimed range;
A PEG-to-poloxamer ratio between 1:3 and 10:1; and
Spray-layered or agglomerated particles compressed into a tablet.

A formulation using PEG 400, PEG 600 or another PEG below 1,500 would fall outside the express PEG limitation in the principal claims. A formulation using a non-poloxamer surfactant may avoid the central combination claims, although other patents could still apply.

A liquid formulation, conventional tacrolimus capsule, lipid-based formulation or amorphous dispersion using a different polymer may also avoid literal infringement of claim 1. The analysis changes if the product contains residual or undisclosed PEG and poloxamer in the relevant concentration and physical state.

What patents protect Envarsus XR and other tacrolimus products?

Tacrolimus has several distinct US product categories. The main commercial products do not present the same patent risk.

Product	Manufacturer or sponsor	Dosage form	Regulatory status	Relationship to US 7,994,214
Prograf	Astellas	Immediate-release capsules, injection and granules	NDA 050708	Comparator expressly identified in claim 34
Astagraf XL	Astellas	Extended-release capsules	NDA 204096	Different extended-release product and patent family
Envarsus XR	Veloxis/Astellas	Extended-release tablets	NDA 206406	Closest commercial technology and likely principal relevance
Generic tacrolimus capsules	Multiple manufacturers	Immediate-release capsules	ANDA products	Generally outside the PEG-poloxamer solid-tablet architecture
Generic extended-release tacrolimus	Multiple potential applicants	Extended-release dosage forms	ANDA pathway	Product-specific patent and formulation analysis required

Envarsus XR is the closest commercial comparator because it is a tacrolimus tablet using the MeltDose formulation platform. The relevant legal assessment cannot stop with US 7,994,214. Later patents in the Envarsus family may have later expiry dates and may cover release profiles, tablet composition, pharmacokinetics or manufacturing features not required by this patent.

What is the Orange Book status of US 7,994,214?

FDA Orange Book relevance depends on the NDA under which the patent was submitted. The patent’s claim 34 expressly identifies the Prograf capsule approved under NDA 050708, but that reference does not establish that the patent was listed against Prograf.

The more relevant regulatory question is whether the patent was listed for Envarsus XR under NDA 206406. FDA patent listings must be checked by NDA and patent number because:

A patent can be enforceable without being Orange Book-listed;
A listed patent can trigger a Paragraph IV notice and 30-month stay;
A patent may be delisted, expired or listed only for a specific dosage form or method of use;
Patent listing does not determine ultimate validity or infringement.

The FDA’s Orange Book and Drugs@FDA databases are the controlling sources for listing status, expiration data and NDA association (U.S. Food and Drug Administration, n.d.-a, n.d.-b).

Tacrolimus itself is not a new chemical entity. The relevant regulatory exclusivity for a later tacrolimus dosage form would generally be three-year clinical-investigation exclusivity, if awarded, rather than five-year NCE exclusivity. Envarsus XR’s three-year exclusivity period would not provide a current barrier to an ANDA applicant. The continuing barrier would be unexpired patents and any applicable litigation stay.

When does US 7,994,214 lose exclusivity?

The patent was issued on August 9, 2011. Its priority chain reaches back to December 2004. On a standard 20-year patent term calculated from the earliest effective nonprovisional filing, the projected expiration is in December 2025, subject to recorded patent-term adjustment, terminal disclaimer or other term modification (U.S. Patent No. 7,994,214, 2011).

The practical timeline is:

Event	Date or period
Earliest priority period	December 2004
US patent issuance	August 9, 2011
Projected standard term expiry	December 2025
Post-expiry position	Composition and process claims no longer enforceable, absent an applicable term adjustment
Later-family exposure	Potentially extends beyond 2025 for separate inventions

Expiration of US 7,994,214 does not clear the entire Envarsus patent estate. A generic or follow-on manufacturer must analyze each later family member and each Orange Book-listed patent separately.

Which companies are challenging tacrolimus patents?

The relevant competitive group includes:

Astellas, which markets Prograf and Astagraf XL;
Veloxis, now part of the Astellas group, which developed Envarsus XR;
Generic manufacturers seeking immediate-release tacrolimus capsules;
Applicants seeking extended-release tacrolimus tablets or capsules; and
Contract manufacturers and formulation companies developing alternative solid dispersions.

Immediate-release generic tacrolimus capsules generally create lower risk under US 7,994,214 because they do not necessarily contain the claimed PEG-poloxamer particulate system. Extended-release tablets present higher risk because they may use solid dispersion, spray-layering, agglomeration and release-modifying excipients.

A Paragraph IV challenge to a listed patent would typically assert one or more of invalidity, noninfringement or unenforceability. The most likely technical positions against this patent would be:

The accused product does not contain PEG with average molecular weight of at least 1,500;
The product does not contain a poloxamer;
The tacrolimus is not present in the claimed concentration;
The product does not contain the required solid carrier or agglomerated particles;
The manufacturing process does not include spraying or mechanical working;
The claims are obvious over known tacrolimus solid dispersions and pharmaceutical processing references; or
Functional limitations such as dissolution or pharmacokinetic performance are indefinite or not met.

How strong is the patent estate?

The patent has moderate claim breadth but limited remaining life. Its technical coverage is strongest where a product uses the exact PEG-poloxamer carrier system and spray-agglomeration process.

Strengths

Claims both product composition and manufacturing method;
Identifies specific high-value excipients, including PEG 6000 and poloxamer 188;
Includes particle-size and ratio limitations that can distinguish commercial formulations;
Covers solvent-free preparation;
Includes tablet, oral, enteric and release-modified dosage forms;
Adds a reduced-dose pharmacokinetic pathway through claim 34.

Weaknesses

Broad excipient and particle claims may face obviousness attacks;
"Ambient temperature," "about," and some functional terms may create indefiniteness disputes;
The phrase "any dissolution test according to USP" does not identify a single apparatus, medium, volume, agitation rate or endpoint;
Claim 34 requires complex pharmacokinetic proof;
Process claims are difficult to enforce without discovery into manufacturing records;
The patent’s remaining term is short compared with later Envarsus patents.

The estate is therefore more valuable as part of a family-level blocking strategy than as a standalone long-term barrier.

What generic launch scenarios exist?

Immediate-release capsule launch

Risk under US 7,994,214 is generally low if the generic uses a conventional capsule formulation without PEG 1500-or-higher and poloxamer solid particles. Other Prograf-related patents and regulatory requirements remain relevant.

Extended-release capsule launch

Risk is product-specific. An extended-release capsule that uses a different matrix polymer, lipid system or granulation process may avoid the patent. A PEG-poloxamer solid dispersion could face claims 1, 7 through 12 and 17 through 35.

Extended-release tablet launch

This is the highest-risk scenario. A tablet based on spray-layered tacrolimus particles, PEG 6000, poloxamer 188 and a solid carrier could fall within claims 1, 43 and 44. The applicant would need a documented noninfringement position or a Paragraph IV strategy.

Post-expiry launch

After expiration of US 7,994,214, the patent cannot block a product that practices its claims. Later patents, regulatory exclusivity, manufacturing patents and Orange Book-listed Envarsus patents could still delay launch.

What licensing and settlement issues matter?

The commercial rights around Envarsus XR involve the Veloxis/Astellas product platform. A licensing or acquisition review should distinguish:

Ownership of US 7,994,214;
Ownership of later family patents;
Patent prosecution and continuation rights;
Manufacturing know-how for spray layering and agglomeration;
Clinical data supporting reduced-dose bioequivalence;
Patent settlements with ANDA applicants; and
Any covenants not to sue or field-of-use restrictions.

A patent assignment does not transfer FDA exclusivity, clinical data rights or manufacturing trade secrets automatically. Those rights must be analyzed separately in transaction documents and regulatory records.

Key Takeaways

US 7,994,214 targets tacrolimus solid dispersions containing PEG of at least 1,500 molecular weight and a poloxamer.
PEG 6000, poloxamer 188, solid carriers, spray layering, agglomeration and tablet compression are central technical features.
Claims 1, 41, 43 and 44 provide the principal composition and manufacturing coverage.
Claim 34 links the formulation to Prograf-equivalent exposure at a reduced tacrolimus dose.
Immediate-release tacrolimus capsules are less likely to infringe than PEG-poloxamer extended-release tablets.
The projected standard expiration is December 2025, subject to the recorded patent term.
Expiration of this patent does not eliminate later Envarsus-related patent risk.
Orange Book status must be assessed by NDA, particularly NDA 206406 for Envarsus XR and NDA 050708 for Prograf.
The most credible design-around routes are use of a PEG below 1,500, omission of poloxamer, a non-particulate formulation, a different carrier system or a different manufacturing process.

FAQs

Does US 7,994,214 cover Prograf capsules?

Not automatically. The patent claims a particular tacrolimus particulate formulation, not tacrolimus capsules generally. Claim 34 uses the Prograf capsule as a pharmacokinetic comparator but does not by itself cover the Prograf product.

Does a tacrolimus tablet infringe US 7,994,214?

A tablet may infringe if its particles contain tacrolimus in PEG 1500 or higher and a poloxamer within the claimed concentration and structural limitations. Tablet form alone is insufficient.

Can a formulation using PEG 400 avoid the patent?

PEG 400 is below the express average molecular-weight threshold in the principal claims. A PEG 400 formulation may avoid those claims, although other patent claims or later patents may apply.

Are tacrolimus biosimilars relevant to this patent?

No. Tacrolimus is a small-molecule drug, not a biologic. The relevant competitors are generic or follow-on tacrolimus manufacturers using ANDA or other small-molecule regulatory pathways.

Does patent expiration permit immediate generic Envarsus XR launch?

No. A generic applicant must clear remaining Orange Book-listed patents, satisfy FDA requirements and address any litigation stay. Expiration of US 7,994,214 removes only that patent as a barrier.

References

U.S. Food and Drug Administration. (n.d.-a). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.fda.gov/drugs/drug-approvals-and-databases/orange-book-approved-drug-products-therapeutic-equivalence-evaluations
U.S. Food and Drug Administration. (n.d.-b). Drugs@FDA: FDA-approved drugs. https://www.accessdata.fda.gov/scripts/cder/daf/
U.S. Patent No. 7,994,214. (2011). Pharmaceutical composition comprising tacrolimus. United States Patent and Trademark Office.
United States Patent and Trademark Office. (n.d.). Patent Center. https://patentcenter.uspto.gov/
U.S. Food and Drug Administration. (2015). Envarsus XR approval information, NDA 206406. Drugs@FDA.
U.S. Food and Drug Administration. (1994). Prograf approval information, NDA 050708. Drugs@FDA.

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
Denmark	2004 00467	Mar 23, 2004

PCT Information
PCT Filed	August 30, 2004	PCT Application Number:	PCT/DK2004/000574
PCT Publication Date:	March 10, 2005	PCT Publication Number:	WO2005/020994

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
Brazil	PI0413927	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 7,994,214

Summary for Patent: 7,994,214