Details for Patent: 8,889,185

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Summary for Patent: 8,889,185

Title:	Modified release compositions comprising tacrolimus
Abstract:	A modified release composition comprising tacrolimus which is useful for the treatment or prevention of rejection reactions by transplantation of organs or tissues.
Inventor(s):	Per Holm, Tomas Norling
Assignee:	Veloxis Pharmaceuticals Inc
Application Number:	US14/079,414
Patent Claim Types: see list of patent claims	Use; Composition; Formulation; Dosage form;

United States Patent 8,889,185 (US 8,889,185): Scope, Claim Strength, and U.S. Patent Landscape for Once-Daily Lower-GI Extended-Release Tacrolimus for Transplant Rejection Suppression

US 8,889,185 is a U.S. method-of-treatment patent that targets a specific clinical outcome (suppression of transplant rejection) via a specific oral dosing and formulation performance profile for tacrolimus. The claim scope is anchored on (i) once-daily extended release (ER), (ii) substantially lower gastrointestinal (GI) tract in vivo release, (iii) pharmacokinetic (PK) performance thresholds including W50 duration and fed-fast AUC ratio, (iv) specific plasma concentration duration banding, and (v) optional dependent claim limitations around release kinetics (zero-order), CYP3A4 metabolism avoidance in the GI tract, and formulation solid state (solid dispersion/solution). This structure creates a measurable, PK-driven infringement test but also narrows enforceable reach to products that match the recited PK outcomes and lower-GI release behavior.

What claims does US 8,889,185 cover for tacrolimus rejection suppression after organ transplantation?

Short answer: The patent covers methods where a transplant recipient is orally dosed with once-daily tacrolimus ER such that drug is released substantially in the lower GI tract, producing specific PK metrics: W50 ≥ 10 hours (with dependent tiers), AUC fed/fasted ≥ ~0.9, and/or plasma 5–20 ng/mL for ≥ 24 hours. Dependent claims further narrow to embodiments with modifying release agents, compressed tablet form, substantially avoids CYP3A4 metabolism in the GI, zero-order release profile, and solid dispersion or solid solution.

Claim 1: Core independent method claim (W50 and lower-GI release)

Claim 1 limitations (mandatory):

• Patient has an organ transplant and method is suppressing rejection reaction.
• Orally administering an oral, once daily, extended release pharmaceutical composition comprising tacrolimus.
• In vivo release substantially in the lower GI tract.
• W50 ≥ 10 hours, where W50 is time the plasma concentration is ≥ 50% of Cmax.

Practical scope: Any generic or branded product that can demonstrate the same lower-GI release and W50 duration would be within reach of Claim 1, regardless of exact excipient identity, as long as it meets the PK thresholds and lower-GI release requirement.

Claim 2–5: W50 “ladder” strengthening the performance profile

• Claim 2: W50 ≥ 11 hours
• Claim 3: W50 ≥ 12 hours
• Claim 4: W50 ≥ 13 hours
• Claim 5: W50 ≥ 14 hours

Practical scope: These dependent claims stratify enforcement leverage. A challenger can try to design to fall below one threshold while matching others. Litigation usually turns on which metric is most provably met for the accused product.

Claim 6: fed/fasted exposure ratio (AUCfed/AUCfasted)

Claim 6 limitations (mandatory):

• Same transplant rejection suppression, oral once-daily tacrolimus ER, and substantially lower-GI release.
• AUCfed/AUCfasted ≥ ~0.9.

Practical scope: This is a diet/food sensitivity performance constraint. It targets formulations designed to reduce variability from gastrointestinal conditions that affect tacrolimus absorption.

Claim 7–10: dependent claim narrowing on formulation and release kinetics

• Claim 7: composition comprises a modifying release agent.
• Claim 8: composition is in compressed tablet form.
• Claim 9: ER composition is designed to substantially avoid CYP3A4 metabolism in the GI tract upon oral administration.
• Claim 10: extended release composition provides zero order release profile.

Practical scope: These dependent claims become infringement hooks if an accused product is structurally and behaviorally aligned. Claim 9 in particular introduces a mechanistic design feature that can become a factual and expert-heavy dispute.

Claim 11–16: plasma concentration banding and duration (5–20 ng/mL for ≥ 24 hours)

Claim 11 limitations (mandatory):

• Same transplant rejection suppression, oral once-daily tacrolimus ER, substantially lower-GI release.
• Oral administration results in plasma concentration about 5 to about 20 ng/mL for at least about 24 hours.

Claims 13–16: nested W50 floors (≥11, ≥12, ≥13, ≥14 hours) layered onto the Claim 11 banding.

Practical scope: This is a clinical exposure window claim. It is potentially broader than W50 for some formulations, because it defines actual concentration range and duration. It also implies that infringement evidence will rely on PK profiles (study data, modeling, or measured concentration time course) under relevant conditions.

Claims 17–19: zero-order release and lower-GI release tied to different bases

• Claim 17: zero order release profile tied to Claim 1.
• Claim 18: zero order release profile tied to Claim 6.
• Claim 19: zero order release profile tied to Claim 11.

Practical scope: These create multiple dependent pathways into the same behavior (zero order release), increasing the chance that an accused product matches at least one claim set depending on its PK behavior and food effects.

Claims 20–29: transplant type narrowing (kidney vs liver)

• Kidney transplant limitations inserted via dependent claims:
  • Claims 20, 22, 24, 26, 28.
• Liver transplant limitations inserted via dependent claims:
  • Claims 21, 23, 25, 27, 29.

Practical scope: The core clinical activity is transplant rejection suppression in a recipient. These dependents restrict enforceable coverage if the accused use is limited to the other organ indication, or if a product is only indicated for one transplant type in the relevant jurisdiction and labeling.

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How is US 8,889,185 likely to be construed in claim scope and infringement terms?

Infringement is PK-metric centric. The claims emphasize objective pharmacokinetic metrics (W50; AUCfed/AUCfasted; concentration band duration) coupled with a physiological placement requirement (“substantially in the lower GI tract”). That combination points to a claim construction centered on:

• What constitutes “substantially” lower GI release (timing and location of release).
• How W50 is measured (definition provided in the claim).
• What qualifies as “about” in the concentration band and “about” in AUC ratio.

Design freedom is constrained by performance. Even if a generic changes excipients or manufacturing, it must still produce the required release location and PK outcomes to avoid infringement.

Means-plus-outcome structure reduces excipient-dependent escape routes. The claims do not require a specific polymer or specific tablet architecture in the independent claim. That makes “same PK, different formulation” harder to design around unless the lower-GI release and W50 floors are not met.

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What is the patent landscape around once-daily extended-release tacrolimus in the U.S.?

The U.S. tacrolimus ER market historically centers on drug products with lower-GI release and once-daily dosing. The most prominent benchmark in this category is Envarsus XR (tacrolimus extended-release tablets), associated with formulations designed to alter absorption and reduce variability. US 8,889,185’s claim architecture is consistent with that formulation strategy: reduced intra- and inter-patient exposure variability, lower-GI release, and extended absorption.

How does US 8,889,185 compare to typical tacrolimus ER claim families?

Tacrolimus ER patent estates in the U.S. commonly split into:

• Method-of-use patents (transplant rejection suppression via dosing regimen and/or PK performance)
• Composition/formulation patents (solid dispersion/solid solution, modifying release agents, tablets)
• Manufacturing/process patents (granulation, compression, coating, release-control steps)
• PK targets and performance patents (bioavailability metrics, food effect reductions, absorption location)

US 8,889,185 is firmly within the method-of-use with performance parameters lane. That typically means fewer direct design escape options: a potential competitor must test whether its product hits the same W50/AUCfed/AUCfasted/concentration-duration targets.

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Which later-stage generics face the biggest risk from US 8,889,185?

PK matching drives risk. The highest infringement risk exists for products that are engineered to replicate Envarsus XR-like absorption behavior:

• Once-daily tacrolimus ER
• Lower GI release profile
• Reduced food effect (AUCfed/AUCfasted near 1)
• Extended “half-max duration” (W50 ≥ 10+ hours)
• Sustained therapeutic concentration range

Generic entry risks increase if the applicant uses bridging studies tied to the same endpoints. Because the claims explicitly recite measurable PK endpoints, an applicant’s bioequivalence package becomes central evidence in any enforcement dispute.

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What litigation and Paragraph IV landscape would US 8,889,185 likely impact?

US 8,889,185’s claim set is structured to be asserted against products that seek approval as tacrolimus ER generics using ANDA and demonstrate bioequivalence. The patent’s enforceability posture in U.S. litigation would typically depend on:

• Whether the accused product is demonstrated to meet the lower-GI release and W50/concentration-duration thresholds
• Whether “substantially avoid CYP3A4 metabolism in GI tract” can be mapped to the accused formulation’s mechanism (Claim 9)

Because the patent is method-of-use, defendants often argue:

• Noninfringement based on PK profile differences (W50 too low, AUC ratio below threshold, concentration band not sustained)
• Indefiniteness or claim construction disputes around “substantially” and “about”
• Nonconformance of the accused product’s release location profile

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How strong is the patent estate for US 8,889,185 based on claim architecture?

Strength indicators:

• Independent claim includes three objective constraints: once-daily ER + lower GI release + W50 ≥ 10 hours.
• Dependent claims ladder additional PK thresholds (W50 ≥ 11 to 14 hours), food-effect exposure ratio (AUCfed/AUCfasted), and therapeutic concentration duration (5–20 ng/mL for ≥ 24 hours).
• Dependent claims include mechanistic and formulation constraints (modifying release agent, compressed tablet, CYP3A4 avoidance in GI, zero order release profile, solid dispersion/solution).

Potential vulnerability indicators (for challengers):

• “Substantially” and “about” qualifiers can create room for expert disputes.
• If an accused product is engineered to slightly shift W50 below a threshold or change absorption timing, it may design around.
• The lower-GI release location requirement can be contested if release location mapping differs.

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How much of the claim scope is “design aroundable” versus “PK unavoidable”?

Design aroundable:

• Products can attempt to adjust absorption to shift W50 below 10 hours or below the dependent tiers.
• Products can aim for AUCfed/AUCfasted < 0.9 or shift exposure variability outside the claim threshold.
• Products can adjust formulation to eliminate zero-order release behavior or to reduce alignment with CYP3A4 GI metabolism avoidance.

PK unavoidable when performance replication is required:

• If a generic’s development strategy is to closely mimic Envarsus XR PK and food effect profile, it becomes likely to match W50 and AUC metrics.
• In that scenario, the design-around levers are limited because the claims are not tied to a specific polymer but to measured systemic outcomes.

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What formulations and dosage forms are explicitly protected or narrowed in dependent claims?

Dependent claim hooks that matter in a freedom-to-operate review:

• Modifying release agent (Claim 7)
• Compressed tablet form (Claim 8)
• Lower-GI CYP3A4 metabolism avoidance (Claim 9)
• Zero order release profile (Claims 10, 17–19)
• Solid dispersion or solid solution (Claim 12)

A generic pursuing alternative dosage forms or release behaviors that do not meet these dependent limitations could still infringe independent Claim 1 or Claim 6 or Claim 11 if the core lower-GI release and PK thresholds are met. These dependent claims mainly create additional paths for infringement if the accused product matches those specific properties.

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Key Takeaways

• US 8,889,185 is a PK-performance method-of-use patent for once-daily tacrolimus ER that suppresses transplant rejection by requiring lower-GI release and measurable systemic outcomes.
• The core independent claim is W50 ≥ 10 hours with substantially lower GI in vivo release after oral once-daily tacrolimus ER dosing.
• The claim set adds enforceable “stop points” through dependent thresholds: W50 ≥ 11–14 hours, AUCfed/AUCfasted ≥ ~0.9, and 5–20 ng/mL for ≥ 24 hours.
• Additional dependent claims create further infringement leverage if an accused product uses modifying release agents, is a compressed tablet, avoids GI CYP3A4 metabolism, provides a zero-order release profile, or uses solid dispersion/solid solution tacrolimus.
• The most meaningful infringement risk for generics is tied to whether their bioequivalence PK packages demonstrate matching W50, fed/fast exposure ratio, concentration-duration banding, and release location behavior.

FAQs

1) What does W50 mean in US 8,889,185 and how does it affect infringement?
W50 is the time during which plasma concentration is at least 50% of Cmax; infringement turns on whether the accused tacrolimus ER regimen yields W50 meeting the claimed thresholds (≥10 hours in Claim 1, with higher dependent tiers).

2) Does US 8,889,185 require a specific tacrolimus dose strength?
The claims provided do not recite a specific dose strength; they recite performance and exposure metrics (W50, AUCfed/AUCfasted, and plasma concentration-duration banding).

3) Can a competitor avoid the patent by changing tablet formulation but matching PK?
If the competitor matches the claim-required PK outcomes and lower-GI release behavior, changing formulation likely does not avoid infringement because the independent claims are outcome-defined.

4) How does the “AUCfed/AUCfasted ≥ ~0.9” claim limit scope?
It restricts coverage to formulations whose fed and fasted exposure are sufficiently close, targeting reduction of food-related variability.

5) Are kidney and liver indications separately protected in US 8,889,185?
Yes. Dependent claims specify kidney transplant and liver transplant embodiments, layered on top of the core lower-GI release and PK-performance elements.

References
No sources were provided in the prompt and no additional citation-capable material is included.

Drugs Protected by US Patent 8,889,185

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

Foreign Priority and PCT Information for Patent: 8,889,185

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

International Family Members for US Patent 8,889,185

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	473003
Austria	531368
Australia	2004267909
Australia	2004267910
Brazil	PI0413927